Boletín Latinoamericano y del Caribe de Plantas Medicinales y

Transcription

ISSN 0717 7917
www.blacpma.cl
Boletín Latinoamericano
y del Caribe de Plantas
Medicinales y Aromáticas
Volumen 7, Número 2, 2008
Especial sobre Interacciones de Productos Naturales y
Fármacos
Gómez-Lechón MJ, Castell JV and Donato MT.
Hepatocytes to investigate drug metabolism and hepatotoxicity
in man.
Foti RS and Wahlstrom JL.
The role of dietary supplements in cytochrome P450-mediated
drug interactions.
Patel JA and Gohil KJ.
Warfarin-herb interactions: a review and study based on
assessment of clinical case reports in literature.
Jarukamjorn K.
Andrographis paniculata: a review of aspects of regulatory
mechanisms of hepatic CYP1A enzymes.
Johannessen Landmark C and Patsalos PN.
Interactions between antiepileptic drugs and herbal medicines.
Gelal A.
Influence of menthol on first pass elimination.
Con el auspicio de
Indexada por CHEMICAL ABSTRACTS® (CAS), IMBIOMED®,
INDEX COPERNICUS®, LATINDEX®, REDALYC®, y QUALIS®
Comité Editorial
Fundadores
José L. Martínez (Chile) - Jorge Rodríguez (Cuba)
Editor Jefe
José L. Martínez, Facultad de Medicina Veterinaria y Ciencias
Pecuarias, UNICIT, Santiago, Chile.
Editor Jefe Científico
José M. Prieto, Centre for Pharmacognosy and Phytotherapy, The
School of Pharmacy, University of London, Reino Unido.
Editores Ejecutivo
Gabino Garrido, Centro de Química Farmacéutica, La Habana, Cuba.
Damaris Silveira, Facultade de Ciências da Saúde, Universidade de
Brasília, Brasil.
Editores de Calidad
Carla Delporte, Facultad de Ciencias Químicas y Farmacéuticas,
Universidad de Chile.
Peter Taylor, Centro de Medicina Experimental, Instituto Venezolano de
Investigaciones Científicas, Caracas, Venezuela.
Editores de eventos
María Inés Isla, Facultad de Farmacia y Bioquímica, Universidad
Nacional de Tucumán, Argentina.
Consejo Editorial
Christian Agyare, College of Health Sciences, Faculty of Pharmacy and
Pharmaceutical Sciences, Department of Pharmaceutics, KNUST, Kumasi, Ghana.
Julio Alarcón, Facultad de Ciencias Básicas, Universidad del Bio Bio, Chillán,
Chile.
Rocío Alarcón, Centre for Pharmacognosy and Phytotherapy, The School of
Pharmacy, University of London, Reino Unido.
Jorge Alonso, Asociación de Fitoterapia de Argentina, Buenos Aires, Argentina.
Giovanni Apendino, DISCAFF, Universidad del Piemonte Oriental, Novara, Italia.
Elizabeth Barrera, Sección Botánica, Museo Nacional de Historia Natural,
Santiago, Chile.
Geofrey Cordell, College of Pharmacy, Illinois University at Chicago, Estados
Unidos.
Rene Delgado, Centro de Química Farmacéuticas, La Habana, Cuba.
Eduardo Dellacasa, Facultad de Química, Universidad de La República,
Montevideo, Uruguay.
Luis Doreste, Laboratorio Vitaplant, Mérida, Venezuela.
Alina Freire-Fierro, Botany Department, Academy of Natural Sciences,
Philadelphia, Estados Unidos.
Mildred García, Escuela de Medicina, Universidad de Costa Rica
Martha Gattusso. Área de Biología Vegetal, Universidad Nacional de Rosario,
Argentina.
Harold Gómez, Facultad de Ciencias Químicas y Farmacéuticas, Cartagena de
Indias, Colombia.
Marcelo Wagner, Facultad de Farmacia y Bioquímica, Universidad de
Buenos Aires, Argentina.
Peter Houghton, Pharmaceutical Sciences Research Division, King's College
London, Reino Unido.
Editores Asociados
Ana Ladio, Departamento de Ecología, Universidad Nacional del Comahue, San
Carlos de Bariloche, Argentina.
Patricia Arenas, Facultad de Ciencias Naturales, Universidad Nacional
de La Plata, Argentina.
Patricia Landazuri, Facultad de Ciencias de la Salud, Universidad del Quindío,
Armenia, Colombia.
Marco Dehesa, Laboratorio RENASE, Quito, Ecuador.
Claudio Laurido, Facultad de Química y Biología, Universidad de Santiago de
Chile.
Jannette Gavillan, Instituto de Investigaciones Interdisciplinarias,
Universidad de Puerto Rico
Vicente Martínez, Escuela de Agricultura, Universidad de San Carlos,
Guatemala.
Abdul Manan Mat-Jais, Department of Biosciences, University of Putra, Putra,
Malasia.
Olga Lock de Ugaz, Departamento de Ciencias, Pontificia Universidad Católica del
Perú.
Leonora Mendoza, Facultad de Química y Biología, Universidad de
Santiago de Chile.
Pedro Melillo de Magalhaes, Centro Pluridisciplinar de Pesquisas Químicas e
Biológicas, UNICAMP, Campinas, Brasil.
Editores Asesores
John A.O. Ojewole, Faculty of Health Sciences, University of KwaZulu-Natal,
Sudafrica.
Arnaldo Bandoni; Facultad de Farmacia y Bioquímica, Universidad de
Buenos Aires, Argentina.
Edgar Pastene, Facultad de Farmacia, Universidad de Concepción, Concepción,
Chile
Norman Farnsworth, College of Pharmacy, University of Illinois at
Chicago, Estados Unidos.
Mahendra Rai, Department of Biotechnology, Amravati University, Maharashtra,
India.
Michael Heinrich, Centre for Pharmacognosy and Phytotherapy, The School of
Pharmacy, University of London, Reino Unido.
Luca Rastrelli, Dipartamento di Scienze Farmaceutiche, Universita de Salerno,
Salerno, Italia.
Francisco Morón, Laboratorio Central, Universidad de Ciencias Medicas
de la Havana, Cuba.
Elsa Rengifo, Instituto de Investigaciones de la Amazonía Peruana, Iquitos, Perú
Patrick Moyna, Facultad de Química, Universidad La República,
Montevideo, Uruguay.
Alicia Rodríguez (Cuba)
Pulok K. Mukherjee, School of Natural Product Studies, Department of
Pharmaceutical Technology, Jadavpur University, Kolkata, India.
Guillermo Schinella, Facultad de Ciencias Médicas, Universidad Nacional de La
Plata, Argentina.
Lionel Germosen Robineau, Facultad de Ciencias Exactas y Naturales,
Universidad de las Antillas y Guyana (UAG), Pointe à Pitre, Guadalupe
Nilka Torres, Centro Regional Universitario de Azuero, Universidad de Panamá.
Presidente de la SLF (2005 - 2008)
Horacio Heinzein, Facultad de Química, Universidad La
República, Montevideo, Uruguay.
José Luís Ríos, Facultad de Farmacia, Universidad de Valencia, España
Aurelio San Martín, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
Yen-Jen Sung, National Yang-Ming University Taipei, Taiwán
René Torres, Facultad de Química y Biología, Universidad de Santiago de Chile.
Carlos Urzúa, Facultad de Química y Biología, Universidad de Santiago de Chile.
Beatriz Varela, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires,
Argentina.
Carlos Vicente, Editor Revista Biodiversidad, Argentina
Elisabeth Williamson, School of Pharmacy, University of Reading, Reino Unido.
Talal Zari, Faculty of Science, King Abdulaziz University, Arabia Saudita.
Bol. Latinoam. Caribe Plant. Med. Aromat. Vol.7 (2) 2008
i
BLACPMA
(1)
OBJETIVOS DEL BOLETÍN
• Estimular a los grupos de trabajo existentes en
Latinoamérica, sean investigadores, productores,
funcionarios o simplemente interesados en las
plantas medicinales y aromáticas, poniendo a su
disposición este Boletín para la difusión y la
divulgación de sus investigaciones y de las
actividades que en general desarrollen en torno a
plantas.
• Ser una herramienta de difusión para la Sociedad
Latinoamericana de Fitoquímica, principalmente,
y de otras sociedades y agrupaciones que se
sientan representadas por este Boletín.
• Constituir un nexo entre los profesionales de
habla hispana, francesa, portuguesa e inglesa de la
región, relacionados con el tema central del
Boletín
El BOLETÍN LATINOAMERICANO Y DEL
CARIBE DE PLANTAS MEDICINALES Y
AROMÁTICAS (BLACPMA), ISSN 0717 7917, es
una publicación científica electrónica bimensual
dirigida a diversos profesionales y técnicos
vinculados al campo de las plantas medicinales y
aromáticas. BLACPMA es una entidad sin ánimo de
lucro. Aunque auspiciada por la Sociedad
Fitoquímica Latinoamericana (SLF), este boletín no
es propiedad de Club o Asociación alguna. Ni
BLACPMA ni la SLF son responsables en ningún
momento de las opiniones vertidas en sus páginas,
que son responsabilidad única de sus respectivos
autores. Todo el material gráfico ha sido creado de
manera genuina o bien remitido por sus autores con
el permiso de éstos. Todas las marcas y logos
referidos en estas páginas son propiedad de sus
respectivos autores o empresas. En Chile, 1 de
Enero de 2008.
(2)
OBJECTIVES OF THE BULLETIN
• To stimulate the existing work groups interested
in the medicinal and aromatic plants in Latin
America, investigators, producers, governmental
agencies or general public interested in the
subject, by publishing a Bulletin dedicated to the
dissemination of their investigations and the
activities that in general they develop around
plants and natural products in general.
• To be a tool of diffusion for the Latin American
Society of Fitoquímica, mainly, and of other
societies and groupings that feel represented by
this Bulletin.
• To constitute a nexus between the professionals of
Hispanic, French, Portuguese and English speech
of the region, related to the central subject of the
Bulletin
The LATIN AMERICAN BULLETIN AND OF the
CARIBBEAN OF MEDICINAL AND AROMATIC
PLANTS (BLACPMA), ISSN 0717 7917, is a bimonthly,
electronic, scientific publication directed to any
professional working in the field of the medicinal and
aromatic plants. BLACPMA is a non profit organization.
Although supported by Latin American Phytochemical
Society (SLF), this bulletin is not property of Club or
Association some. Neither BLACPMA nor the SLF are not
responsible for the opinions published in this bulletin, that
are unique responsibility of their respective authors. All
the graphical material is original or published with the
permission of its original authors. All the marks and logos
referred in these pages are property of their respective
authors or companies. In Chile, 1st January of 2008.
BLACPMA WEB Site: www.blacpma.cl
Envio de trabajos a nuestra editorial
Author’s Submission Package
E-mail Submission
http://www.blacpma.cl/submissions.htm
[email protected]
BLACPMA esta Indexada por:
INDEX COPERNICUS (Impacto 4.80) www.indexcopernicus.com
IMBIOMED
www.imbiomed.com.mx
LATINDEX
www.latindex.unam.mx
REDALYC
redalyc.uaemex.mx
QUALIS
Bol. Latinoam. Caribe Plant. Med. Aromat. Vol. 7 (2) 2008
www.capes.gov.br
ii
Instrucciones para los Autores
INSTRUCCIONES PARA LOS AUTORES
El BOLETÍN LATINOAMERICANO Y DEL CARIBE DE PLANTAS MEDICINALES
(BLACPMA), ISSN 0717 7917, es una publicación científica electrónica bimensual dirigida a
profesionales y técnicos que trabajen tanto en productos naturales de plantas medicinales o
nutracéuticos en general como en plantas medicinales y aromáticas. Serán aceptados aquéllos
trabajos relacionados con alguna de las áreas abarcadas por el Boletín tales como agronomía,
antropología y etnobotánica, aplicaciones industriales, botánica, calidad y normalización, ecología
y biodiversidad, economía y marketing, farmacología, fotoquímica, farmacognosia, aspectos de
regulación y legislación, información y difusión de eventos, cursos, premios, novedades,
monografías, revisión de libros y cualquier otro tipo de material que se considere importante
comunicar.
tipo DE LA CONTRIBUCIÓN
Los autores podrán presentar revisiones sobre un tema en particular así como un trabajo original
de una investigación científica, en la forma de trabajo completo o comunicación corta. Cualquiera
de estas contribuciones deberán estar escritas en español, inglés, portugués o francés, sin límite de
extensión la cual deberá estar razonablemente ajustada al objetivo del trabajo. Sin embargo, los
anuncios, novedades y eventos no deberán exceder una página. En todos los casos, las figuras
están incluídas.
FORMATO DE LA CONTRIBUCIÓN
La contribución deberá realizarse mediante el uso del Documento Único para Autores,
también abreviado ASP (Author’s Submission Package), que se puede descargar de la
pagina Web www.blacpma.cl o en caso necesario se puede pedir a los editores por correo
electrónico a [email protected] .
El estilo de nuestra revista se detalla a continuación:
Los trabajos serán presentados en formato Microsof Word (versión 3.1 o superior usando Times
New Roman número 11).
Los trabajos constarán de Introducción, Material y Métodos, resultados, Discusión, Conclusiones
y Bibliografía. En cualquiera de las modalidades en las que se presente el trabajo, en la primera
página deberá constar el Título del trabajo (en español y en inglés), autores, institución a la que
pertenecen, la dirección y correo electrónico del autor principal. También deberá llevar un
resumen en español y en inglés de no más de 100 palabras, un título corto y un máximo de 6
palabras clave. Los números de las tablas y figuras deben ser arábigos.
Resumen
Deberá llevar no más de 150 palabras e incluir los métodos usados, los resultados relevantes y las
conclusiones.
Texto
Artículos originales: constarán de Introducción, Materiales y Métodos (descripción extensa),
Resultados (referidos a las tablas y figuras), Discusión (extensión libre), y Conclusiones (lo más
corta posible).
Revisiones estarán estructuradas de acuerdo a las necesidades del autor.
Comunicaciones breves o notas: deberán llevar una breve Introducción, Materiales y Métodos
(breve descripción o sólo referencia al protocolo publicado), Resultados y Conclusión.
El nombre completo de la especie en latín y la familia (ej: Inula viscosa (L.) Aiton. – Asteraceae)
deberán ser mencionados in extenso al menos en la sección Materiales. A lo largo del trabajo sólo
se usará el nombre corto en latín (I. viscosa)
Tablas
Las tablas deberán ser escritas usando un procesador Word y nunca seran figuras.
Favor de no usar otras líneas distintas de las negras de 1 pt. El texto deberá estar en Times New
Roman 10 ó 9 puntos. Incluir siempre Título (numerado y citado en el trabajo) y la leyenda de las
abreviaturas, en los casos en que corresponda.
Figuras
Incluir las referencias por separado (no incluir las leyendas en la figura). Necesitamos la imagen
en cualquiera de los siguientes formatos (JPEG, JPG; GIF, BMP o TIFF). Sin embargo evitar
TIFF si es demasiado grande y GIF si la imagen es de baja calidad.
No hay restricciones en el número y color de las figuras, pero la inclusión de cualquier figura debe
estar justificada.
No es posible publicar una imagen que haya sido copiada de otra publicación..Sólo es posible
publicar copias de imágenes libres de derecho de autor, de lo contrario deberán ser rediseñadas
con un programa adecuado. Puede hallar versiones libres en Internet.
Le sugerimos:
MarvinSketch (para Windows y otros sistemas) (descargar gratis luego de registrarse
http://www.chemaxon.com/product/msketch.html )
EasyChem for MacOS (http://sourceforge.net/project/showfiles.php?group_id=90102 )
Referencias
Las citas en el texto deberán incluir el apellido del autor y el año, separado por coma y colocados
entre paréntesis (ej. Bruneton, 1995); si hay más de un trabajo del mismo autor, se separarán por
comas (ej. Bruneton, 1987, 1995, 2001). Si hay dos autores se citarán separados por “y” o su
equivalente, respetando el idioma original de la fuente. Si hay más de dos autores, sólo se citará el
primero seguido de la expresión et al. En tanto que en bibliografía deberán figurar todos los
autores. Si hay varios trabajos de un mismo autor y año, se citará con una letra en secuencia
adosada al año (ejemplo: Mayer et al. 1987a, 1987b). Si un trabajo no tiene autor se lo citará como
Anónimo, seguido de la fecha de publicación. Si hubiera más de una cita de esta tipo en el mismo
año, se adosará una letra correlativamente (ejemplo: Anónimo, 2002a, Anónimo, 2002b).
La bibliografía incluirá SÓLO las referencias mencionadas en el texto, ordenadas alfabéticamente
por el apellido del primer autor, sin número que lo anteceda y sin sangría.
Apellido/s del autor seguido de las iniciales del nombre sin puntos ni separación entre ellas.
El nombre de la revista se colocará abreviado según normativas ISO de acuerdo con el Botanico
Periodicum Huntianum (disponible solamente en edición impresa) o Pubmed Journals Database
(http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Journal, ISO abbreviation) que ofrece al
posibilidad de confirmar on line el nombre y abreviatura de un enorme número de revistas. Por
último se citará el volumen de la publicación, seguido del número entre paréntesis, dos puntos y el
número de páginas desde x hasta y, sin espacios entre medio.
Las citas de libros deben explicitar las páginas consultadas así como el año de edición.
No se admitirán citas incompletas y el incumplimiento de estas normas será motivo de retraso del
artículo hasta su corrección.
Modelos
Publicaciones periódicas
Grove H, Rovirosa J, San Martin TO, Argandoña V. 1994. Secondary Metabolites of Dictyota
crenulata. Bol. Soc. Chil. Quím. 39(3):173-178.
Libros
Durand AND, Miranda M, Cuellar A.1986. Manual of practical of laboratory of Pharmacognosy.
Ed. I
People and Education, Havana, Cuba, pp. 90, 120-121.
Capítulos de libros editados
Lopes of Almeida JM. 2000. Pharmaceutical formulation of phytotherapeutic products, pp. 113124. In Sharapin N: Foundations of technology of phytotherapeutic products. Ed. CAB and
CYTED, Bogotá, Colombia.
Tesis (aceptable sólo si no hay fuente alternativa)
González of Cid D. 2000. Cianobacteria study with noxious effects (deleterious and toxic) in
aquatic atmospheres of the county of San Luís. Doctoral thesis, National University of San Luís,
Argentina, pp. 234, 245-244.
Comunicaciones a Congresos
Si no hay libro oficial de Abstracts:
Novak TO, Brown of Santayana M, Blackish JM. 2006. Antioxidant activity and fingerprinting
of Spanish Bupleurum species used ace anti-inflammatory remedies. Communication to the
British Pharmaceutical Conference 2006 (Royal Pharmaceutical Society of Great Britain,
Manchester, UK, 4-6 September).
Si hay libro official de Abstracts:
of Spanish Bupleurum species used ace anti-inflammatory remedies. Summaries of the British
Pharmaceutical Conference 2006 (Royal Pharmaceutical Society of Great Britain, Manchester,
UK, 4-6 September) p.23.
Si los resúmenes fueron publicados en una revista, se menciona SÓLO la revista como si fuera un
artículo más.
of Spanish Bupleurum species used ace anti-inflammatory remedies. J. Pharm. Pharmacol.
58(Suppl. 1): 82.
Recursos electrónicos
Nota: si es necesario cortar alguna dirección se recomienda hacerlo después de una barra
inclinada.
ATENCIÓN: hoy existen muchos otros tipos de dominios que no son http. Por ejemplo los hay
https o
ftp. Igualmente existen muchos dominios que no son www, sino www2 u otros. Por tanto preste
atención a la dirección completa y no suma que por defecto van a ser http o www.
Duncan R. 2000. Nano-sized particles ace "nanomedicines".
http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dDocName=con2022821&Revi
sionSelectionMethod=Latest. [Consulted October 6, 2006].
En caso de no haber un autor, o cuando no hay un responsable principal, se toma la institución
responsable como equivalente al autor y en el texto se cita (CNN,200).
CNN. Cuba's health care manages despite seizure.
http://www.cnn.com/TRANSCRIPTS/0108/18/yh.00.html [Consulted 5 October, 2006].
Boletines o revistas on line con ISSN, la fuente debe ser citada como cualquier otra revista.
Prieto JM. 2005. El Bálsamo de Fierabrás. BLACPMA 4(3):48-51.
Importante NOTA sobre la citación de páginas Web
En éstos días se está comprobando el creciente ABUSO de la citación de páginas Web para avalar
afirmaciones científicas hechas por los autores . resulta muy peligroso para su credibilidad como
autor, y APRA la credibilidad de este Boletín, citar información obtenida en páginas Web que no
tengan ninguna entidad científicamente reconocida que se haga responsable de la susodicha
información. Las páginas Web “anónimas” sólo deben ser usadas en casos muy justificados y ante
la absoluta ausencia de ninguna otra fuente primaria científicamente reconocida. El Comité
editorial de esta revista realizará todo esfuerzo para eliminar el recurso fácil a páginas Web
seudocientíficas y desde luego los autores deben dar en todo caso una explicación de por qué han
recurrido a éste tipo de fuente. Todo abuso será motivo de rechazo para su publicación, incluso si
este ya fue (erróneamente) aceptado por los revisores.
Si se trata de boletines o revistas on-line con ISSN, la fuente debe ser citada como cualquier
otra
revista.
Envío de los trabajos y procedimiento de edición
Se podrán enviar tanto por correo electrónico a la dirección [email protected] o por
correo aéreo en disco de 3.5 pulgadas a Lic. José Luis Martínez, Editor, Casilla de Correo 70036,
Santiago 7, Chile. Los trabajos se acompañarán de una lista conteniendo el correo electrónico y la
dirección de TODOS los autores. El autor principal será el responsable de manifestar su
conformidad en nombre de todos los autores, en relación a la publicación en BLACPMA así como
de cualquier problema que se origine por la autoridad y/o originalidad del trabajo. Esto quedará
claramente establecido en una nota formal que acompañará el trabajo enviado. Una vez recibido,
el trabajo será arbitrado por un par de revisores, que podrán ser miembros de nuestro comité
editorial, académicos o profesionales reconocidos, quienes decidirán su aprobación o rechazo. De
todas maneras, el editor tiene la facultad para decidir si el trabajo cumple con el enfoque del
boletín y tiene la libertad de modificar el manuscrito definitivo (ver el apartado siguiente).
Autoridad final del Comité Editorial.
Los editores se reservan el derecho de corregir o modificar el manuscrito aceptado para su
publicación en BLACPMA, previa consulta con el autor para que se adecue mejor al estilo y
objetivos del boletín. Este procedimiento tendrá lugar en aquellos casos en que los manuscritos no
concuerdan con los modelos científicos generalmente aceptados o si el contenido es
innecesariamente largo, redundante o no suficientemente claro. Estas modificaciones pueden ser
requeridas directamente a los autores y podrán retrasar la publicación del manuscrito.
Gracias por su importante contribución y por tener en cuenta estas normas.
Comité Editorial BLACPMA
iii
Author's guidelines
The LATIN AMERICAN AND CARIBBEAN BULLETIN OF MEDICINAL AND
AROMATIC PLANTS (BLACPMA), ISSN 0717 7917, it is a bimonthly electronic scientific
publication directed to any professional or technician working both on natural products of
medicinal or nutraceutical interest in general or with interest on medicinal and aromatic plants .
Works related with any of the areas covered by the Bulletin will be accepted such as: agronomy,
anthropology and ethnobotany, industrial applications, botany, quality and normalization, ecology
and biodiversity, economy and marketing, pharmacology, phytochemistry, pharmacognosy,
legislation and regulatory affaires, information and diffusion of events, courses, prizes, news,
reports, book reviews, or any other material type which may be important to communicate.
Type of contributions
Authors will be able to present reviews on a particular subject as well as original scientific
research, in the form of both full papers and short communications. Essays on hot topics for
debate are also welcome. Any of these contributions may be written in Spanish, English,
Portuguese or French , without limits on their extension which must be reasonably adjusted to the
objective of the work. However Announcements, news and events reports should not exceed one
page. In all the cases figures are included.
Format of the contributions
Authors must submit their contributions using the ASP (Author’s Submission Package)
downloadable from www.blacpma.cl . Otherwise they will not be considered. If you
experience any problem in obtaining this document please ask our editorial office for a copy
([email protected]). What follows are the style accepted for publication in
BLACPMA: The works will be presented in Microsoft Word format (version 3.1 or superior,
using Times New Roman size 11 points). The works will be conformed by Introduction, Material
and Methods, Results, Discussion, Conclusions and Bibliography. In anyone of the modalities in
which the works be presented, in the first page it should appear: Title of the work (in Spanish and
English), authors, the institution they belong to, the main author's address and e-mail. It should
also appear a summary in Spanish and English with not more than 100 words, a short title and a
maximum of 6 key words. The numbers of the tables and the figures should be Arabic.
Abstract
It must be not more than 200 words and contain the name of the methods used, all relevant results
and conclusions,
Text
Original articles: divided it in Introduction, Materials and Methods (extended description),
Results (refer to tables and figures), Discussion (free extension), and Conclusions (must be as
short as possible).
Reviews are structured according the author’s needs.
Short Communications or letters must have a brief intro, Materials and Methods (brief
description or only reference to the protocol already published), Results and Conclusion.
Species’s complete Latin name and family ( like Inula viscosa (L.) Aiton. – Asteraceae- ) is
required to be mentioned in extenso at least in Materials section. Throughout the paper only use
the short latin name (I. viscose).
Tables
Tables must be written using a word processor.
Images of tables ARE NOT ACCEPTED
Please do not use other lines than black 1 pt. Text must be Times New Roman 10 or 9 points.
Always Provide Title (numbered and cited in the paper). Provide abbreviation’s legend when
necessary.
Figures
Provide the caption in a separate (do not include legends or captions in the figure)
We need the images in any of the following formats (JPEG, JPG, GIF, BMP or TIFF). However,
avoid TIFF as they are too big and GIF as they are low-quality.
There are not restrictions on the number and colours of figures, but the inclusion of any figure
must be justified.
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• MarvinSketch (for windows and other systems) (free download after registration
http://www.chemaxon.com/product/msketch.html )
• EasyChem for MacOS (http://sourceforge.net/project/showfiles.php?group_id=90102 )
References
The citations in the text will include the author's last name and year, separated by coma and placed
between parenthesis (example: Bruneton, 1995); if there is more than one work by the same
author, they must be separated by comas (example: Bruneton, 1987, 1995, 2001). If there are two
authors they must do a separated citation by "and" or its equivalent one, respecting the original
source language. If there are more than two authors, it will be cited only the first one followed by
the expression et al. highlighted in italic letter (example: Dixon et al., 1999), as long as in the
bibliography all the authors will figure. If there are several works of the same author and year, it
will make an appointment with a letter in sequence joined to the year (example: Mayer et al.
1987a, 1987b). If a work doesn't have author, it should be done a citation as Anonymous, followed
by the publication date. If there were more than an anonymous citation in the same year, it will be
correlatively joined to a letter (example Anonymous, 2002a, Anonymous, 2002b). The
bibliography must include ONLY the references mentioned in the text, in alphabetical order for
the first author's last name, without preceding by number or sangria. The author's last name
followed by the first name initials without points neither separation among them.
The journal’s name will be placed abbreviated according to ISO normative and in italic letter in
agreement with the Botanical Periodicum Huntianum, (available only in printed edition) or with
the more convenient Pubmed Journals Database
(http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Journal, ISO abbreviation) that offers the
possibility of checking online the name and abbreviation (in both senses) of an enormous number
of magazines. At last it should be cited the volume of the publication, better if followed by the
number between parenthesis, two points and the page number from x until y, without spaces
between them.
The citations of books must explain which pages were consulted and the year of edition (you must
pay attention to not mistaking the year of the first edition with of the edition you are consulting).
Incomplete citations won't be admitted and any other defect will be late reason of the article until
its correction agreement to these norms.
Models
Periodic publications
Grove H, Rovirosa J, San Martin TO, Argandoña V. 1994. Secondary Metabolites of Dictyota
crenulata. Bol. Soc. Chil. Quím. 39(3):173-178.
Books
Durand AND, Miranda M, Cuellar A.1986. Manual of practical of laboratory of Pharmacognosy.
Ed. I
People and Education, Havana, Cuba, pp. 90, 120-121.
Chapters of published books
Lopes of Almeida JM. 2000. Pharmaceutical formulation of phytotherapeutic products, pp. 113124. In Sharapin N: Foundations of technology of phytotherapeutic products. Ed. CAB and
CYTED, Bogotá, Colombia.
Thesis (acceptable only if there is not alternative source) González of Cid D. 2000. Cianobacteria
study with noxious effects (deleterious and toxic) in aquatic atmospheres of the county of San
Luís. Doctoral thesis, National University of San Luís, Argentina, pp. 234, 245-244.
Communications to Congresses
If there is not official book of abstracts:
Novak TO, Brown of Santayana M, Blackish JM. 2006. Antioxidant activity and fingerprinting of
Spanish Bupleurum species used ace anti-inflammatory remedies. Communication to the British
UK, 4-6 September).
If there is an official book of abstracts:
Spanish Bupleurum species used ace anti-inflammatory remedies. Summaries of the British
UK, 4-6 September) p.23.
If the summaries were also published in a magazine, it will only be mentioned the magazine, just
as another article.
Spanish Bupleurum species used ace anti-inflammatory remedies. J. Pharm. Pharmacol. 58(Suppl.
1): 82.
Electronic resources
Note: If it is necessary to separate some address it is recommended to make it after an inclined
bar. ATTENTION: today there are many other types of domains which are not http. For example
there are https or ftp. It also exist many domains that are not www, but www2 or others.
Therefore pay attention to the complete address and don't assume that for default they will be
http or www.
Duncan R. 2000. Nano-sized particles ace "nanomedicines".
http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dDocName=con2022821&Revi
sionSelectionMethod=Latest. [Consulted October 6, 2006].
In the event of not having an author, or when there is not a responsible one main, it takes the
responsible institution as equivalent to the author, and in the text it makes an appointment (CNN,
2000).
CNN. Cuba's health care manages despite seizure.
http://www.cnn.com/TRANSCRIPTS/0108/18/yh.00.html [Consulted 5 October, 2006].
Bulletins or on-line magazines with ISSN, the source should be mentioned as any other magazine.
Prieto JM. 2005. El Balsamo de Fierabrás. BLACPMA 4(3):48-51.
Important NOTE on the citation of Web pages
In these days it is being checked the growing ABUSE of citation of Web pages to endorse
scientific
statements made by the authors. It is very dangerous for their credibility like author, and for the
credibility of this Bulletin, to mention information obtained in Web pages, which don't have any
scientifically recognized entity that becomes responsible for this information. The "anonymous"
Web pages should be used in very justified cases only and in the absolute absence of any other
scientifically recognized primary source. The Editorial Committee of this magazine will make all
necessary effort to eliminate easy use of pseudo-scientists Web pages and certainly the authors in
any event should give an explanation why they have appealed to this type of sources. All abuse
will be reason of rejection for publication, even if this was already (erroneously) accepted by the
reviewers. If it is bulletins or on-line magazines with ISSN, the source should be mentioned as any
other magazine
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the information asked in its first and last page, please e-mail it to the address
[email protected] or by air mail in a diskette of 3.5 inches to: Lic. José Luis
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Note that we need a list of ALL authors' e-mail and addresses. The main author will be responsible
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next chapter).
Final authority of The Editorial
The editors reserve the right of correcting or altering the manuscripts accepted for publication in
BLACPMA, always previous consultation with the authors, to best suit the journal’s style and
aims. This procedure will be executed in those cases where the manuscripts don't agree to
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Thank you for your important contributions and for the observance of these rules.
The Editorial Committee of BLACPMA
iv
NOTA EDITORIAL
BLACPMA SERA INDEXADO POR CHEMICAL ABSTRACTS
y CAB ABSTRACTS
Casi a cierre de este número llegan dos importantes correos: BLACPMA sera indexado por CAS y CAB
Abstracts.
Chemical Abstracts ha evaluado BLACPMA y ha aceptado, sin ningún otro requerimiento, indexarlo en su
mundialmente prestigioso índice. Se proponen incluir todo articulo que trate de la temática de CAS, es decir
química en general, a empezar por el V7N1 de este 2008.
En paralelo, la prestigiosa organización sin animo de lucro CABI internacional, sin duda conocida por todos
aquellos que trabajan en el mundo de las Plantas y la Agricultura ha confirmado de manera informal que
BLACPMA será igualmente indexado por su sistema CAB Abstracts, que ya recoge 5 millones de entradas
sobre las ciencias de la vida. BLACPMA se encuentra también en conversaciones con BIOSIS y SCIELO,
cuyos veredictos tardaran un poco mas, ya que han sido contactadas recientemente. Aparte estamos
proponiendola en muchos otros índices Open Access como Directory of Open Access Journals (DOAJ,
http://www.doaj.org ).
Con esto BLACPMA es reconocida como Revista Científica de Nivel Mundial de facto. La alegría de todos los
que hemos dedicado mucho tiempo y energías a este proyecto es indescriptible. Es el justo resultado de una
perseverancia en rodearnos de la gente adecuada, de exigir el nivel adecuado y de trabajar en equipo sin pedir
nada a cambio. Y por supuesto de todos los lectores y autores que nos apoyan. El siguiente paso será asegurar un
futuro sostenible para esta revista, para convertirla en una revista con índice de impacto. No perdemos ese
Norte, como tampoco el de ofrecer una revista de carácter científico e independiente donde los latinoamericanos
se puedan expresar en su lengua materna y que los escuchen en el mundo entero.
Un brindis por aquella idea de servicio que nació de la amistad de un chileno y un cubano, y que se hizo realidad
un no tan lejano día de 2002.
José Luis Martínez
Editor Jefe BLACPMA
Jose M. Prieto
Editor Jefe Cientifico BLACPMA
Damaris Silveira
Editor Ejecutivo BLACPMA
Bol. Latinoam. Caribe Plant. Med. Aromaticas Vol. 7 (2) 2008
v
Tercera Reunion de Comité Editorial BLACPMA
(Primera Circular)
El Boletín Latinoamericano y del Caribe de Plantas Medicinales y Aromáticas (BLACPMA) se complace en
anunciarles la Tercera Reunión Anual a realizarse del 7 al 9 de Enero de 2009 en la ciudad de Chillán (Chile)
adherido al Primer Congreso Internacional de Farmacobotánica que organiza la Universidad de Concepción en
esa ciudad.
Haciendo un poco de historia, la primera reunión de BLACPMA fue realizada en 2006 en Varadero (Cuba)
junto a FAPRONATURA; posteriormente en 2007 la segunda reunión se realizó en La Plata (Argentina) junto a
la reunión anual de SILAE.
El evento de la Universidad de Concepción esta organizado en 7 áreas:
1.
2.
3.
4.
5.
6.
7.
Agronomía
Fitoquímica
Farmacognosia
Farmacología y Actividad Biológica
Biotecnología
Botánica y etnobotánica
Ciencias Sociales y Antropología
Al igual que en los eventos anteriores BLACPMA entregará una distinción al mejor investigador joven de entre
los participantes.
El Directorio de la reunión de BLACPMA esta formado por:
•
•
•
•
•
Leonora Mendoza (Chile) como Presidente
Damaris Silveira (Brasil) como Vicepresidente
José María Prieto (Inglaterra) como Secretario
José Luis Martínez (Chile) como Director
Gabino Garrido (Cuba) como Director
El Congreso Internacional de Farmacobotánica tiene como sus principales autoridades:
• Angélica Urbina, como Presidente
• Fidelina González, como Secretaria
• Nelson Zapata, como Presidente de la Comisión Científica
Por parte de BLACPMA se espera la asistencia de Peter Taylor (Venezuela), Damaris Silveira (Brasil), Vicente
Martínez (Guatemala), Marcelo Wagner (Argentina), Gabino Garrido (Cuba), José María Prieto (Inglaterra),
Geoffrey Cordell (USA); además de todos los chilenos miembros del comité editorial de BLACPMA.
Esperamos también que otros muchos amigos lectores de este su boletín se animen a venir y celebrar tan
destacado evento.
José Luis Martínez
Editor Jefe BLACPMA
47
Editorial
Estimado lector,
En la batalla por introducir a BLACPMA dentro de
las revistas más leídas en el campo de los productos
naturales y, de esta forma, convertirla en un foro de
comunicación, actualización y discusión de todos los
profesionales implicados en la investigación,
desarrollo y producción de este tipo de productos, es
que emitimos el primer número relacionado con las
interacciones de los medicamentos y los productos
naturales.
La base de estas interacciones es de origen
farmacodinámico y farmacocinético lo que se traduce
en una inhibición o inducción de enzimas clave (p. ej.
las diferentes isoenzimas del citocromo P450). Una
inhibición de alguna de estas enzimas puede aumentar
las concentraciones plasmáticas del fármaco y
conducir a efectos adversos o tóxicos. Por el contrario,
si existe una inducción enzimática, traducida en un
aumento en la cantidad y actividad de la enzima que
metaboliza el fármaco, esta puede incrementar la
eliminación de dicho medicamento y atenuar su efecto
farmacológico como resultado de la disminución de
las concentraciones plasmáticas de éste.
En los últimos años se ha incrementado el
consumo de productos naturales a escala mundial
basado, fundamentalmente, en la creencia de que “si
es natural no tiene efectos adversos” y, además,
porque se ha demostrado su eficacia en algunas
patologías. La composición química de los productos
naturales los convierten en agentes potencialmente
activos sobre el cuerpo humano. Por consiguiente, la
administración de fármacos y productos naturales
puede inducir variaciones en la magnitud del efecto de
los medicamentos.
En la actualidad, muchas instituciones llevan a
cabo estudios de interacción fármaco-fármaco o
fármacos-productos naturales para predecir el
potencial de interacción de ellos. De esta forma se
persiguen como objetivos primordiales convertir los
tratamientos de los enfermos en seguros y efectivos y
también minimizar las pérdidas de las compañías que
investigan nuevas entidades moleculares.
En este número, y aprovechando la celebración del
1er. Simposio Internacional sobre Farmacología del
Citocromo P450 que se celebrará en la playa de
Varadero, Cuba, del 19 al 22 de abril de 2008 en el
marco de ImmunoPharmacology 2008, es que
emitimos el primero de dos números sobre esta
temática. En la presente emisión usted podrá encontrar
artículos de revisión que tratan sobre las
investigaciones más actuales que se llevan a cabo para
elucidar la interacción de medicamentos y productos
naturales, específicamente productos herbales.
Agradecimientos especiales a los autores
correspondientes de cada uno de los artículos, los que
mostraron en todo momento una disposición
incondicional para que la obra llegara a este final. Mi
gratitud para los colegas María José Gómez-Lechón
(Gómez-Lechón et al., 2008), Robert S. Foti (Foti y
Wahlstrom, 2008), Jagruti A. Patel (Patel y Gohil,
2008), Kanokwan Jarukamjorn (Jarukamjorn, 2008),
Philip N. Patsalos (Johannessen Landmark y Patsalos,
2008) y Ayse Gelal (Gelal, 2008).
Tenemos la esperanza que usted encontrará en
estas páginas el material valioso que necesita, si así
resulta habrá valido la pena todo el esfuerzo realizado.
Saludos cordiales,
Dr. Gabino Garrido Garrido
Coordinador del Especial sobre Interacciones
de Productos Naturales y Fármacos
Editor Ejecutivo de BLACPMA
REFERENCIAS
Gómez-Lechón MJ, Castell JV and Donato MT. 2008.
Hepatocytes to investigate drug metabolism and
hepatotoxicity in man. BLACPMA 7(2):49-65.
Foti RS and Wahlstrom JL. 2008. The role of dietary
supplements in cytochrome P450-mediated drug
interactions. BLACPMA 7(2):66-84.
Patel JA and Gohil KJ. 2008. Warfarin-herb interactions: a
review and study based on assessment of clinical case
reports in literature. BLACPMA 7(2):85-99.
Jarukamjorn K. 2008. Andrographis paniculata: a review of
aspects of regulatory mechanisms of hepatic CYP1A
enzymes. BLACPMA 7(2):100-107.
Johannessen Landmark C and Patsalos PN. 2008.
Interactions between antiepileptic drugs and herbal
medicines. BLACPMA 7(2):108-118.
Gelal A. 2008. Influence of menthol on first pass
elimination. BLACPMA 7(2):118-124.
48
RETRACCIÓN | RETRACTION
Boletín Latinoamericano y del Caribe de Plantas Medicinales y Aromáticas, 7 (2), 49 – 65.
This notification will serve as retraction of
“Hepatocytes to investigate drug metabolism and
hepatotoxicity in man. ” by Gomez-Lechon et al., which
appeared in the March 2008 issue of the Boletín
Latinoamericano y del Caribe de Plantas Medicinales y
Aromáticas, 7 (2), 49 – 65.
Esta notificación sirve como retracción del articulo
“Hepatocytes to investigate drug metabolism and
hepatotoxicity in man. ” de Gomez-Lechón et al., que
aparecio publicado en el numero de Marzo de 2008 del
Boletín Latinoamericano y del Caribe de Plantas
Medicinales y Aromáticas, 7 (2), 49 – 65.
It has come to our attention that data from this
manuscript was published previously in ChemicoBiological Interactions (“Hepatocytes—the choice to
investigate drug metabolism and toxicity in man: In
vitro variability as a reflection of in vivo” by GomezLechon et al., Chemico-Biological Interactions 168
(2007) 30–50), and thus we announce an official
retraction. Anyone citing this article must cite from the
Chemico-Biological Interactions and not from
BLACPMA.
Ha llegado hasta nuestra redacción la notificación de
que este manuscrito fue esencialmente publicado en
Chemico-Biological Interactions (“Hepatocytes—the
choice to investigate drug metabolism and toxicity in
man: In vitro variability as a reflection of in vivo” by
Gomez-Lechón et al., Chemico-Biological Interactions
168 (2007) 30–50), y por tanto anunciamos una
retraccion oficial del mismo. Cualquiera que cite este
articulo debe citar el publicado por Chemico-Biological
Interactions y no el publicado por BLACPMA..
We regret any inconvenience that this retraction
might cause to our readers.
Lamentamos cualquier inconveniente causado a
nuestros lectores por esta retraccion.
The Editorial Board
BLACPMA
El Comite Editorial
BLACPMA
Bol.
Latinoam.
Caribe
Plant.
Med.
Aromaticas
Vol.
7
(2)
2008
1
© 2008 Los Autores
Derechos de Publicación © 2008 Boletín Latinoamericano y del Caribe de Plantas Medicinales y Aromáticas, 7 (2), 66 - 84
BLACPMA ISSN 0717 7917
Especial sobre Interacción de Productos Naturales y Fármacos / Special Issue on Natural Products and Drug Interactions
The role of dietary supplements in cytochrome P450-mediated drug
interactions
[El papel de los suplementos dietarios en las interacciones de fármacos mediadas por el citocromo P450]
Robert S. FOTI* and Jan L.WAHLSTROM
Pharmacokinetics and Drug Metabolism, Amgen, Inc. 1201 Amgen Court W. Seattle, WA 98119, USA
*Contact: E-mail: [email protected]
Submitted January 24, 2008; Accepted January 26, 2008
Abstract
Due in part to the increased consumption of herbal products on a global scale, a sharp rise in the reported number of both in vitro and in vivo
interactions of herbals with prescription drugs that are metabolized by cytochrome P450 (CYP) enzymes has been observed. Popular
products such as ginseng, saw palmetto and St. John’s wort have demonstrated potent in vitro inhibition or induction of CYP activity. While
reports of in vivo interactions are not as numerous, natural products such as garlic, goldenseal and grapefruit juice have shown the potential to
affect CYP activity in vivo. As the wide-spread use of herbal and alternative medicines continues, an increased awareness on the part of the
research and medical communities should afford safer use of these products in the future.
Keywords: Herbal remedies, Alternative and comparative medicines, Cytochrome P450, Herb-drug interactions, Drug-drug interactions.
Resumen
Debido, en parte, al consumo elevado de productos herbales a escala global se ha observado un incremento en el número de publicaciones
relacionadas con las interacciones tanto in vitro como in vivo de hierbas con fármacos prescritos que son metabolizados por enzimas del
citocromo P450 (CYP). Productos populares tales como ginseng, palma serrucho y hierba de San Juan han demostrado una potente actividad
in vitro de inducción o inhibición de CYP. Los estudios sobre interacciones in vivo no son tan numerosos; sin embargo, productos naturales
tales como ajo, sello de oro y jugo de toronja afectan la actividad in vivo de CYP. Como continúa el amplio espectro en el uso de medicinas
herbales y alternativas, es necesario incrementar el conocimiento por parte de los investigadores y las comunidades médicas para garantizar
en el futuro el uso más seguro de estos productos.
Palabras clave: Remedios herbales, Medicinas alternativas y comparativas, Citocromo P450, Interacciones fármaco-hierba, Interacciones fármaco-fármaco.
Abbreviations:
ADR, adverse drug reactions;
DDI, drug-drug interaction;
INTRODUCTION
The use of complimentary and alternative
medicines has become an increasingly common trend
both in the United States and around the world. The
total estimated sales of herbal remedies in the United
States alone rose from approximately $2.02 billion in
1994 to over $4.4 billion in 2005 (Ferrier et al.,
2006). These sales figures include both herbal
monotherapies and the increasingly popular
combination therapies. Along with the increase in
CYP, cytochrome P450;
MI, metabolic-intermediate complex.
sales, a concurrent increase in the number of reported
adverse safety events relating to herbal supplements
has also been reported. A report from 2005 links over
5000 adverse reactions, 17 000 health care visits and
12 000 medical outcomes to the use of dietary
supplements (Hurley, 2007).
Not surprisingly, the scientific community has
also displayed an increased awareness of both the use
of alternative medicines as well as there possible role
in adverse reactions and drug interactions. A search
CYP-Mediated Herb-Drug Interactions
Foti and Wahlstrom
of the literature from 1980 through 2007 (SciFinder®)
reveals a sharp rise in the number of research articles
relating to both the use of alternative medicines as
well as to the role of herbal therapies in cytochrome
P450-meditated drug interactions (Fig. 1). While
manuscripts pertaining to alternative medicines were
scarce prior to 1980, there were over 600 such
articles published in 2007. In a similar fashion, the
number of articles dealing with herbal remedies and
drug interactions has increased to approximately 3040 per year since 2002.
The cytochromes P450 (CYP) are a superfamily
of heme-containing enzymes that are involved in the
metabolism of the majority of drugs on the market
today. The major CYP enzymes that play a role in
drug metabolism include CYP1A2, CYP2C9,
CYP2C19, CYP2D6 and CYP3A4/5 (Nelson, 2008).
Other isoforms, such as CYP2A6, CYP2B6, CYP2C8
and CYP2E1 have also been shown to have important
roles in drug metabolism. With adverse drug
reactions (ADRs) totaling over 2 million per year in
the United States alone (Gurwitz et al., 2000), the
ability to predict drug interactions involving the CYP
enzymes has become a key component of the drug
discovery process.
CYP inhibition can occur in a number of ways,
which ultimately can be divided into reversible or
irreversible inhibition of the enzyme. Screening for
reversible inhibition whereby a perpetrator molecule
affects the catalytic capacity of the enzyme towards a
second molecule has become commonplace in
pharmaceutical research (Rodrigues and Lin, 2001).
While the same rigor is not required for herbal-based
remedies, a number of very thorough reviews have
examined the potential for these substances to
interact with CYP enzymes (Ioannides, 2002; Brazier
and Levine, 2003; Zhou et al., 2003; Delgoda and
Westlake, 2004; Zhou et al., 2004a; Zhou et al.,
2004b; Izzo, 2005). The potential for herbal remedies
to induce CYP levels has also been examined (Raucy,
2003; Tirona and Bailey, 2006). While this review
will deal primarily with inhibition of CYP activity,
herbals such as St. John’s wort (CYP1A2, CYP2C9,
CYP2C19, CYP2E1 and CYP3A4), Echinacea
(CYP3A4) ginkgo (CYP2C19) and ginseng
(CYP2C9) have been shown to be CYP inducers as
well (Tirona and Bailey, 2006).
Figure 1. The number of publications by year (1980–2007) pertaining to alternative medicine (vertical bars; left y-axis)
or CYP-mediated herb-drug interactions (HDI, solid line; right y-axis).
FIGURE 1
Alternative Medicine
CYP-Mediated HDI
700
# of Pu bications o n "Alternative Medicine"
50
600
40
500
30
400
300
20
200
10
100
2007
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
1987
1986
1985
1984
1983
1982
1981
0
1980
0
# of Publicati ons on CYP-Med iated Herb-Drug In teractions
60
800
67
Metabolic bioactivation of a compound may also
lead to CYP-mediated drug interactions (DDIs). The
general terminology for loss of CYP activity over
time due to compound turnover is time-dependent
inhibition. The time-dependence may be due to
formation of an inhibitory metabolite, formation of a
covalent linkage to the apoprotein, or formation of a
linkage to or destruction of the prosthetic heme. If a
number of additional criteria are met, such as a 1:1
stoichiometric ratio of inactivator to enzyme and a
lack of enzyme activity restoration after dialysis, the
compound may be referred to a mechanism based
inactivator. The in vitro potency of a time dependent
inhibitor is defined by two terms, KI and kinact. The KI
parameter indicates the inhibitor concentration
necessary to produce a half-maximal rate of
inactivation, while the kinact parameter reflects the
maximal inactivation rate. Intermediates formed by
CYP-mediated metabolism may also escape the CYP
active site and react with other cellular constituents
such as proteins or DNA (Uetrecht, 2003), although
the potential resultant toxicity may be unrelated to
DDIs. A number of natural products with varying
structural motifs known to be time-dependent CYP
inhibitors in vitro are shown in Fig. 2.
It is important to note that while numerous
examples of herbal remedies that inhibit CYP activity
in vitro have been reported, many of these drug
interactions do not translate into the clinic. A number
of experimental explanations for this disconnect have
been proposed, including extraction techniques and
solvents used in vitro and the poor absorbance/bioavailability properties of the marketed
products in vivo (Gurley, 2005). In fact, one of the
biggest criticisms given to in vitro screening of
herbal-drug interactions is the lack of clinical
evidence to support the in vitro findings. Fortunately,
as alternative therapies become more popular, the
number of clinical drug interaction studies with these
remedies has also increased.
The focus of this review will be to examine the
potential of commonly used herbal remedies to
interact with CYP-mediated drug metabolism. With
research constantly ongoing, the number of CYPmediated herb-drug interactions is also constantly
increasing. A comprehensive list of herbal remedies
known to be CYP inhibitors in vitro is shown in
Table 1. As our knowledge of herb-drug interactions
increases, the ability to monitor and predict negative
outcomes when alternative therapies are coprescribed with conventional medicines should also
increase.
Foti and Wahlstrom
Herbal Remedies that Interact with Cytochrome
P450-Mediated Drug Metabolism
Angelica dahurica
The Angelica dahurica root, more commonly
known as Bai Zhi, has been used in traditional
Chinese medicine for thousands of years. Uses of the
root are numerous, though it has been shown to have
analgesic, antibacterial, diuretic and stimulating
properties. (Duke and Ayensu, 1985; Yeung, 1985).
The root has also been shown to be effective in
treating certain types of staphylococcus infections
(Lechner et al., 2004) and is contraindicated in
pregnant women (Chevallier, 1996).
More recently, the Angelica dahurica root has
been implicated as a potential inhibitor of CYP3A4 in
vitro. It has been suggested that the inhibitory
potential of the root is contained in the numerous
furanocoumarin derivatives, which have been isolated
from this root (Hata et al., 1963; Hata et al., 1981;
Bergendorff et al., 1997; Kimura and Okuda, 1997;
Kwon et al., 1997; Guo et al., 2001). Furthermore,
inhibition of 6β-hydroxytestosterone formation in
liver microsomes was observed when extracts of the
root were included in the incubation (Guo et al.,
2001).
Black Cohosh
Black cohosh (Cimicifuga racemosa) is a
perennial plant that is indigenous to North America.
The extract from this plant has been used in the
treatment of multiple menopause-related disorders,
including sleep disturbances, depression and hot
flashes (Liske et al., 2002). Though the pharmacological properties of black cohosh have been
attributed to its estrogen-like properties, this claim
has been widely debated (Mahady et al., 2002; Beck
et al., 2003; Dugoua et al., 2006). In addition, the use
of black cohosh during pregnancy has been contraindicated due its potential labor-inducing effects
(Dugoua et al., 2006).
In vitro, black cohosh extracts have been shown to
be relatively weak inhibitors of CYP activity. The
inhibitory activity has been attributed to six triterpene
glycosides that were isolated from black cohosh, with
CYP3A4 (nifedipine oxidation) IC50 values ranging
from 0.10 to 7.78 mM (Tsukamoto et al., 2005a).
Interestingly, the authors report an IC50 value for the
whole extract against CYP3A4-catalyzed nifedipine
oxidation to be 0.027 mg/ml, a relatively low value
when the C50 values of the individual components
68
Foti and Wahlstrom
Table 1. Herbal remedies that are inhibitors of cytochrome P450 activity in vitro.
CYP
Herbal Remedies
CYP1A2
Black/green tea, dan shen, devil’s claw, Echinacea, fo-ti, ginkgo, ginseng, grapefruit juice, kava, licorice,
resveratrol, St. John’s wort, wu-chu-yu tang
CYP2B6
Licorice, luteolin
CYP2C8
Devil’s claw, fo-ti, ginkgo, usnic acid
CYP2C9
Cranberry, devil’s claw, Echinacea, eucalyptus oil, evening primrose, fo-ti, garlic, genistein, ginger,
ginkgo, ginseng, goldenseal, grapefruit juice, grapeseed extract, green tea, kava, licorice, luteolin, milk
thistle, saw palmetto, St. John’s wort, soy, tumeric, usnic acid, valerian
CYP2C19
Devil’s claw, Echinacea, eucalyptus oil, evening primrose, fo-ti, garlic, ginko, ginseng, kava, milk thistle,
St. John’s wort, usnic acid, valerian
CYP2D6
Black cohosh, black pepper, C. roseus, devil’s caw, dong quai, Echinacea, eucalyptus oil, evening
primrose, fo-ti, genistein, ginger, ginseng, ginkgo, goldenseal, grapefruit juice, grapeseed extract, green
tea, kava, luteolin, milk thistle, saw palmetto, St. John’s wort, soy, yohimbine
CYP2E1
Echinacea, garlic, ginseng, kava, resveratrol, St. John’s wort, watercress
CYP3A4
A. dahurica, β-carotene, black cohosh, black pepper, black mulberry, black raspberry, C. aurantium, cat’s
claw, chamomile, cranberry, dan shen, devil’s claw, dong quai, Echinacea, eluthero, eucalyptus oil,
evening primrose, feverfew, fo-ti, garlic, genistein, ginkgo, ginseng, goldenseal, grapefruit juice,
grapeseed extract, green tea, kava, licorice, luteolin, milk thistle, oregano, pomegranate, pomelo, red
clover, resveratrol, sage, saw palmetto, schisandra fruit, St. John’s wort, soy, tumeric, valerian, wild
grape
are taken into consideration.
The drug interaction potential of black cohosh has
also been evaluated in vivo by Gurley, et al. (Gurley et
al., 2005b; Gurley et al., 2006a; Gurley et al., 2006b).
No effect was observed on CYP3A4 in clinical trials,
while only a minor effect was seen for CYP2D6. As
such, the potential for clinically relevant drug
interactions with black cohosh appears to be low (van
den Bout-van den Beukel et al., 2006).
Black Pepper
The use of black pepper (Piper nigrum) is often
found in traditional anti-diarrheal remedies. The major
component that contributes to the pharmacological
activity of black pepper is the alkaloid piperine (Hu et
al., 2005). In pre-clinical animal models, black pepper
has been shown to slow the gastric emptying of both
liquids and solids in a time- and dose-dependent
fashion (Bajad et al., 2001).
Only limited in vitro data on the drug interaction
potential of black pepper is available. The interaction
of black pepper and CYP3A4-catalyzed verapamil
metabolism (to norverapamil and metabolite D-617) in
human liver microsomes has been investigated
(Bhardwaj et al., 2002). Piperine appeared to be a
linear-mixed type inhibitor of CYP3A4 with a Ki of
approximately 60 µM for norverapamil and 43 µM for
the D-617 metabolite of verapamil. Piperine is also an
inhibitor of CYP3A4 in recombinant preparations
(Tsukamoto et al., 2002). In addition, multiple
alkylamides that were isolated from black pepper
showed considerable time dependent inhibition of
CYP2D6 activity in vitro (Subehan et al., 2006). The
most potent time-dependent alkylamides tested also
had methylenedioxyphenyl moieties, a structural
feature that is known to cause time-dependent
inhibition of CYP activity.
Interestingly, there appears to be more data
available on the potential of black pepper to cause
drug interactions in vivo. The interactions of black
pepper with propranolol, rifampicin (P-gp interaction),
spartein, theophylline and phenytoin have been
assessed in clinical trials. In trials with propranolol, an
increase in the Cmax and AUC of a 40 mg dose of
propranolol was observed following 20 mg of piperine
for 7 days (Bano et al., 1991), possibly indicating that
piperine is inhibiting CYP1A1, CYP1A2 and/or
CYP2D6 in humans as these are the primary enzymes
responsible for the clearance of propranolol (Hu et al.,
2005). Similarly, plasma concentrations of spartein,
another CYP2D6 substrate, were increased following
administration of piperine in human volunteers (Atal
et al., 1981). Most likely due to its inhibition of
69
CYP1A1 and CYP1A2, the AUC and Cmax values
following a 150 mg dose of theophylline also
increased in clinical trials following 20 mg/day of
piperine for 1 week (Bano et al., 1991). Thus it
appears that black pepper may affect CYP1A,
CYP2D6 and possible CYP3A4 in vivo.
β-Carotene
β-carotene is a form of vitamin A that can be found
in carrots, sweet potatoes, various greens as well as in
dietary supplements (Pitchford, 2003). It is converted
to retinal, another form of vitamin A, by β-carotene
dioxygenase in the mucosa of the small intestine. As
an herbal supplement, claims have been made as to its
ability to prevent cognitive decline and age-related
macular degeneration, as well as to treat cases of
melasma (Kar, 2002; Grodstein et al., 2007; Jones and
Smith, 2007). Unfortunately, numerous studies have
also reported a link between β-carotene consumption
and an increased risk of lung cancer (AlphaTocopherol Beta Carotene Cancer Prevention Study
Group, 1994; Omenn et al., 1996a; Omenn et al.,
1996b).
Limited data on the potential of β-carotene to cause
drug interactions is available; however studies have
demonstrated that the retinoid may be able to induce
CYP3A4 in vitro. (Wang et al., 2006). Additionally,
others have shown that β-carotene is able to activate
human PXR and subsequently induce target genes
(such as CYP3A4) that are controlled by PXR (Ruhl
et al., 2004).
Catharanthus roseus
The Catharanthus roseus, also referred to as Vinca
rosea, Ammocallis rosea or Lochnera rosea, is widely
cultivated in tropical and subtropical areas of the
world. Traditionally, the plant has been used to treat
Hodgkin’s disease, diabetes and malaria (Usia et al.,
2005; Yaniv and Bachrach, 2005). Some of the plants
pharmacological properties may stem from the
alkaloids that have been isolated from Catharanthus
roseus, namely vinblastine and vincristine. The
isolated alkaloids are prescribed in chemotherapy
regimens, under the brand names Velbe® and
Oncovin®, respectively.
In vitro, the extract of Catharanthus roseus has
been shown to inhibit CYP2D6 activity with an IC50
value of 11 µg/mL (Usia et al., 2006). Ajmalicine and
serpentine, two additional alkaloids that were
extracted from the plant, inhibited the dealkylation of
14
C-dextromethorphan by CYP2D6 in vitro with IC50
Foti and Wahlstrom
values of 0.0023 and 3.51 µM, respectively. In
addition, serpentine was shown to be a time-dependent
inhibitor of CYP2D6 in vitro, with a KI of 0.148 µM
and a Kinact of 0.090 min-1 (Usia et al., 2005).
Devil’s Claw
The herbal remedy devil’s claw (Harpagophytum
procumbens) has gained increasing popularity as an
analgesic and a treatment for rheumatic diseases
(Gunther and Schmidt, 2005). In a study designed to
evaluate the efficacy of devil’s claw in treating lower
back pain, no significant differences were noted in a
group of 44 patients who received an extract of devil’s
claw when compared to another group of 44 who
received rofecoxib (Chrubasik et al., 2003). The active
ingredients in devil’s claw are believed to be
harpagosides, a glycoside derivative, which are found
in the root system of the plant.
In an in vitro study, extracts from devil’s claw
were found to primarily inhibit CYP2C8, CYP2C9,
CYP2C19 and CYP3A4 (IC50 121 to 335 µg/mL) and
CYP1A2 and CYP2D6 to a much lesser extent (IC50 ~
1 mg/mL) (Unger and Frank, 2004).
Echinacea
Echinacea (Echinacea purpurea) is one of the top
selling herbal remedies in the United States. Its most
common uses are for the treatment of common cold
and influenza symptoms. The immunomodulatory
activity of Echinacea is thought to be due the
alkylamides that have been isolated from the herb
(Woelkart and Bauer, 2007).
Oddly, as popular as Echinacea has become, data
surrounding its potential for drug interactions has not
been as forthcoming. A recent study in baculovirusexpressed CYP enzymes demonstrated that an
Echinacea extract was able to mildly inhibit CYP1A2,
CYP2C19, CYP2D6 and CYP3A4 activity (Modarai
et al., 2007). Other studies have shown inhibition of
CYP2C9 and CYP3A4 activity with no inhibition of
CYP2D6 (Yale and Glurich, 2005; van den Bout-van
den Beukel et al., 2006). Alkylamides from Echinacea
have also been implicated in the inhibition of CYP2E1
at concentrations as low as 25 µM (Raner et al., 2007).
In vivo, the risks of Echinacea induced drug
interactions appear to be minor, though further
investigation is ongoing. When co-administered to
healthy volunteers, the effects of Echinacea extract on
CYP1A2, CYP2D6, CYP2E1 or CYP3A4 tend to be
relatively small (Gorski et al., 2004; Gurley et al.,
2004). In the study by Gorski et al., an induction of
70
Foti and Wahlstrom
administration. CYP2C9, on the other hand, does
appear to be susceptible to inhibition by Echinacea in
vivo, where a significant increase in the AUC of
tolbutamide was observed in the presence of
Echinacea (Gorski et al., 2004).
hepatic CYP3A4 activity (approximately 34%
increase) was observed, while an inhibition of
intestinal CYP3A4 activity was also noted. The two
studies also note a possibility of a reduction in
CYP1A2 activity in vivo due to Echinacea
Figure 2. Structures of natural products known to be time-dependent inhibitors of CYP activity in vitro. Common
structural motifs include furanocoumarin, methylenedioxyphenyl, polyphenol and alkaloid compounds.
A. Furanocoumarins
O
O
O
O
O
O
O
O
Bergamottin (Grapefruit Juice)
8-Methoxypsoralen
B. Methylenedioxyphenyls
O
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
HO
O
Methysticin (Kava)
Hydrastine (Goldenseal)
Gomisin C (Schisandra Fruit)
C. Polyphenols
O
O
OH
OH
O
HO
O
O
HO
O
OH
HO
OH
OH
OH
O
OH
Glabridin (Licorice)
Silybin (Milk Thistle)
Resveratrol
D. Alkaloids
N+
H
O
N
N
H
NO
H
N
O
O
Rutaecarpine (Wu-chu-yu Tang)
Serpentine (C. Roseus)
71
Fo-Ti
Multiple herbal therapies that are sold today claim
to have estrogen-like properties, including soy,
licorice and red clover extracts. Fo-Ti (Polygonum
multiflorum) is a plant native to China that was shown
to contain considerable amounts of estrogen
bioactivity (Oerter Klein et al., 2003), which may
indicate a potential for the herb to treat symptoms
related to menopause. Other therapeutic claims
include increased vitality, decreased cholesterol, and
relief from constipation.
At higher concentrations in vitro, the Fo-Ti root
was shown to be an inhibitor of multiple CYP
isoforms (Unger and Frank, 2004). Relatively weak
inhibition of CYP1A2, CYP2C8, CYP2C9,
CYP2C19, CYP2D6 and CYP3A4 was observed with
IC50 values around 500 µg/mL for all isoforms tested.
Garlic
Numerous reports in the literature support the use
of garlic as a therapeutic agent. It has been suggested
that garlic may contain antilipidemic, antihypertensive, antiglycemic and antithrombotic properties
(Ackermann et al., 2001). It has also been noted that
the therapeutic properties of garlic are highly
dependent on the preparation and extraction processes
used (Greenblatt et al., 2006a).
In vitro, it appears that garlic has the ability to
inhibit a number of CYP isoforms, including
CYP2C9, CYP2C19 and CYP3A (Foster et al., 2001).
Additionally, the diallyl sulfide component found in
most garlic preparations has been shown to be an
inhibitor of CYP2E1 (Taubert et al., 2006).
Conversely, an in vitro study that examined the
inhibition potential of water soluble components of
garlic such as alliin or methylin found no significant
inhibition of CYP activity. S-methyl-L-cysteine and
S-allyl-L-cysteine showed only a modest inhibition of
CYP3A4 in vitro (Greenblatt et al., 2006a). Certain
components of garlic may also have the ability to
increase CYP3A4 activity, though data is somewhat
scarce (Wu et al., 2002; Lee et al., 2006b).
Clinical trials using garlic have been limited,
though a few studies have reported the inhibition of
CYP activity in vivo. For instance, following
consumption of garlic for 28 days, the in vivo activity
of CYP2E1 was decreased by approximately 22%.
Other studies have noted that no significant effects on
CYP2D6 or CYP3A4 activity in vivo are likely
following consumption of garlic supplements
(Markowitz et al., 2003a).
Foti and Wahlstrom
Ginkgo biloba
Ginkgo biloba is often used for its antioxidant and
neuroprotective effects. It is claimed that ginkgo can
increase circulation and reduce memory loss, cerebral
insufficiencies and anxiety or stress levels (De Smet,
2002). Due to its potent anti-platelet properties, the
use of ginkgo with other anti-platelet agents such as
warfarin or aspirin has been the focus of much debate.
Similar pharmacodynamic interactions can also occur
if gingko is taken in combination with other herbal
remedies that have similar anti-platelet properties such
as garlic or ginseng (Sierpina et al., 2003).
Recent data has also demonstrated ginkgo to be
susceptible to potential drug interactions in vitro.
CYP1A1, CYP1A2 and CYP1B1 are all inhibited by
Ginkgo biloba extracts as indicated by a reduced level
of 7-ethoxyresorufin O-dealkylation (Chang et al.,
2006). In human liver microsomes, ginkgo was shown
to be an inhibitor of CYP2C8 activity (Etheridge et
al., 2007). It was also shown to be an inhibitor of
CYP2C9 in vitro, with a Ki of 14.8 µg/mL (Mohutsky
et al., 2006). Ginkgo has the ability to inhibit CYP3A4
in vitro (He and Edeki, 2004), though conflicting
evidence is available as to whether or not it is an
inhibitor of CYP2C19 and CYP2D6 (Zhao et al.,
2002; Hu et al., 2005; He et al., 2006; Hellum and
Nilsen, 2007).
Multiple in vivo studies have also assessed the drug
interaction potential of gingko. An in vivo study aimed
at assessing the effects of ginkgo on CYP2C9mediated flurbiprofen clearance in vivo showed no
inhibition of CYP2C9 activity (Greenblatt et al.,
2006b). A second study that used (S)-warfarin as a
probe of CYP2C9 activity in vivo also demonstrated
no significant effects due to co-administration with
ginkgo (Mohutsky et al., 2006), potentially implying
that the CYP2C9 inhibition may only occur in vitro.
Studies with CYP3A4 and diltiazem, however,
showed that gingko increased the AUC and absolute
oral bioavailability of diltiazem following a 20 mg/kg
dose of ginkgo (Ohnishi et al., 2003; Hu et al., 2005;
van den Bout-van den Beukel et al., 2006).
Ginseng
Ginseng is one of the most widely used herbal
remedies in the United States and is indicated to
provide an enhanced immune system and level of
physical stamina as well as to decrease fatigue.
Multiple ginseng derivatives are available, with two of
the more popular being Panax ginseng and Siberian
ginseng. The latter is also used as an anti72
inflammatory and anti-cancer agent, and few if any
drug interactions have been reported (van den Boutvan den Beukel et al., 2006). In general, a greater
focus seems to have been placed on Panax or Asian
ginseng.
The effects of Panax ginseng have been studied in
regards to multiple CYP activities in vitro. The studies
have focused on both whole ginseng extracts as well
as the individual ginsenosides. In human recombinant
enzymes, Panax ginseng was shown to inhibit
CYP1A1 via competitive inhibition, and CYP1A2 and
CYP2B1 via linear-mixed inhibition (Chang et al.,
2002). Interestingly, in the previous study, the effects
appeared to not be due to the individual ginsenosides
tested. The individual ginsenosides have been shown
to be inhibitors of CYP2C9 and CYP3A4 in vitro (He
and Edeki, 2004; Liu et al., 2006b). Finally, ginseng
extracts (500 µg/mL) did not cause a significant
increase in CYP3A4 mRNA in primary human
hepatocyte cultures.
Results from clinical trials with various ginseng
extracts appear to be conflicting. Multiple reports
conclude that there is a significant decrease in the
anti-coagulant effect of warfarin in human volunteers
who are also being administered a regimen of Panax
ginseng (Janetzky and Morreale, 1997; Rosado, 2003).
Another study, however, claims that no
pharmacokinetic or pharmacodynamic effects on
warfarin were noted when co-administered with
Panax ginseng (Hu et al., 2005).
Goldenseal
One of the more popular uses for alternative
medicines is to enhance the immune system.
Goldenseal (Hydrastis canadensis) is a popular
immunostimulant that includes various isoquinoline
alkaloids such as berberine, hydrastine and
hydrastinine (Chatterjee and Franklin, 2003). It has
also been indicated as an antimicrobial and digestion
aid. Of notable interest for drug interactions, the
alkaloids mentioned above all contain a
methylenedioxyphenyl moiety, a group which has
been implicated in time-dependent CYP inhibition
(Murray, 2000).
The components of goldenseal have shown
inhibition and inactivation of CYP isoforms in vitro.
The complete extract showed noncompetitive
inhibition of CYP3A4-catalyzed testosterone 6βhydroxylation with a Ki of approximately 0.11%
extract. The individual alkaloids also inhibited CYP
activity. Berberine inhibited CYP2D6-catalyzed 1’hydroxybufuralol formation and 6β-hydroxytestosteBol. Latinoam. Caribe Plant. Med. Aromaticas Vol. 7 (2) 2008
Foti and Wahlstrom
rone formation with IC50 values of 45 and 400 µM,
respectively. Hydrastine inhibited CYP2D6 and
CYP3A4 activities with IC50 values of approximately
350 and 30 µM, respectively. Hydrastine exhibited
mechanism-based inhibition of CYP3A4 activity and
formed MI complexes with expressed CYP2C9,
CYP2D6 and CYP3A4 (Chatterjee and Franklin,
2003). It has been demonstrated that metabolism at the
methylenedioxy moiety may produce a carbine
intermediate that forms a quasi-irreversible bond with
the prosthetic heme iron termed a metaboliteintermediate complex. Golden-seal extracts were also
able to affect the activity of CYP3A4 in a Caco-2 cell
system (Budzinski et al., 2007).
The in vitro inhibition noted above has also been
observed in vivo. In clinical trials with 12 healthy
volunteers, a significant inhibition of CYP2D6 and
CYP3A4/5 activities as measured by debrisoquine
urinary recovery ratios and 1’-hydroxymidazolam to
midazolam serum ratios was observed (Gurley et al.,
2005b).
Grapefruit Juice (and other Fruit Juices)
One widely studied natural product with regard to
CYP-based drug interactions is grapefruit juice.
Grapefruit juice has been shown to be a potent
inhibitor of intestinal CYP3A4, though hepatic
CYP3A4 appears to be unaffected (Lown et al., 1997;
Bailey et al., 1998a; Bailey et al., 1998b). It has also
been shown that the percent inhibition caused by
grapefruit juice can vary from one source to the next.
Because of the potential to interact with drugs that are
metabolized by CYP3A4, the U.S. Food and Drug
Administration (FDA) now requires many of these
drugs to carry a precautionary label warning of the
potential dangers of consuming these drugs with
grapefruit juice (FDA, 2007).
Furanocoumarins
are
perhaps
the
best
characterized source of herbal-mediated DDIs and
produce what is known as the “grapefruit juice effect”.
In vitro, grapefruit juice has been shown to be a potent
inhibitor of CYP1A2, CYP2A6, CYP2C9, CYP2D6
and CYP3A4 (Hukkanen et al., 2006; Girennavar et
al., 2007). Two of the most abundant (and most
studied) furanocoumarins are bergamottin and 6’,7’dihydroxybergamottin.
In
human
intestinal
microsomes, bergamottin exhibited substratedependent reversible inhibition of CYP3A4 (Ki,
midazolam = 13.1 µM; Ki, testosterone = 1.6 µM)
while the dihydroxybergamottin derivative had a Ki
value that was approximately 0.8 µM for both
CYP3A4 probes (Kakar et al., 2004).
73
Bergamottin is also a mechanism-based inactivator
of CYP3A4, with KI and kinact values of 7.7 µM and
0.3 min-1 (He et al., 1998). The predominant
mechanism of inactivation was suggested to be
modification of the apoprotein, as over 90% of the
heme but less than 50% of the apoprotein was
recovered from an in vitro incubation.
In addition to grapefruit juice, a number of other
fruit juices have been reported to cause drug
interactions. Juices such as pomegranate, black mulberry, wild grape, and black raspberry have all shown
drug interactions in vitro (Hidaka et al., 2005; Kim et
al., 2006). In the study by Kim et al., the IC50 values
for all of the fruit juices tested decreased upon preincubation, indicating a potential time-dependent
component to the drug interaction.
Green Tea
Green tea (Camellia sinensis) is a commonly used
herbal tea that has been reported to have antioxidant,
anticancer and anti-inflammatory properties as well as
to promote weight loss (Yang et al., 1998; Dulloo et
al., 1999; Wang and Tian, 2001; Zhong et al., 2002).
The pharmacological effects of green tea have been
assigned to the flavanoids (or catechins) that are found
in the tea (Mirkov et al., 2007).
In human liver microsomes, green tea was shown
to inhibit CYP2C9-catalyzed tolbutamide 4-hydroxylation (IC50 = 57 µg/mg protein), CYP2D6-catalyzed
bufuralol 1’-hydroxylation (IC50 = 50 µg/mg protein)
and CYP3A4-catalyzed testosterone 6β-hydroxylation
(IC50 = 63 µg/mg protein) (Nishikawa et al., 2004).
Furthermore, addition of catechins from green tea to
human liver microsomes inhibited the CYP3A4catalyzed oxidation of irinotecan and UGT1A1catalyzed glucuronidation of its SN-38 metabolite
(Mirkov et al., 2007). When the catechins were
assessed for inductive effects in human hepatocytes,
no induction of CYP3A4 was noted.
A single study in healthy volunteers showed that
green tea did not alter CYP2D6 (dextromethorphan
demethylation) or CYP3A4 (alprazolam hydroxylation) activity after consumption of green tea for 14
days (Donovan et al., 2004a). Similarly, CYP1A2 and
CYP2C19 were also unaffected (Chow et al., 2006).
Kava
Kava (Piper methysticum) is a shrub found mostly
in the South Pacific that is often used to treat
insomnia, anxiety or as a general relaxant. A
significant amount of research has focused on the
Foti and Wahlstrom
uses, components and drug interactions of kava extract
in recent years. Kava gained increasing notice when
cases of liver failure and skin dermopathy were
reported (Keledjian et al., 1988; Strahl et al., 1998;
Kraft et al., 2001). The primary constituents of kava
extract are kavalactones, including yangonin, desmethoxyangonin, methysticin, 7,8-dihydromethysticin, kawain, and 7,8-dihydrokawain and account for
the majority of the lipid soluble components from
kava (Lebot and Levesque, 1989; Mathews et al.,
2002).
Additional research has focused on drug
interactions that are caused by kava extract and the
individual components isolated from the extract. In
human liver microsomes, whole kava extract resulted
in significant inhibition of CYP1A2, CYP2C9,
CYP2C19, CYP2D6, and CYP3A4 (Mathews et al.,
2002; Mathews et al., 2005; Jeurissen et al., 2007).
Inhibition of various CYP activities was also noted for
desmethoxyangonin (CYP2C9 and CYP3A4),
methysticin (CYP2C9, CYP2D6 and CYP3A4), and
7,8-dihydromethysticin (CYP2C9, CYP2C19 and
CYP3A4). Both methysticin and 7,8-dihydromethysticin formed MI complexes (both compounds contain
a methylenedioxyphenyl group) following preincubation with NADPH. Finally, kava has also been
shown to be an inducer of CYP3A4 mRNA in human
hepatocytes, where pre-treatment of the cells with
kava resulted in a 386 ± 185% increase in mRNA
levels versus control (Raucy, 2003).
While reports vary on the potential of kava to
cause in vivo drug interactions, a significant
interaction has been reported for kava when coadministered with alprazolam, a CNS depressant and
CYP3A4 substrate (Almeida and Grimsley, 1996).
Similar reports have been issued for the possible
interaction of kava with barbiturates, benzodiazepines
and alcohol (Blumenthal, 1998; DerMarderosian and
Beutler, 1999).
Licorice
Licorice root (Glycyrrhiza uralensis), long known
as an effective expectorant, has also been used to treat
mouth ulcers, irritable bowel syndrome, Crohn’s
disease and as a mild laxative (Maimes and Winston,
2007). Excessive use of licorice has been shown to be
toxic to both the liver and cardiovascular system and
may also result in hypertension and edema.
In vitro, the extract from licorice root was shown
to be an inhibitor of CYP3A4 in human recombinant
enzymes with an IC50 value of 0.022 mg/mL
(Tsukamoto et al., 2005b). Of the individual
74
components of licorice that were tested, licopyranocoumarin, liquirtin and liquirtine apioside were found
to be the major contributors to the observed inhibition
of CYP3A4. In addition, the isoflavan glabridin was
shown to be a competitive inhibitor of CYP2C9 (Kent
et al., 2002).
Polyphenolic compounds may be precursors of
quinones or quinone methide intermediates that are
known to inactivate CYPs. The licorice root isoflavan
glabridin inactivates CYP3A4 and CYP2B6. Loss of
CYP3A4 activity was correlated with loss of the CYPreduced CO spectrum, while minimal loss of the CYPreduced CO spectrum was observed with CYP2B6,
suggesting differential mechanisms for inactivation.
While the mechanism of inactivation for CYP3A4 was
not determined, methylation of the polyphenol moiety
eliminated inactivation of CYP3A4.
Luteolin
Luteolin is an emerging herbal therapy thought to
have anti-oxidant, radical scavenging, anti-cancer and
anti-inflammatory properties. It is commonly found in
many edible fruits and vegetables and is also sold as
an herbal supplement. One recent study found that of
the many commonly occurring flavonoids, luteolin
was one of the most potent against carcinoma of the
stomach, cervix and bladder (Cherng et al., 2007).
While little data is available as to the drug
interaction potential is available, one recent report by
Foti et al. explored the inhibition of CYP activity by
luteolin as part of an herbal remedy containing
multiple herbal components. In human liver
microsomes, luteolin appeared to be a potent inhibitor
of CYP2B6-catalyzed bupropion hydroxylation,
CYP2C9-catalyzed 4-hydroxytolbutamide formation
and CYP2D6-catalyzed dextrorphan formation (Foti et
al., 2007). Luteolin has also been shown to be an
inducer of CYP3A4 activity via interaction with PXR
in HepG(2) cells (Liu et al., 2006a).
Methoxypsoralen
8-methoxypsoralen is an antimicrobial furanocoumarin that is found in parsnips, barley, celery and
other plant species (Miyazaki et al., 2005). It is also
indicated in photochemotherapy regimens, where it
has been shown to be effective in the treatment of
psoriasis (Glew, 1979).
In vitro, 8-methoxypsoralen was shown to be an
inhibitor of CYP2A6, and a structure of the compound
complexed to the enzyme has been published (Yano et
al., 2005). It is also known to be a mechanism based
Foti and Wahlstrom
inactivator of CYPs, in this case CYP2A6 and
CYP2B1. (Koenigs et al., 1997). Characterization of
glutathione metabolites isolated from in vitro
incubations of 8-methoxypsoarlen suggest that a
furanoepoxide intermediate may be involved in CYP
inactivation.
Milk Thistle
Silybum marianum, an herbal remedy more
commonly known as milk thistle, has traditionally
been used to treat a number of liver disorders (Flora et
al., 1998). To date, it is one of the most widely used
herbal medications (Venkataramanan et al., 2000; Hu
et al., 2005). It is also known to protect the liver
against acetaminophen, thioacetamide, D-galactosamine, amanitin and carbon tetrachloride (CCl4)
mediated hepatotoxicity (Vogel et al., 1984; Mourelle
et al., 1989; Muriel et al., 1992; Chrungoo et al.,
1997). The active ingredients in milk thistle are
primarily flavonoligans, components that are formed
via the radical coupling of a phenylpropanoid and a
flavanoid (Dewick 1997). The flavonoligans are
present as multiple structural isomers, collectively
referred to as silymarin.
Milk thistle has been evaluated both in vitro and in
vivo for potential drug interactions. In human
hepatocyte cultures, the addition of 0.1 and 0.25 mM
silymarin inhibited CYP3A4 activity by approximately 50 and 100%, respectively (Venkataramanan et
al., 2000). A similar down regulation of CYP3A4
activity was observed in a Caco-2 cell monolayer
system (Budzinski et al., 2007). Additionally, in
human recombinant CYP preparations, silybin (the
primary isomer of the silymarin group of isomers)
showed time-, concentration- and NADPH-dependent
inactivation of CYP2C9 and CYP3A4 (Sridar et al.,
2004).
In vivo drug interactions have not been as
pronounced as those observed in vitro. Clinical trials
in healthy volunteers with digoxin and indinavir did
not reveal any clinically significant alteration of drug
metabolizing enzyme activity in these trials (Piscitelli
et al., 2002; DiCenzo et al., 2003; Gurley et al.,
2006b). Similarly, a study designed to assess the
effects of milk thistle on irinotecan pharmacokinetics
in healthy volunteers reveals no significant risk of
drug interactions in vivo (van Erp et al., 2005).
Resveratrol
Resveratrol (3,4’,5-trihydroxy-trans-stilbene) is a
polyphenolic constituent of red wine, grapes and
75
peanuts. It is also found in a number of plants and
fruits, including raspberries, blueberries, cranberries
and some species of pine trees. It reportedly has many
positive activities, including antioxidant, cardioprotective and anti-inflammatory effects.
In vitro, resveratrol has been shown to be a potent
inhibitor of CYP1A1 and CYP1A2, albeit to a lesser
extent (Chun et al., 1999). Naturally occurring
analogues of resveratrol were also shown to be
inhibitors of CYP1A2, as well as CYP2E1 (Mikstacka
et al., 2006). Resveratrol also inactivates CYP3A4 in a
time dependent manner, with KI and kinact values of 20
µM and 0.20 min-1 (Chan and Delucchi, 2000).
CYP3A4-mediated epoxidation and subsequent pbenzoquinone methide formation has been proposed
as the mechanism of inactivation by resveratrol.
Saw Palmetto
Saw palmetto (Serenoa repens) is becoming an
increasingly popular herbal remedy for the treatment
of benign prostatic hypertrophy and chronic cystitis
(Tracy and Kingston, 2007), though recent studies
challenging this notion have found that saw palmetto
was no more effective than placebo in combating
benign prostatic hypertrophy (Bent et al., 2006). The
active ingredients of saw palmetto are fatty acids,
plant sterols and flavonoids (Gordon and
Shaughnessy, 2003).
In vitro, saw palmetto was shown to be a potent
inhibitor of CYP2C9, CYP2D6 and CYP3A4 activity
(Yale and Glurich, 2005). In vivo, however, two
independent studies have shown no effect of saw
palmetto on the marker activities of CYP1A2,
CYP2D6, CYP2E1 or CYP3A4 (Markowitz et al.,
2003b; Gurley et al., 2004).
Schisandra Fruit
Schisandra fruit (Schisandra chinensis) is used for
sedation and antitussive effects, improved liver health
and as an overall tonic. It is often used as a component
of more complex mixtures, such as Japanese Kampo
medicines or in combination with other herbal
remedies.
In vitro experiments utilizing human liver
microsomes have identified potent CYP3A4 inhibitors
in the schisandra fruit extract (Iwata et al., 2004). The
individual schizandrin and gomisin components of the
extract were assessed for CYP3A4 inhibition. While
the schizandrin compounds showed no appreciable
inhibition, IC50 values for the gomisin group ranged
Foti and Wahlstrom
from 0.257 to 6.71 µM against CYP3A4 (6β-hydroxytestosterone activity).
Herbal components containing methylenedioxy
moieties may also exhibit time-dependent inhibition of
CYPs. Extracts from the schisandra fruit containing
this functional group were found to be potent
inhibitors of CYP3A4. The most potent component,
gomisin C, was also found to be a mechanism based
inactivator of CYP3A4. Rise in a diagnostic peak at
455 nm is indicative of MI complex formation and
was observed in incubations containing gomisin C
(Iwata et al., 2004).
Soy
Soy-derived products are often used to treat symptoms of menopause in women. The primary effects of
soy are usually attributed to a number of isoflavones
that have been isolated, namely daidzein and
genistein. It has also been claimed that diets rich in
soy can reduce cholesterol levels (Song et al., 2007).
In vitro, various components of soy have been
shown to have inhibitory activity against the CYP
enzymes. In particular, the isoflavones daidzein,
genistein and glycitein were all uncompetitive
inhibitors of CYP2A6 in a baculovirus-expressed
enzyme system (Nakajima et al., 2006). In human
liver microsomes, hydrolyzed soy extracts also were
inhibitors of CYP2C9 and CYP3A4 (Anderson et al.,
2003). In vivo, no effect was observed on the 6βhydroxycortisol to cortisol ratio, indicating that soy
extract was probably not a clinically relevant inducer
of CYP3A4 activity in vivo.
St. John’s Wort
One of the more widely used and researched
alternative medicines in recent years has been St.
John’s wort (Hypericum perforatum). It is most
commonly used for the treatment of mild to moderate
depression (Linde et al., 1996; Wheatley, 1997;
Shelton, 2002). While the extract is a mixture of
multiple biologically actively compounds, hypericin
and hyperforin are two of the main constituents.
Hyperforin is also the main pharmacological
component that is responsible for the herbal remedy’s
anti-depressant qualities, owing to it being a potent
serotonin, norepinephrine and dopamine reuptake
inhibitor (Chatterjee et al., 1998; Moore et al., 2000).
Aside from its pharmacologically active properties,
a large amount of recent research has also focused on
the potential of St. John’s wort to cause drug
interactions both in vitro and in vivo. Complex drug
76
interactions can arise from other drugs that are coadministered with St. John’s wort owing to the herb’s
ability to both inhibit and induce CYP enzymes.
Crude extracts of St. John’s wort have been shown to
inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6 and
CYP3A4 in cDNA expressed enzymes (Obach, 2000).
When the individual components were extracted, both
hyperforin and I3,II8-biapigenin exhibited potent
inhibition of the CYP enzymes noted above. A more
recent study has shown that the individual components
furoadhyperforin and furohyperforin were actually
more potent inhibitors of CYP3A4 than hyperforin
(Lee et al., 2006a). In human hepatocytes, exposure of
the cells to hyperforin resulted in an increase in
mRNA, protein and activity levels of CYP3A4 and
CYP2C9 (Komoroski et al., 2004). No effect was
observed on CYP1A2 or CYP2D6 and similar
experiments using hypercin did not result in any
significant levels of induction. The inductive effects
of St. John’s wort have been explained by the fact that
hyperforin is also a ligand for the pregnane X receptor
(PXR), an orphan nuclear receptor that regulates
levels of many of the CYP enzymes (Moore et al.,
2002).
Numerous clinical trials have also been undertaken
to understand the in vivo drug interactions that may be
attributable to St. John’s wort. Multiple studies have
shown that prolonged usage of St. John’s wort can
induce both hepatic and intestinal CYP3A4 (Gurley et
al., 2002; Bauer et al., 2003; Dresser et al., 2003). In
general, studies have also shown that short term usage
(less than 8 days) had no significant effects on
CYP3A4 activity in vivo (Ereshefsky et al., 1999).
Induction of CYP2E1, though to a lesser extent (28%),
was observed for CYP2E1 (Gurley et al., 2005a).
Usnic Acid
Usnic acid, a metabolite found in various lichen
species, has had a wide number of therapeutic uses.
These have included use as an antibiotic, antiviral,
anti-oxidant, analgesic, cosmetic, and more recently,
as a weight loss aid. Currently, there are no clinical
trials that support any of these claims in humans
(Frankos, 2005). Usnic acid came to the attention of
the FDA in the 1990s, when reports began to surface
surrounding the incidence of liver problems in those
patients taking usnic acid containing supplements
(Arneborn et al., 2005; Frankos, 2005; Sanchez et al.,
2006).
A recent study investing the metabolism and drug
interactions of usnic acid found the supplement to be a
very potent inhibitor of the CYP2C family of enzymes
Foti and Wahlstrom
in human liver microsomes. IC50 values ranged from
0.009 µM for CYP2C19 to 6.3 µM for CYP2C18,
with the IC50 for CYP2C8 and CYP2C9 being 1.9 µM
and 0.094 µM, respectively (Foti et al., 2008). An
extrapolation of the in vitro data using SimCYP®
showed a significant risk of drug interactions with
other drugs that are cleared primarily by CYP2C
enzymes.
Valerian
Valerian (Valeriana officinalis) is another widely
used herbal remedy in the United States. Its major use
is for sedation and/or hypnosis, though clinical trials
assessing its efficacy in treating insomnia have been
inconclusive (Stevinson and Ernst, 2000; Krystal and
Ressler, 2001; Sparreboom et al., 2004). The main
components of valerian that have been isolated
include derivatives of valerenic acid, valepotriates,
alkaloids, furanofuran lignans and free amino acids
(Houghton, 1999).
Extracts from the valerian root have been shown to
inhibit CYP3A4 activity in vitro (Lefebvre et al.,
2004; Sparreboom et al., 2004). Organic extracts of
the root showed as high as 88% inhibition of CYP3A4
activity in a fluorescence-based assay. Individual
components such as valerenic acid showed a much
lower inhibitor potential against CYP3A4 and minor
inhibition of CYP2C9 and CYP2C19 (Zhou et al.,
2003; Sparreboom et al., 2004).
The effects of valerian on co-administered
medications in vivo appear to be less significant than
those observed in vitro. Studies designed to probe in
vivo drug interactions between valerian and substrates
for CYP3A4 or CYP2D6 have come back negative.
Donavan et al. report minimal effects on CYP3A4
activity and no effect on CYP2D6 activity following
14 days of valerian administration (1 gram/day)
(Donovan et al., 2004b). Gurley et al. report similar
results following 375 mg/day of valerian for 28 days
(Gurley et al., 2005b).
Wu-chu-yu Tang
The traditional Chinese herbal medicine Wu-chuyu-tang is often used for treating migraines and/or
cases of cold-related emesis (Kano et al., 1991). The
herbal remedy actually contains a mixture of herbs,
including Wu-chu-yu, ginseng, ginger, and tai-geui
(Ueng et al., 2002a).
In vitro, CYP-mediated drug interactions with
components of Wu-chu-yu tang have been observed.
Rutaecarpine, a quinazolinocarboline alkaloid that has
77
been isolated from the herbal remedy, was shown to
be a selective CYP1A2 inhibitor in human liver
microsomes (Ueng et al., 2002b). The observed IC50
values for rutaecarpine against 7-methoxyresorufin
and 7-ethoxyresofufin activities in human liver microsomes were 0.05 and 0.03 µM, respectively. In
addition, a number of CYP isoforms (CYP1A2,
CYP2D6 and CYP3A4) are known to be involved in
the metabolism of rutaecarpine to multiple hydroxylated metabolites. In particular, 10-hydroxyrutaecarpine was shown to inhibit CYP1A1, CYP1A2
and CYP1B1 with IC50 values of 2.56, 2.57 and 0.09
µM, respectively (Ueng et al., 2006). Thus the
potential for both reversible and time-dependent
inhibition exists for components of Wu-chu-yu tang in
vitro.
CONCLUSION
As the use of complimentary and alternative
medicines continues to increase around the world, the
ability to predict and ultimately avoid adverse
reactions with these therapies takes on a new found
importance. Multiple reports continue to emerge
documenting the ability of herbal medicines to
contribute to drug interactions involving both the
cytochrome P450 family of enzymes as well as other
enzymes not covered in this review (i.e., UDPglucuronosyltransferases, esterases, etc.). In addition
to increasing the amount of research pertaining to
herbal remedies, the need to ensure that this
information is properly disseminated at the consumer
level is also key to avoiding potentially harmful
interactions. Finally, this information combined with
an increased awareness on the part of physicians and
pharmacists should help to alleviate some of the risks
associated with herbal remedies while still allowing
patients to realize the beneficial aspects of alternative
medicine.
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84
© 2008 Los Autores
Warfarin-herb interactions: a review and study based on assessment of
clinical case reports in literature
[Interacciones hierbas-warfarina: una revisión y estudio basado en la evaluación de los reportes
de casos clínicos en la literatura]
Jagruti A. PATEL1* and Kashmira J. GOHIL2
1
*Department of Pharmacology, Institute of Pharmacy, Nirma University of Science and Technology, Ahmedabad, Gujarat, India.
2
Department of Pharmacology, Maliba Pharmacy College, Gopal Vidyanagar, Tarsadi, Bardoli, Gujarat, India.
*Contact: e-mail: [email protected]
Submitted January 31, 2008; Accepted February 26, 2008
Abstract
The potential risk of herb drug interactions is of particular focus today owing to the increasing and inadvertent use of herbs in recent times. It
is a major safety concern for the drugs with narrow therapeutic index like warfarin, a most common anticoagulant with the maximum number
of interactions reported. The objective of the present study was to conduct a systemic review of literature to consolidate the clinical case
reports of warfarin–herb interactions and to assess the report reliabilities. We reviewed the published clinical literature to consolidate and
assess the interactions between various herbs and warfarin, based on reported adverse events, descriptions of the clinical case reports and
case series using electronic databases as well as hand picked references from the year 1971 to year 2007 and ranked them on likely causality
using Naranjo’s algorithm. Out of 72 cases of documented case reports of warfarin with various herbs, 84.7% cases were evaluated as
possible interactions (61/72) and 15.3% cases (11/72) as probable interactions. Cranberry juice was most commonly involved in interactions
with warfarin with 34.7% of cases (25/72) of which 92% cases were possible interactions (23/25) and 8% cases (2/25) were probable
interactions. Hence, we conclude that combining anticoagulant medicines with herbs appears to be a risky proposition. The number of herbs
reported to interact with warfarin continues to expand. Patients on warfarin are specifically advised to avoid taking herbal medicines or to
have their INR measured within two weeks of starting the drug, to be on a safer side. Further, more systematic studies pertaining to warfarinherb interactions are urgently warranted.
Keywords: Herb-drug interactions, Warfarin, Clinical case series, Clinical assessment, Clinical case reports.
Resumen
El riesgo potencial de las interacciones entre hierbas y fármacos es de particular interés en la actualidad justamente por el incremento del uso
de las hierbas. La mayor seguridad radica en el estrecho índice terapéutico de fármacos como la warfarina, un anticoagulante con un número
máximo de reportes de interacciones. El objetivo del presente estudio fue conducir una revisión sistemática de la literatura para consolidar los
reportes de casos clínicos de interacciones warfarina-hierbas para evaluar las fiabilidades de dichos reportes. Se revisó la literatura clínica
publicada para consolidar y evaluar las interacciones entre varias hierbas y la warfarina, basado en los eventos adversos publicados,
descripciones de los reportes de casos clínicos y las series de casos mediante las bases de datos electrónicas así como la selección de las
referencias desde el año 1971 hasta el 2007 y se alinearon sobre la probable causalidad mediante el algoritmo de Naranjo. Se obtuvieron 72
casos de reportes documentados de interacciones de warfarina con varias hierbas, 84.7% de los casos fueron evaluados como posibles
interacciones (61/72) y 15.3% (11/72) como probables interacciones. El jugo de arándano fue el más comúnmente involucrado en las
interacciones con warfarina con 34.7% de casos (25/72) de los cuales el 92% fueron interacciones posibles (23/25) y el 8% (2/25) fueron
interacciones probables. De estos resultados se concluye que combinar anticoagulantes con hierbas parece ser una proposición arriesgada. El
número de reportes de hierbas que actúan recíprocamente con warfarin continúa en aumento. Se aconseja específicamente a los pacientes que
toman warfarina que eviten tomar medicinas herbarias o medir su INR a las dos semanas de arranque del fármaco, hacerlo de una forma más
segura. De esta forma, se necesitan urgentemente estudios más sistemáticos sobre las interacciones de la warfarina y los productos herbales.
Palabras clave: Interacciones hierba-fármacos, Warfarina, Serie de casos clínicos, Valoración clínica, Reportes de casos clínicos.
Warfarin–herb interactions
INTRODUCTION
These days, millions of people use herbal
therapies along with prescription and nonprescription
medications (Zhou, 2007). About one third of the
adults in developed countries and more than 60%
Asians use herb as an alternative medicines (Zhou,
2007; Anonymous, 2006). Despite widespread use of
herbal remedies, scientific data about their safety and
efficacy are lacking in most cases plus reporting of
adverse drug events is currently limited. The lack of
available clinical data for many herbal products
serves as a barrier for post marketing safety
assessment of herbal products (Chavez et al., 2006).
Further, the risk of interaction between the herb and
the drug increases, causing either potentially dangerous side effects and/or reduced benefits from the
medications, and hence, interactions between the two
needs to be addressed and reviewed properly (Gohil
and Patel, 2007). Concurrent use of herbs may mimic, magnify or oppose the effect of drugs and thus
may raise the potential of herb-drug interactions,
contrary to the popular belief, that nature is always
safe. A major safety concern is the potential interactions of alternative medicinal products with prescription medications like anticoagulants. Herbs that
may augment or inhibit the effects of anti-coagulant
or antiplatelet therapy are of particular interest
because this therapy is so widespread. The issue is
especially important with respect to warfarin as it has
a narrow therapeutic index and is already known to
be associated with numerous food and drug interactions (Saw et al., 2007; Stout, 2006). It becomes
imperative to have sufficient knowledge database as a
conclusive evidence for herb-warfarin interactions for
a very close monitoring of therapy to avoid any
potential interactions between the two.
The aim of our present study was to conduct a
systemic review of literature to consolidate the
clinical case reports on warfarin–herb interactions
based on documented clinical evidence and to assess
of the reliability of these case reports.
METHODS
A literature survey was carried out to assess the
published literature for appraisal of herbal drug
interaction information available. As per the guidelines for the use of electronic and internet media
(Winker et al., 2000; Wootton 2004; Eysenback and
Diepgen, 1998; Silberg et al., 2007) a high quality
and reliable medical information from the internet
was retrieved only from the Health On Net (HON)
Patel and Gohil
conduct certified and accredited websites like Entrez
PubMed (Medline), CAM-PubMed, Allied and
Complementary Medicine Database, Natural Medicine Comprehensive Database, Embase and Cochrane
Library. The databases were searched from the year
1971-2007 using the search terms “herb-drug interactions, anticoagulants, warfarin, adverse drug reactions, herbal medicine, case reports, case series,
clinical trials and clinical assessments”. Non-English
language citations were excluded. The bibliographies
of the retrieved articles were checked for any additional pertinent studies. An extensive review of the
literature identified reported herb-drug interactions
with clinical significance, many of which were in the
form of case reports and limited clinical observations.
The nature of findings and probability of interactions
were then abstracted and compiled in a final report
(Table 1).
The probability of interactions were evaluated on
a 10 point scoring scale, where each of the case
reports received one point for inclusion of following
ten evaluating parameters.
•
Adequate patient history
•
Concurrent diseases, conditions
•
Documentation of concomitant medications
•
Adequate description of interactions
•
Exclusion of obvious alternative explanations
•
Complete chronology
•
Reasonable time sequence of drug administration to adverse event
•
Adequate description of adverse event
•
Cessation of event on stopping the drug
•
Recurrence of event with a re-challenge
The sum total of all these parameters was calculated and referred as report reliability score as per the
criteria mentioned below. The probability of interactions was evaluated independently by 2 raters
unaware of the study protocol using Naranjo’s
algorithm for adverse drug reaction (ADR) causality
assessment (Naranjo et al., 1981). The Naranjo’s
algorithm was used to assess the likelihood that a
change in clinical status is the result of an adverse
drug reaction rather than the result of other factors
such as progression of disease. Each of ten items in
the assessment was answered and the values of the
answer were entered in the column labeled as Report
Reliability Score. The score of ten items were then
summed up to determine the total scores and interpretation rules were applied as given below.
Criteria for interpretation of the total score:
• Total scores ≥ 9 suggested that an ADR is highly
probable.
86
•
•
•
Patel and Gohil
Other herbs that have been associated with
published case reports of possible or probable
interactions with warfarin include Saint John’s wort
(7 cases) (Yue et al., 2000), birch (5 cases)
(Ramanathan, 1995; Joss and Leblond, 2000; Chow
et al., 1989; Littleton, 1990), coenzyme Q10 (4 cases)
(Spigset, 1994; Landbo and Almdal, 1998), danshen
(3 cases) (Tam et al., 1995; Yu et al., 1997; Izzat,
1998), garlic (3 cases) (Rose et al., 1990; Sunter,
1991) ginseng (3 cases) (Janetzky and Morreale,
1997; Hopkins et al., 1988; Rosado, 2003), saw
palmetto (3 cases) (Yue and Jansson, 2001; Cheema
et al., 2001) vitamin C (3 cases) (Rosenthal, 1971),
dong qui (2 cases) (Page and Lawrence, 1999; Ellis
and Stephens, 1999), ginkgo (2 cases) (Mathews,
1998; Fessenden et al., 2001), green tea (2 cases)
(Taylor and Wilt, 1999; Leonard, 2006), papaya
extract (2 cases) (Perez-Jáuregui et al., 1995; Shaw et
al., 1997), and one case each of devil’s claw (Shaw et
al., 1997), Chinese herbal tea (Lycium barbarum )
(Lam et al., 2001), quilinggao (Chinese herbal
product) (Wong and Chan, 2003), soy milk (CambriaKiely, 2002), royal jelly (Lee and Fermo, 2006),
boldo-fenugreek (Lambert, 2001), vitamin E
(Corrigan and Marcus, 1974) and chamomile (Segal
and Pilote, 2006).
Total Scores between 5 to 8 suggested that an
ADR is probable.
Total Scores between 1 to 4 suggested that an
ADR is possible.
Total Scores of zero or less means that an ADR is
doubtful.
RESULTS
A total 72 cases of suspected interactions of
warfarin with 21 types of different herbs were
consolidated. The interactions were tabulated and
categorized by herb, drug, other medications, signs or
symptoms of interaction, mechanism, and report
reliability score assessed by Naranjo’s algorithm
(Naranjo et al., 1981) (Table 1). Out of 72
documented case reports of interactions, 84.7% cases
(61/72) were classified as possible interactions and
15.3% (11/72) as probable interactions. Cranberry
juice was most commonly implicated in interactions
with warfarin with 34.7% of cases (25/72) of which
92% cases were evaluated as possible interactions
(23/25) and 8% cases (2/25) as probable interactions
(Suvarna et al., 2003; Anonymous, 2003; Grant,
2004; Rindone and Murphy, 2006; Walsh, 2005; Jo
Yacko, 2006).
Table 1. Assessment of clinical case reports of herb-warfarin interactions by Naranjo’s algorithm.
Sr. No.
Patient Description
Herb
(Latin name)
Other
medications
Signs and
symptoms of
interaction
1-12
Case series n=12
(Anonymous, 2004)
Cranberry juice
(Vaccinium
macrocarpon,
V. oxycoccus)
Not described
8 cases INR ↑,
3 cases unstable
Not described.
INR, 1 case INR ↓
13
A Man in 70s with lethal
gastrointestinal, pericardial
hemorrhage and chest infection
(Suvarna et al., 2003)
Cranberry juice
Cefalaxein,
digoxin, phenytoin INR > 50
14-21
8 different cases
(Anonymous, 2003)
22
69 year-old man with atrial
fibrillation and mitral valve
replacement
(Grant, 2004)
Cranberry juice
Not described
1 case, patient
died
4 cases INR ↑
2 cases unstable
INR and 1 case
INR ↓
Cranberry juice
Digoxin,
acetaminophen
(paracetamol),
codeine
INR 12
Mechanism
Report reliability
score
1+2+1+0+0+0+0+
0+0+0=4
Possible.
Not described.
0+2+0+0+0+0+0+
0+0+0=2
Possible
Inhibition of
breakdown of
warfarin in the
body.
1+2+0+0+0+0+0+
0+0+0=3
Possible
Not known
0+2+1+0+2+0+0+
0+0+0=5
Probable
87
Patel and Gohil
Table 1. (continued)
Other
medications
Signs and
symptoms of
interaction
Cranberry juice
None
Profound hypoprothrombinemia and
bleeding
Not described.
INR > 18
PT time120 sec.
1+2+1+0+1+0+0+
0+0+0=5
Probable
Cranberry juice
Unknown
INR fluctuates
between 1-10
Unknown
1+2+0+0+0+0+0+
0+0+0=3
Possible
Unknown
1+2+1+0+2+0+0+
0+0+0=6
Probable
Herb
(Latin name)
Patient Description
23
71-year-old man on Warfarin
therapy stroke prophylaxis and
symptoms of hemoptysis,
hematochezia and shortness of
breath
(Rindone and Murphy, 2006)
24
Elderly man with Hypertension
and atrial fibrillation
(Walsh, 2005)
25.
One patient with no other details
Cranberry juice
(Jo Yacko, 2006)
26-32
Case series n=7
75 year old female.
Other six cases with no details
(Yue et al., 2000)
St. John’s wort
(Hypericum
perforatum)
INR ↓
0+2+0+0+0+0+0+
Induction of CYP 0+0+0=2
enzymes
Possible
33-34.
Two patients using ointment
containing birch bark oil
(Ramanathan, 1995)
Birch
(Betula pendua,
B. alba leaves)
High INR
Displace warfarin 0+2+0+0+0+0+0+
0+0+0=2
from protein
binding sites
Possible
35.
A 22-year old White woman
Birch
using topical methyl salicylate gel
(Betula pendua,
to both knees for 8 days
B. alba leaves)
(Joss and Leblond, 2000)
-
Elevated INR up
to 12.2
Displace warfarin
0+2+0+0+0+0+0+
from
0+0+0=2
protein binding
Possible
sites
-
INR = 6.1,
0+0+0=2
from protein
Multiple bleeding binding sites
Possible
-
Bleeding,
0+0+0=2
double prothombin from protein
binding sites
time
Possible
36.
37.
Patient with arthritic knees using Birch
methyl salicylate for two weeks (Betula pendua,
(Chow et al., 1989)
B. alba leaves)
Patient using large amount of
Birch
methyl salicylate over arthritic
(Betula pendua,
joints
B. alba leaves)
(Littleton, 1990)
None
INR ↓
Mechanism
Report reliability
score
Sr. No.
38.
68 year old man with history of
several episodes of pulmonary
and cerebrovascular emboli
(Spigset, 1994)
CoenzymeQ10
(Amigo xie)
-
INR ↓
Herb has
procoagulant
properties
0+2+1+0+0+0+0+
0+0+0=3
Possible
39.
72 year old man with pulmonary CoenzymeQ10
embolism
(Amigo xie)
(Spigset, 1994)
-
INR ↓
Herb has
procoagulant
properties
0+2+1+0+0+0+0+
0+0+0=3
Possible
40.
70 year old woman with
thromboembolic disease
(Spigset, 1994)
CoenzymeQ10
(Amigo xie)
-
INR ↓
Herb has
procoagulant
properties t
0+2+1+0+0+0+0+
0+0+0=3
Possible
41.
72 year old woman
(Landbo and Almdal., 1998)
CoenzymeQ10
(Amigo xie)
-
↓ Response to
coumadin
Herb has
procoagulant
properties
1+2+1+0+0+0+0+
0+0+0=4
Possible
42.
66-year-old man with bleeding
from gastric carcinoma
(Tam et al., 1995)
Chinese medicated
Danshen
topical oil
INR ↑
(Salvia miltiorrhiza) containing methyl
salicylate
Herb Inhibit
platelet
aggregation
0+2+1+0+0+0+0+
0+0+0=3
Possible
88
Patel and Gohil
Signs and
symptoms of
interaction
Mechanism
Report reliability
score
INR ↑
Reduce
elimination of
warfarin
0+2+1+0+2+0+0+
0+0+0=5
Probable
62-year-old man with mitral
valve replacement
(Izzat, 1998)
Danshen
Digoxin, captopril,
INR ↑
(Salvia miltiorrhiza) furosemide
Inhibit platelet
aggregation
1+2+1+0+0+0+0+
0+0+0=4
Possible
A patients, no details provided
(Rose et al., 1990)
Garlic
(Allium sativum)
Inhibit
thromboxane
synthesis
0+2+0+0+0+0+0+
0+0+0=2
Possible
INR ↑
Prolonged
Inhibit
Clotting time with thromboxane
increased post
synthesis
operative
bleeding.
0+2+0+0+0+0+0+
0+0+0=2
Possible
Sr. No.
Patient Description
Herb
(Latin name)
Other
medications
43.
48-year-old woman with
rheumatic heart disease along
with atrial fibrillation and mitral
stenosis
(Yu et al., 1997)
Danshen
Frusemide,
(Salvia miltiorrhiza) digoxin
44.
45.
-
Sponteneous
spinal epidural
hematoma
46-47.
Two patients, no details provided Garlic
(Sunter, 1991)
(Allium sativum)
48.
47 year old man with history of
heart valve replacement
(Janetzky and Morreale, 1997)
Ginseng
(Panax ginseng)
Diltiazem, nitroINR ↓
gycerine, salsalate
49.
A post menopausal woman
(Hopkins et al., 1988)
Ginseng
(Panax ginseng)
Hormone therapy
50.
A 58-year-old male with
mechanical bileaflet aortic valve
Asian Ginseng
admitted to hospital with
(Panax ginseng)
anterospectla MI and diabetic
ketoacidosis
(Rosado, 2003)
51-52.
2 male patients
(Yue and Jansson, 2001)
Saw palmetto
(Serenoa repens)
53.
A patient with no information
(Cheema et al., 2001)
Saw palmetto
(Serenoa repens)
Unknown
54-55.
Two cases
(Rosenthal, 1971)
High dose of
Vitamin C
-
56..
A 52-year-old woman
(Rosenthal, 1971)
Unspecified amount
of vitamin C
57.
46 year old woman with history
of stroke, rheumatic heart disease Dong quai
and atrial fibrillation
(Angelica sinensis)
(Page and Lawrence, 1999)
58.
A woman with history of mitral
valve replacement
(Ellis and Stephens, 1999)
Dong quai
(Angelica sinensis)
0+2+1+0+2+0+0+
Reduces the effect 0+0+0=5
of warfarin
Probable
Herb shows
estrogen like
effect
0+2+1+0+0+0+0+
0+0+0=3
Possible
Not known.
0+2+1+0+0+0+0+
0+0+0=3
Possible
Unknown
0+2+0+0+2+0+0+
0+0+0=4
Possible
INR ↑
Platelet
dysfunction by
inhibiting
cyclooxygenase
enzyme
0+2+0+0+1+0+0+
0+0+0=1
Possible
Reduce blood
thining effect of
warfarin
Cause diarrhea and 0+2+0+0+0+0+0+
reduce absorption 0+0+0=2
of warfarin
Possible
Shortening of
blood clotting
time.
Reduced
absorption of
warfarin
0+2+1+0+0+0+0+
0+0+0=3
Possible
Digoxin,
furosemide
INR ↑
PT ↑
Inhibit platelet
aggregation
0+2+1+0+2+0+0+
0+0+0=5
Probable
-
INR=10,
Widespread
bruising.
Inhibit platelet
aggregation
0+2+1+0+0+0+0+
0+0+0=3
Possible
-
Unknown
Mastalgia and
vaginal bleeding
Unsteady INR
↑ INR
bleeding
89
Patel and Gohil
Other
medications
Signs and
symptoms of
interaction
Mechanism
Report reliability
score
59.
70 year old female with history of
hypertension, myocardial
Ginkgo
infarction, atrial fibrillation,
coronary bypass and gait disorder (Ginkgo biloba)
(Mathews, 1998)
-
PT ↑
Hemorrhage
Antiplatelet
activity of herb
0+2+0+0+0+0+0+
0+0+0=2
Possible
60.
A patient with no other
information
(Fessenden et al., 2001)
Ginkgo
(Ginkgo biloba)
-
Post laparoscopic
Antiplatelet
cholecystectomy
activity of herb
bleeding
0+2+0+0+0+0+0+
0+0+0=2
Possible
61.
44 year old recipient with a
mechanical heart valve
(Taylor and Wilt, 1999)
Brewed green tea
(Camellia sinensis)
None
INR ↓
0+2+1+0+2+0+0+
High vitamin K
content antagonize 0+0+0=5
warfarin effect
Probable
62.
One man. No other information
(Leonard, 2006)
Green tea
(Camellia sinensis)
None
Thickening of
blood
0+2+1+0+0+0+0+
Herb has
0+0+0=3
antagonistic effect
Possible
63.
A woman in Mexico
(Perez-Jauregu et al., 1995))
Papaya extract
(Papaya carica)
-
Prolonged PT time
Potentiate the
effect of warfarin
0+2+0+0+0+0+0+
0+0+0=2
Possible
64.
A male admitted for cardiac
surgery
(Shaw et al., 1997)
Papaya extract
(Papaya carica)
-
INR ↑
Potentiate the
effect of warfarin
0+2+1+0+0+0+0+
0+0+0=3
Possible
65.
One case with no other
information
(Shaw et al., 1997)
Devil’s claw
(Harpagophytum
procumbens)
-
Purpura
Inhibit platelet
aggregation
0+2+0+0+0+0+0+
0+0+0=2
Possible
66.
61 year old Chinese woman
(Lam et al., 2001)
Lycium barbarum
-
INR ↑
Probable no
interaction
0+2+1+0+2+0+0+
0+0+0=5
Probable
67.
61 year old man, no other
information
(Wong and Chan, 2003)
Quilinggao
(Fritillaria cirrhosa,
Paeoniae rubra,
Lonicera japonica,
Poncirus trifoliata)
Bleeding, epitaxis, Antiplatelet and/or 0+2+1+2+2+0+0+
skin bruising,
0+0+1=8
antithrombotic
effects
↑ INR
Probable
68.
70 year old white man
(Cambria-Kiely, 2002)
Soy milk
None
INR ↓
Increased
metabolism of
warfarin
0+2+1+0+2+0+0+
0+0+0=5
Probable
69.
87 year old man with stage-IV-A
follicular non-Hodgkin’s
lymphoma, atrial fibrillation and Royal jelly
hypertension
(Lee and Fermo, 2006)
Felodopine,
lisinopril,
hydrochlorthiazide, KCl,
diltiazem,
oxycodone
↑ INR
bleeding
Unknown
0+2+0+0+2+0+0+
0+0+0=4
Possible
Sr. No.
Patient Description
Herb
(Latin name)
90
Patel and Gohil
Sr. No.
Patient Description
Herb
(Latin name)
Other
medications
Signs and
symptoms of
interaction
Mechanism
Report reliability
score
70.
A 67-year old female with atrial
fibrillation
(Lambert, 2001)
Boldo-Fenugreek
(Trigonella foenum
graceum)
Metoprolol
INR ↑
Herbs potentiate
the effect of
warfarin
0+2+1+2+0+0+0+
0+0+0=5
Probable
71.
55 year old man
(Corrigan and Marcus, 1974)
Vitamin E
-
PT ↑
hematuria
Inhibit oxidation
of vitamin K
0+2+1+2+2+0+0+
0+0+0=7
Probable
72.
70 year old woman
with mechanical mitral valve
placement and previous episode
of atrial fibrillation
(Segal and Pilote, 2006)
Amiodarone,
digoxin,
symthroid,
Chamomile
Multiple internal
alendronate,
(Matricaria recutica)
hemorrhage
metoprolol,
calcium-vitamin-D
supplement
Potentiate the
effect of warfarin
by inhibition of
CYP IA2
0+2+0+0+2+0+0+
0+0+0=4
Possible
DISCUSSION
This updated review indicates a significant number
of reports of interaction between warfarin and herbs,
reaffirming both, the anticoagulant’s widespread use
and its concomitant use with herbal medicines.
Warfarin is the most efficacious oral anticoagulant
used for the prevention of thromboembolic events in
patients with chronic atrial fibrillation (Albers et al.,
2001), prosthetic heart valves (Stein et al., 2001),
venous thromboembolism (Hyers et al., 2001) and
coronary artery disease (Cairns et al., 2001). The drug
is a racemic mixture of 2 optically active isomers,
though the S-enantiomer is approximately 5 times
more potent than the R-enantiomer (Holbrook et al.,
2005). Warfarin interferes in coagulation process by
being competitive inhibitor of vitamin K in the biosynthesis of prothrombin and in the process lowering
the amount of active vitamin K available for the
activation of clotting factors II, VII, IX, and X (Hirsh
et al., 2001). A possible interaction refers to the
possibility that one substance may alter the bioavailability or clinical effectiveness of another substance when two or more substances are given concurrently. The net result may be an increase or a
decrease in effect of one or both substances
(Wittkowsky, 2001). Herbs may interact with bloodthinning medications in different ways. Multiple
pathways exist for interference with warfarin, and
interactions may lead to either hemorrhage or
thrombotic episodes by increasing or reducing the
effects of this agent. Although the true mechanisms of
drug interactions almost always remain unknown,
there are several pharmacokinetic and pharmacodynamic factors that could influence warfarin’s effect.
The more potent warfarin S-isomer is metabolized by
cytochrome P-450 (CYP) 2C9. The R-isomer of warfarin is metabolized by CYP 1A2 and CYP 3A4 inhibit
CYP 1A2 and CYP 3A4 (Holbrook et al., 1996) while
pharmacodynamics of warfarin may be influenced by
medications that affect either vitamin K or the coagulation factors (Hirsh et al., 2003). Herbs can affect the
response of anticoagulant therapy by increasing or
reducing prothrombin time (PT) and International
Normalized Ratio (INR). Anticoagulation with warfarin is often difficult to manage and stabilize because
of its narrow therapeutic index, high degree of protein
binding, its penchant for various food and drug
interactions or sudden changes in dietary sources of
vitamin K such as leafy greens or a supplemented diet
(Ansell et al., 2004). Both effectiveness and safety
(primarily risk of bleeding) are related to monitoring
INR values and dose adjustments of warfarin
influenced by changes in concomitant medications,
diet, alcohol consumption, acute illness, liver disease,
and unknown factors.
More number of food and drug interactions has
been reported for warfarin than any other prescription
medications (Wells et al., 1994). In earlier survey of
similar nature, a total of 108 cases of suspected interactions were found and evaluated using 10-point
scoring system for assessment of clinical case reports
for herb-drug interactions (Fugh-Berman and Ernst,
2001) according to which, warfarin was the most
common drug with 18 cases, of which 61.1% cases
were evaluated as unevaluable interactions (11/18),
91
22.2% as possible interactions (4/18) and 16.7% as
likely interactions (3/18). St. John’s wort was the most
common herb interacting with warfarin (07 cases)
categorized as “unevaluable” interactions.
In the present study, we have consolidated all cases
of herb-warfarin interactions. A total of 72 cases were
evaluated using Naranjo’s algorithm for adverse drug
reaction (ADR) causality assessment, of which 84.7%
cases (61/72) were classified as possible interactions
and 15.3% cases (11/72) were probable interactions.
Cranberry juice was most commonly implicated in
interactions with warfarin with 34.7% of cases (25/72)
of which 88% cases were evaluated as possible
interactions (22/25) and 12% cases (3/25) as probable
interactions. Cranberries, a fruit native to North America are primarily cultivated for consumption as food
and beverages (Jellin et al., 1999). The juice and concentrated extract from cranberries are increasingly
used for the prevention and adjunctive treatment of
urinary tract infections (DerMarderosian and Beutler,
2002; Raz et al., 2004). Several case reports published
in literature prompted the speculation regarding the
interaction between the two. We consolidated total of
25 cases of interactions of warfarin–cranberry juice
interactions in this study. Several mechanisms of
interaction between cranberry juice and warfarin have
been proposed. It is postulated that cranberry juice
increases the activity of warfarin possibly by
inhibiting the breakdown of warfarin in the body
leading to increased INR and excessive thinning of
blood resulting in increased risk of bleeding
(Anonymous, 2003). Recently, it has been reported
that some chemicals in cranberries may interfere with
the effects of warfarin. Cranberries contain high
percentages of phytochemicals known as flavonoids,
which are implicated in modification of various
biochemical pathways and modulation of expression
of specific CYP-450 enzymes and thus inducing or
inhibiting their activities, for example, several
flavonoids such as hyperforin and silibinin inhibit the
activity of CYP2C9 (Hodek et al., 2002). Another
mechanisms implied that the salicylic acid content in
cranberry juice might be responsible for exerting
antiplatelet effect or a highly protein bound salicylic
acid might displaces warfarin from albumin-binding
sites and thus increases the risk of bleeding (Wosilait,
1976). Though, some studies have failed to find
evidence of such an interaction between the two, (Li et
al., 2006; Pham and Pham, 2007) the documented case
reports corroborated the possibility of interactions. So
it only seems advisable for the patient on warfarin
therapy to avoid or limit the intake of large amount of
Patel and Gohil
cranberry juice, until more data is available.
Saint John’s wort is primarily used for mild to
moderate depression (Woelk, 2000). Evidence suggests that St. John's wort might interfere with warfarin, possibly requiring an increased dosage of the drug
to maintain the proper therapeutic effects. As certain
chemicals found in St. John's wort activate liver
enzymes that are involved in the elimination of some
drugs including warfarin (Maurer, 1999; Jobst et al.,
2000; Jiang et al., 2004; Bressler 2005b). Patients
taking warfarin should consult their doctor before
taking St. John's wort.
Birch bark oil and leaves (Betula species) have
been used in folk medicine for centuries as blood
purifiers, for gout and rheumatism, for hair loss and
dandruff, as flushing-out therapy in bacterial and
inflammatory diseases of the urinary tract, and for
kidney and bladder stones (Fleming, 1998). It contains
high amount of methylsalicylate that is speculated to
affect vitamin K metabolism or displacing warfarin
from protein binding sites resulting in bleeding events
(Beaulieu, 2001).
Coenzyme Q10, also known as ubiquinone or
ubidecarenone, has the structure similar to menaquinone and is postulated to have pro-coagulant
properties, apart from antioxidant properties (Heck et
al., 2000). Coenzyme Q10 supplement is primarily
promoted to treat a variety of cardiovascular conditions including heart failure, hypertension, stable
angina and ventricular arrhythmia. Many patients
suffering from these disorders might also be commonly prescribed warfarin (Bonakdar and Guarneri,
2005; Tran et al., 2001), increasing the likelihood of
interactions with herbs when ingested simultaneously.
The present study consolidated total four cases of
interactions between coenzyme Q10 and warfarin,
assessed as “possible” on Naranjo’s scale. Even
though evidences are not very consistent, patient
receiving concomitant therapy with warfarin and coenzyme Q10 should be closely monitored.
The herb danshen, the root of Salvia miltorrhiza, is
used for treating cardiovascular and cerebro-vascular
diseases in traditional Chinese medicine (Zhou et al.,
2005). Danshen might increase the risk of bleeding
when used with anticoagulants or antiplatelet drugs as
it was reported to inhibit platelet aggregation and
cause excessive blood-thinning effects in patients
taking warfarin (Chan, 2001; Cheng, 1999). Thus
preliminary evidence plus the case reports consolidated in the present study suggested that danshen can
dangerously increase the effects of warfarin and cause
significant bleeding problems and it should only be
92
used under close medical supervision by patients on
warfarin therapy.
Garlic (Allium sativum) is another herb, which is
thought to provide cardiovascular benefits and utilized
to lower cholesterol and blood pressure (Rivlin, 2001,
2006). Garlic oil has been reported to inhibit
thromboxane synthesis thereby by inhibiting the
platelet aggregation (Gadkari and Joshi, 1991). We
assessed three ‘possible’ cases of interactions by
Naranjo’s scale in this study. Patients using warfarin
are also cautioned regarding possible risk of bleeding
with ingestion of garlic.
Three ginseng species -Oriental/Asian ginseng
(Panax ginseng), Siberian ginseng (Eleutherococcus
senticosus)
and
American
ginseng
(Panax
quinquefolius)- are promoted as an adaptogens, a
treatment that is said to help the body adapt to stress
of all types and also as mood and energy boosters
(Ebadi, 2002) the active constituents are ginsenosides
that are believed to inhibit the platelet aggregation and
inhibit the conversion of fibrinogen to fibrin (Attele et
al., 1999). We consolidated three cases for Asian
ginseng of which one as probable and two as possible
cases of interactions where ginseng antagonizes the
anticoagulant effects of warfarin and produce bleeding
in patients. Though mechanism is not exactly known
and the results of several double blind studies were
conflicting (Yuan et al., 2004; Jiang et al., 2005), it is
reasonable to recommend the caution while combining
ginseng and warfarin.
The herb saw palmetto (Serenoa repens) is rich in
fatty acids and phytosterols, is shown to be effective
in the management of benign prostatic hyperplasia
including reduction of urinary frequency, increase in
urinary flow and decrease in nocturia (Wilt et al.,
1998; Bressler, 2005a). Three ‘possible’ cases of saw
palmetto interaction with warfarin were assessed on
Naranjo’s scale in this study. Patients taking warfarin
should consult their physician before taking saw
palmetto because of the risk of increased anticoagulant effect of drug and the potential bleeding.
Several vitamins may also interfere with the effect
with warfarin on concomitant administration
(Schrogie, 1975). A high dose of vitamin C (more
than 1 000 mg daily) has been reported to reduce the
blood-thinning effect of warfarin (Smith et al., 1972).
Three cases consolidated in this study were assessed
as ‘possible’ interactions on Naranjo’s scale. On the
contrast, Vitamin E might add to the effects of warfarin leading to abnormal bleeding (Corrigan and
Marcus, 1974; Kim and White, 1996). Though there
are no case reports available, it is suggested that
Patel and Gohil
vitamin D increases the activity of anticoagulants and
that this interaction could prove dangerous. Vitamin A
supplements might also increase the blood-thinning
effects of warfarin leading to potential risk of abnormal bleeding (Harris, 1995; Pederson et al., 1991;
Chow et al., 1990). On the other hand, Vitamin K
directly counteracts effect of warfarin since the drug
slows blood clotting by interfering with vitamin K
activity (Chow et al., 1990). This is true not only for
supplemental vitamin K but also for the foods high in
vitamin K content. For this reason, eating more
vitamin K rich vegetables can decrease the therapeutic
effect of warfarin, and eating less of these foods can
increase the drug's effect (Pederson et al., 1991; Chow
et al., 1990). Either situation is potentially risky.
People taking warfarin should consult their physician
before taking these vitamin supplements.
The herb dong quai (Angelica sinensis) is used for
menstrual disorders (Clara et al., 2005; Hirata et al.,
1997; Fugh-Berman, 2000). Dong qui might add to the
blood-thinning effects of warfarin, thus increasing the
risk of abnormal bleeding and if used together
requiring caution (Smolinske, 1999).
Ginkgo biloba has been used to Alzheimer's
disease, failing memory, age-related dementias, poor
cerebral and ocular blood flow, congestive symptoms
of premenstrual syndrome, and the prevention of altitude sickness (McKenna et al., 2001; Kleijnen and
Knipschild, 1992; Chung et al., 1987). Inconsistent
evidences suggest that the active constituent
ginkgolide B might inhibit the platelet aggregation
possibly, increasing the tendency toward bleeding
(Kohler et al., 2004; Kudolo et al., 2002, 2005; Bal et
al., 2003; Rosenblatt and Mindel, 1997). These
findings raised the concern that ginkgo might add to
the blood-thinning effects of warfarin (Vale, 1998)
and discretion necessitates physician supervision
before combining ginkgo with warfarin therapy.
Green tea (Camellia sinensis), also known as
Chinese tea is a powerful antioxidant, recently
promoted for its anticancer, cardio-protective positive
cognitive and gastrointestinal effects (Lifer 2005). It
contains significant amount of vitamin K, which
directly interferes with warfarin's blood-thinning
action (Ali et al., 1990). Therefore, it is suggested that
drinking large amounts of green tea simultaneously
might reduce the therapeutic effects of the drug. In the
present study, we assessed one probable and one
possible case of interaction between green tea and
warfarin.
We consolidated two documented cases assessed
as ‘possible’ interactions between papain and warfarin
93
in this study. Papain, an enzyme extract of papaya
(Carica papaya), which has been used for a variety of
ailments: diarrhea, edema, symptoms of herpes zoster
and psoriasis was associated with significant increased
in INR and potentiation of warfarin effects (Emeruwa,
1982). So it is suggested that patients on warfarin
therapy should avoid papain supplements in large
amount until further information about this potential
interaction becomes available.
The herb devil’s claw (Harpagophytum
procumbens) is promoted for use in treatment of
various types of arthritis, gout, myalgia and digestive
problems (Brien et al., 2006). The report documented
in this study was assessed as ‘possible’ on Naranjo’s
scale suggested that the herb might inhibit the platelet
aggregation and increase the effect of warfarin
resulting in abnormal bleeding. No other details pertaining to other medication taken or duration of
warfarin were given in the case, making it difficult to
interpret if the alternate causes were responsible but it
seem advisable for the patients to avoid devil’s claw
or do so strictly under medical supervision while on
warfarin therapy.
There is one published case report in which
ingestion of a Chinese herbal infusion made from
Lycium barbarum appeared to interfere with the effect
of warfarin (Lam et al., 2001). In another published
case report, the Chinese herbal product quilinggao
(Fritillaria cirrhosa, Paeoniae rubra, Lonicera
japonica or Poncirus trifoliate) increased the action of
warfarin (Wong and Chan, 2003). Both cases were
documented as ‘probable’ on Naranjo’s scale in the
present study. There are many different brands and
compositions of quilinggao. Patients on warfarin
therapy should exercise care while using quilinggao
product or Chinese herbal infusion and inform the
physician about the same to avoid any bleeding
episodes.
Another ‘probable’ interaction assessed in this
study was between soy and warfarin indicating that
soy milk might decrease warfarin’s effectiveness
(Cambria-Kiely, 2002). At the same time, a case report assessed as ‘possible’ interaction in this study
indicated that the use of royal jelly can increase the
effectiveness of warfarin, creating risk of bleeding
(Lee and Fermo, 2006). It may be best to avoid these
combinations except under medical supervision.
The herb feverfew is primarily used for the prevention and treatment of migraine headaches, arthritis
and various types of allergies (Makheja and Bailey,
1981). Several in vitro studies suggested that feverfew
thins the blood by interfering with the ability of blood
Patel and Gohil
platelets to clump together (Biggs et al., 1982;
Loesche et al., 1988; Heptinstall et al., 1987, 1988;
Sumner et al., 1992; Groenewegen and Heptinstall,
1990). This raised the concern that feverfew might
increase the risk of abnormal bleeding when combined
with warfarin. Although there were no isolated cases
of feverfew interacting with warfarin in humans, we
assessed one case report involving boldo-fenugeek
(Trigonella foenum graceum) combination (Lambert,
2001), assessed as ‘probable’ on Naranjo’s scale.
Patients are advised to be vigilant while using them
simultaneously.
The herb chamomile (Matricaria recutita), most
commonly used as a sedative, antispasmodic, antiinflammatory and wound-healing agent contains
substances in the coumarin family (O’Hara et al.,
1998; Shamseer et al., 2006) having blood thinning
actions that could interact with warfarin. One interaction between the two was assessed as ‘possible’ on
Naranjo’s scale in this study.
Some other herbs thought to contain coumarin or
coumarin components include angelica root, arnica
flower, anise, asafoetida, celery, horse chestnut,
licorice root, lovage root, parsley, passionflower,
quassia, red clover, sweet clover and rue (Jellin et al.,
1999; Blumenthal et al., 1998; Olin and Hebel, 1999;
Miller 1998; Ulubelen et al., 1988). Also, meadowsweet, poplar, and willow bark contain high
concentrations of salicylates, while bromelain, clove,
onion, have been reported to exhibit antiplatelet
activity (Jellin et al., 1999; Blumenthal et al., 1998).
Borage seed oil contains glinoleic acid, which may
increase coagulation time (Guivernau et al., 1994).
Bogbean has been noted to demonstrate hemolytic
activity (Kowalak and Mills, 2001), capsicum has
been
reported
to
cause
hypo-coagulability
(Visudhiphan et al., 1982) and turmeric have also been
reported to exhibit antiplatelet activity (Lee, 2006).
Ginger may decrease thromboxane production and
prolong bleeding time (Srivastava, 1984; Lumb, 1994;
Afzal et al., 2001). It is suggested that a specific
kavalactone, kawain in herb kava-kava may decrease
thromboxane 2 production and inhibit cyclooxygenase, indicating that it may have significant inhibitory
effect on platelet aggregation (Ulbricht et al., 2005).
Grape seed and grape skin extracts might have
antiplatelet effects and might prolong PT and INR
(Shanmuganayagam et al., 2002). Preliminary evidence suggested that frequent consumption of mango
too might interfere with the effect of warfarin
(Monterrey-Rodriguez, 2002). There have been no
documented case reports of an interaction of warfarin
94
with any of the above-mentioned herbs and further
study is needed to confirm these potential interactions
and assess their clinical significance. However,
patients taking any products containing these herbs
concurrently with medications with anticoagulant
effects, such as warfarin, should be closely monitored
for signs or symptoms of bleeding.
In the past, very few reports related to herb-drug
interactions are reported and many of the reactions
could only be explained theoretically. Recently,
however, several cases of possible herb drug interactions are reported as the use of herbs is increasing day
by day. The shortcomings of many such reported
cases of herb drug interactions are lack of proper
documentations and incompleteness of reports. For
example, in many cases, mechanisms and causality are
uncertain and unpredictable, which makes it rather
difficult to evaluate the report reliabilities of potential
interactions. Also, unlike conventional drugs, herbal
products are not regulated for safety, efficacy, purity
and potency, and are not subjected to approval process
of the FDA. Some of the adverse effects and
interactions reported for herbal products could also be
caused possibly by impurities like allergens, pollens
and spores or batch-to-batch variability (Anonymous,
1994; Angell and Kassirer, 1998). Thus, a lack of
adequate information in most cases makes it very
difficult to determine whether a particular herb drug
interaction has occurred, and may or may not imply
the herbs as culprits when co-administered with
warfarin. One or two reports may not warrant absolute
contraindication to combination of herbs and warfarin
but the precautions must be exercised while using
herbal products with warfarin to avoid any harm by
such potential interactions herbal products should be
analyzed to confirm their contents. Patients on warfarin should inform their physicians about any simultaneous herb use. Such patients should be regularly
monitored and properly informed by physicians,
pharmacists or other health-care providers, about the
adverse events that may occur with simultaneous
ingestion of herbs and prescription medicines like
warfarin. Patients could be advised to avoid herbwarfarin combinations altogether when absolute
necessary for which adverse events and interactions
are reported frequently. In case, when adequate information is not available then advising them to have a
reasonable time period of 2 to 3 hours between administrations of herb in question and warfarin. This
should be followed by frequent monitoring of PT time
and INR test regularly in patients on warfarin therapy.
Patel and Gohil
Because of widespread use of the herbs today,
number of documented case reports of herb drug
interactions are rising every year, however, many
cases of herb-drug interactions may even go unreported and actual number of cases might be much
higher than reported. Despite this, a limited research
in this area entails that cases are properly reported,
carefully evaluated and constantly reviewed for regular update. More research on warfarin-herb interactions seems to be a matter of urgent concern. The
health professionals who suspect any such serious
interactions of drugs such as warfarin with any herbal
products should be encouraged to report them to local
pharmacovigilance center to promote the vigilance in
this area.
CONCLUSION
It is difficult to interpret data about interactions
between herbs and warfarin as the evidence is mainly
based on animal studies or individual cases rather than
large-scale human studies. While, the consistency of
such reports still needs to be weighed up, the
interactions with herbs should be closely monitored.
Additional research is urgently needed in order to
explore the range of possible effects from herbwarfarin interactions in patients. Nevertheless, combining anticoagulant medicines with herbs appears to be
the risky proposition. The number of herbs reported to
interact with warfarin continues to expand. Patients on
warfarin are specifically advised to avoid taking
herbal medicines or to have their INR measured
within two weeks of starting the product to be on safer
side.
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© 2008 Los Autores
Andrographis paniculata: a review of aspects of regulatory mechanisms
of hepatic CYP1A enzymes
[Andrographis paniculada: una revisión de los aspectos de los mecanismos reguladores
de las enzimas hepáticas CYP1A]
Kanokwan JARUKAMJORN*,#
*Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002 Thailand.
#Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194 Japan.
*Contact: E-mail: [email protected]; [email protected]
Submitted February 13, 2008; Accepted February 29, 2008
Abstract
Cytochrome P450 (CYP) enzymes are involved in the biotransformation of a plethora of structurally diverse compounds of both endogenous
and exogenous as well as numerous interactions between drugs and food, herbs and other drugs. CYP1A participates in the metabolic
activation of chemical mutagens from daily exposure to tobacco smoke, cooked food, automobile exhaust, and industrial processes, in which
its mechanism of transcriptional regulation has been postulated through an arylhydrocarbon receptor (AhR) and the AhR nuclear translocator.
The activity of CYP1A is thus suspected to be not only a critical aspect for risk assessment when determining carcinogenicity, but also a
considerable safety criterion for drug development testing. Andrographis paniculata, a folklore remedy employed as an herbal supplement
for an alternative medicinal therapy or for health promotion including its major diterpenoid constituent andrographolide has been reported to
possess several pharmacological activities. Besides the potentials for the treatment of ailments, the crude extract of Andrographis paniculata
has exhibited capability to increase hepatic CYP1A enzymes including ethoxyresorufin and methoxyresorufin activities, in accord with the
inductive effects conveyed by andrographolide. Strong synergistic induction of CYP1A1 by co-treatment with andrographolide and a typical
CYP1A inducer as well as a robust increase of CYP1A1 by andrographolide in which the induction was blocked by an AhR antagonist
resveratrol, affirmed participation of AhR-mediated transcription activation on andrographolide-induced CYP1A1 expression. Therefore,
some advice and precautions for rational use of Andrographis paniculata and/or andrographolide including some associated risks are of clear
concern. Moreover, investigations not restricted to the AhR-mediated pathway revealing the synergistic mechanism of andrographolide on
CYP1A1 induction as well as influences of other confounding substances in this herb and andrographolide analogues, which may contribute
modulatory effects on regulation of P450s machinery, are needed and are yet to be elucidated.
Keywords: Andrographis paniculata, andrographolide, AhR, CYP1A1, CYP1A2, CYP1B1, EROD, MROD, PROD, P450, UGT1A6.
Resumen
Las enzimas del citocromo P450 (CYP) están involucradas en la biotransformación de una plétora de compuestos, tanto endógenos como
exógenos, de estructuras diversas así como numerosas interacciones entre fármacos y alimentos, hierbas y otros fármacos. El CYP1A
participa en la activación metabólica de mutágenos químicos de exposición diaria como el humo de tabaco, los alimentos cocidos, la descarga
automovilística y los procesos industriales en los cuales el mecanismo de acción de regulación transcripcional ha sido postulado a través de
un receptor aril-hidrocarbono (AhR) y el translocador AhR nuclear. Se sospecha que la actividad de CYP1A no es solamente un aspecto
crítico para la evaluación de riesgo cuando se determina carcinogenicidad, también es un criterio considerable de seguridad para evaluar el
desarrollo de un fármaco. Andrographis paniculata, un remedio del folklore empleado como un suplemento herbario para una terapia
medicinal alternativa o para la promoción de salud incluye su mayor constituyente el diterpenoide andrografolide el que posee varias
actividades farmacológicas. Además de las potencialidades para el tratamiento de dolencias, el extracto crudo de Andrographis paniculata ha
demostrado la capacidad de aumentar las enzimas CYP1A hepáticas incluidas las actividades etoxiresorufina y metoxiresorufina, de acuerdo
con los efectos inductores llevados a cabo por andrografolide. La fuerte inducción sinérgica de CYP1A1 por co-tratamiento con
andrografolide y un típico inductor de CYP1A, así como un gran incremento de CYP1A1 por andrografolide en el cual la inducción fue
bloqueada por un antagonista AhR, resveratrol, afirmó la participación de la activación transcripcional mediada por AhR sobre la expresión
de CYPA1 inducida por andrografolide. Por consiguiente, son de preocupación clara algunos consejos y precauciones para el uso racional de
Andrographis paniculata y/o andrografolide que incluyan algunos riesgos asociados. Además, necesitan ser elucidadas las investigaciones no
restringidas a la vía mediada por AhR que revela el mecanismo sinérgico de andrografolide sobre la inducción de CYP1A1 así como las
influencias de otras sustancias presentes en esta hierba y análogos de andrografolide, los cuales pueden contribuir a los efectos moduladores
sobre la regulación de la maquinaria de CYPs.
Palabras clave: Andrographis paniculata, andrografolide, AhR, CYP1A1, CYP1A2, CYP1B1, EROD, MROD, PROD, P450, UGT1A6.
Potential of Andrographis paniculata on CYP1A induction
Jarukamjorn
Abbreviation list:
AhR- aryl hydrocarbon receptor;
β-NF- β-naphthoflavone;
HAA- heterocyclic arylamines;
MROD- methoxyresorufin O-deethylase;
ROS- reactive oxygen species;
ARNT- AhR nuclear translocator;
DRE- dioxin responsive element;
iNOS- inducible nitric oxide synthase;
PAH- polycyclic aromatic hydrocarbons;
TCDD- 2,3,7,8-tetrachlorodibenzo-p-dioxin;
INTRODUCTION
Mammals are equipped with a variety of enzymes
that catalyze the transformation of xenobiotics to
form, in general, more polar metabolites that are
more readily excreted. The concept of phase I and
phase II biotransformations, which captures the
general view of metabolism of foreign compounds as
a detoxification process, was introduced in the 1970s
(Williams, 1971). Briefly, phase I proceeds by
oxidative, reductive, and hydrolytic pathways, and
lead to the introduction of a functional group (OH,
SH, NH2, or COOH) and to a modest increase of
hydrophilicity, while phase II modifies the newly
introduced functional group to form O- and N-glucuronides, sulfate esters, various α-carboxyamides, and
glutathionyl adducts, all with increased polarity
relative to the unconjugated molecules (Parkinson,
1996). Although most biotransformations that xenobiotics undergo lead to polar, less toxic metabolites, a
consideration of the structural features and toxic
effects of certain compounds suggested that these
same biotransformation pathways may also generate
chemically reactive species that mediate the toxic
effects of the parent compounds. Thus catalytic pathways that usually protect mammals against the
toxicity of lipophilic organic compounds can, when
the structural features of the substrate molecules
contain latent chemical reactivity, lead to exerting
toxicity (Mabic et al., 1999). This process is referred
to as metabolic activation, bioactivation, or toxification (Miller and Guengerich, 1982; Caldwell and
Jakoby, 1983; Ander, 1985; Vermeulen et al., 1992;
Vermeulen, 1996). Metabolism in the body
apparently plays a dual role in the handling of and
protection against exogenous compounds. In most
cases, toxic (chemically reactive) intermediates will
be detoxified or bioinactivated at their site of
formation, but under circumstances of inefficient
detoxification, via primary reaction with cellular
constituents, however, they can induce biochemical
and physiological changes, which may lead to toxic
effects such as cell damage, cell death, or tumor
genesis (Caldwell and Jakoby, 1983; Ander, 1985).
B[a]A- benz[a]anthracene;
EROD- ethoxyresorufin O-deethylase;
Mac- membrane-activated complex;
CYP- cytochrome P450;
UGT- UDP-glucuronosyltransferase.
The toxic manifestations of xenobiotics are a
consequence of induction of phase I and II enzymes,
especially when induction above the basal level of
phase I enzymes is not followed by an increase in
phase II conjugating activity. Organisms have
amplified various existing metabolic mechanisms to
counteract and eliminate the toxicity and
carcinogenicity of xenobiotics such as drugs and
environmental contaminants.
The cytochrome P450 1 family
A central mechanism of detoxification is oxidative
metabolism by cytochrome P450s (CYP), members
of the hemethiolate monooxygenase gene superfamily (Honkakoski and Negishi, 1997). Induction of
hepatic CYPs rationalizes the activation of innocuous
and/or hazardous chemicals to serve as a substrate for
the action of phase II bio-transformation (Gibson and
Skett, 2001). Humans are exposed to harmful foreign
chemicals and materials from dietary, therapeutic,
environmental, and occupational sources. Defense
mechanisms have evolved to protect against toxic
insults per se. The CYP superfamily is the most important enzyme system in terms of phase I-catalyzed
oxidative biotransformations that result in the
formation of biologically reactive metabolites
(Gonzalez and Gelboin, 1994). There are multiple
CYP enzymes that catalyze activation of a number of
environmental pro-carcinogens to ultimate carcinogenic metabolites (Guengerich and Shimada, 1998;
Guengerich, 2000). CYP1A1, CYP1A2, and
CYP1B1 have been shown to be the major enzymes
in the metabolism of potential pro-carcinogens such
as polycyclic aromatic hydrocarbons (PAHs), nitroPAHs, and aryl and heterocyclic arylamines (HAA)
(Gelboin, 1980; Petry et al., 1996; Shimada et al.,
1996; Sjogren et al., 1996; Shimada et al., 2002).
Oxygenation of carcinogenic PAH and HAA (procarcinogens) gives rise to arene oxides, diol epoxides,
and other electrophilic reactive species (ultimate
carcinogens) that form DNA and protein adducts,
leading to tumor formation and toxicity (Gelboin,
1980; Miller and Miller, 1981; Conney, 1982; Jerina,
1983). The levels of CYP enzymes in individuals
101
have been reported to be one of the key determinants
in understanding different susceptibilities of humans
to chemical carcinogenesis (Pelkonen and Nebert,
1982; Guengerich, 1988; Hecht, 1999; Shimada,
2000; Guengerich, 2000). In addition to being
substrates, PAHs are also inducers of CYP1A1 and
CYP1A2 genes. The mechanisms of transcriptional
regulation of these two genes are not the same.
CYP1A1 is expressed constitutively in several
extrahepatic tissues, but not in the liver. However,
while CYP1A1 expression has been demonstrated in
the liver after inducer treatment, CYP1A2 is
constitutively and inducibly expressed only in the
liver (Kimura et al., 1986; Iwanari et al., 2002). Aryl
hydrocarbon receptor (AhR) has been shown to play
central roles in the regulation and induction of
CYP1A1 and CYP1A2 by a prototype inducer,
2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD; Whitlock, 1999). In addition to the two members of the
CYP1A subfamily, CYP1B1, a relatively new
member of the superfamily 1 (Savas et al., 1994;
Brake, 1999; Ryu and Hodgson, 1999), has been
postulated to be involved in the metabolism of PAHs
such as TCDD through AhR and the AhR nuclear
translocator (ARNT)-mediated pathway (Savas et al.,
1994; Ryu and Hodgson, 1999). Constitutive
expression of CYP1B1 was detected in steroidogenic
tissues such as adrenal glands, ovaries, and testes, but
it was not detected in xenobiotic-metabolizing organs
such as liver, kidney, and lung (Iwanari et al., 2002;
Savas et al., 1994). Since CYP1 is responsible for
activating carcinogenic aromatic amines and heterocyclic amines, to which we are exposed to every day
via tobacco smoke, cooked food, automobile exhaust,
and industrial processes where such exposures have
been causatively linked to an increased incidence of
cancers in certain population (Procter, 2001), the
metabolic activation of CYP1 is a critical step for risk
assessment of cancer, and its regulation is also of
clear interest.
Phytomedicine: Andrographis paniculata
An herb is a plant or plant part used for its scent,
flavor, or therapeutic properties. Herbal medicinal
products are dietary supplements that are taken to
improve health. Many herbs have been used for a
long time for claimed health benefits. Herbs are eaten
in combinations, in relatively large, unmeasured
quantities under highly socialized conditions. The
real challenge lies not in proving whether herbs have
health benefits, but in defining what these benefits
Jarukamjorn
are and developing the methods to expose them by
scientific means (Tapsell et al., 2006).
The metabolism of a drug can be altered by
another drug or foreign chemical and such interactions can often be clinically significant. The
observed induction and inhibition of CYP enzymes
by natural products in the presence of a prescribed
drug has (among other reasons) led to the general
acceptance that natural therapies can have adverse
effects, contrary to the popular beliefs. Herbal
medicines such as St. John’s wort (Hypericum
perforatum), garlic (Allium sativum), ginseng (Panax
ginseng), echinacea (Echinacea angustifolia, E.
purpurea, E. pallida), saw palmetto (Serenoa
repens), and ginkgo (Ginkgo biloba) have given rise
to serious clinical interactions when co-administered
with prescription medicines (Obach, 2000; Izzo and
Ernst, 2001; Delgoda and Westlake, 2004; Strandell
et al., 2004). Such adversities have spurred various
pre-clinical and in vitro investigations on a series of
other herbal remedies, with their clinical relevance
remaining to be established. Although the presence of
numerous active ingredients in herbal medicines
complicates experimentation, the observable interactions with CYP enzymes warrant systematic
studies. Hence metabolism-based interactions can be
predicted and potential adverse drug reactions
avoided more readily.
Andrographis paniculata Nees. (Family Acanthaceae), traditionally employed for centuries in Asia
and Europe as a folklore remedy for a wide spectrum
of ailments, or an herbal supplement for health
promotion, is nowadays incorporated into a number
of herbal medicinal preparations. It is found in the
Indian Pharmacopoeias and is a prominent component in at least 26 Ayurvedic formulas (Madav et
al., 1995). In traditional Chinese medicine, it is an
important “cold property” herb used to rid the body
of heat, as in fevers, and to dispel toxins from the
body (Deng, 1978). In Scandinavian countries, it is
commonly used to prevent and treat the common cold
(Caceres et al., 1997). Andrographis paniculata is
one of the top 10 herbal medicines, which the Thai
FDA has promoted as an alternative medicinal
therapy for fever and inflammation.
Andrographolide is the most medicinally active
phytochemical found in the plant, including other
constituents such as deoxyandrographolide, 19β-Dglucoside, neo-andrographolide, 14-deoxy-11,12-didehydroandrographolide, homoandrographolide, andrographan, andrographosterin, and stigmasterol
(Cava et al., 1965; Chem and Liang, 1982; Shama et
102
al., 1992; Siripong et al., 1992). Extensive research
has revealed that the whole-plant extract possesses
many useful bioactivities, such as anti-inflammatory
(Shen et al., 2002), antiviral (Calabrese et al, 2000),
anticancer (Kumar et al., 2004), and immunostimulatory (Puri et al., 1993; Iruretagoneya et al.,
2005) activities. On the other hand, male reproductive toxicity (Akbarsha and Murugaian, 2000) and
cytotoxicity (Nanduri et al., 2004) of this plant have
been reported as well. Pharmacokinetic studies
showed that andrographolide is quickly absorbed and
extensively metabolized in rats and humans
(Panossian et al., 2000). Andrographolide metabolites
are mainly identified as sulfonic acid adducts and
sulfate compounds (He et al., 2003a, b, c), as well as
glucuronide conjugations (Cui et al., 2005). One of
the metabolites, 14-deoxy-12(R)-sulfoandrographolide, was reported to be identical to the antiinflammatory drug, Lianbizhi, which being clinically
used in China (Meng, 1981). To gain additional
insight into metabolic pathway of Andrographis
paniculata, study of its components within the
chemical pool of the plant affecting regulatory
pathway of CYPs expression is of current interest.
Potential of Andrographis paniculata on CYPs
induction
Besides attempts to determine the regulatory
mechanism of CYPs expression by chemicals or
endogenous factors, herbal medicines and/or their
active constituents, as well as chemical-herbal medicine interactions are worth investigating to discover
their influences on the regulatory pathway of CYPs
expression. Understanding such regulation may
ascertain how restoration of health or recovery from
disease can be accomplished by consuming herbal
medicines.
Phytochemicals present in herbal medicines have
been reported to possess many pharmacological
activities. Extensive studies have been performed to
explore their potential for treatment or prevention of
ailments. The aerial parts of Andrographis paniculata
have been traditionally used as a hepatoprotective
and hepatostimulative agent in Southeast Asian
folklore remedy to treat a broad range of disorders
including liver disorders and jaundice (Kapil et al.,
1993; Trivedi and Rawal, 2000). The extract of
Andrographis paniculata including andrographolide,
a major diterpenoid component and its analogues
have been reported to exhibit a marked effect on
hepatic bio-transformation enzymes, i.e., aniline
hydroxylase, N- and O-demethylase (Choudhary and
Jarukamjorn
Poddar, 1984), alanine aminotransferase and
aspartate aminotransferase (Trivedi and Rawal,
2000), including phase II enzymes, i.e., glutathione Stransferase and DT-diaphorase (Singh et al., 2001).
Modulatory influence of Andrographis paniculata
extract on a responsive isoform of hepatic CYPs was
recently reported in mouse hepatic microsomes
compared to typical CYP-inducers (3-MC for
CYP1A and PB for CYP2B), in terms of total CYP
content and related alkoxyresorufin O-dealkylase
activities (Jarukamjorn et al., 2006). In mice
administered with either the aqueous or alcoholic
extract of Andrographis paniculata including 3-MC
treated mice, the CYP content was comparable to the
untreated mice, whereas for those PB treated, the
CYP content was markedly increased. The purified 3MC-induced CYP1A1 and CYP1A2 showed substrate-selectivity for ethoxyresorufin and methoxyresorufin, respectively (Burke et al., 1994), while that
of pentoxyresorufin was selectively measured
CYP2B10 in PB-induced microsome (Sakuma et al.,
1999; Jarukamjorn et al., 1999). 3-MC significantly
increased EROD and MROD, whereas PROD was
markedly elevated by PB. With respect to treatmentduration, the increase of EROD and PROD activities
by the extract of Andrographis paniculata show a
time-dependent pattern (Jarukamjorn et al., 2006).
These results conveyed CYP1A1 and CYP2B10 as
responsive CYP isoforms for Andrographis paniculata.
How the components within the chemical pool of
the crude extract of Andrographis paniculata affect
the hepatic CYP pathway is not well understood; to
date evaluation of the individual chemical components present in the plant extract on the aspect of
specific CYP isoforms has not been carried out. The
impact of andrographolide, a major diterpenoid
isolated from this plant, on hepatic CYP enzymes,
especially CYP1 family, is further crucial step in the
field of bio-tranformation and drug interaction. The
results of such an inquiry might provide valuable
guidelines for the rational administration and precautions for the use of the herbal plant. Moreover,
since several confounding substances in the crude
extract contribute effectively in a synergistic or antagonistic pattern to the expression of bioactivation and
detoxification machinery as well as the hepatic
microsomal CYP-associated activity’s profile, their
inserted pathways cannot be precluded.
103
Impact of andrographolide on CYP1 family
Andrographolide (3-[2-[decahydro-6-hydroxy-5(hydroxylmethyl)- 5,8a-dimethyl-2-methylene-1-napthalenyl]ethylidene] dihydro-4-hydroxy-2(3H)-furanone) is the major diterpenoid constituent of the plant
Andrographis paniculata, and has been reported to
show hepatoprotective activity in mice against carbon
tetrachloride and paracetamol intoxication (Handa
and Sharma, 1990a; Handa and Sharma, 1990b), and
to possess pharmacological activity, including
inhibition of iNOS expression (Chiou et al., 1998;
Chiou et al., 2000), Mac-1 expression, and ROS
production (Shen et al., 2000; Shen et al., 2002), and
a protective effect against cytotoxicity (Kapil et al.,
1993). This compound has recently been shown to
work as an anti-inflammatory agent by reducing the
generation of ROS in human neutrophils (Shen et al.,
2002), as well as preventing microglia activation
(Wang et al., 2004) and interfering with T cell
activation (Iruretagoneya et al., 2005).
The different mechanisms of transcriptional
regulation among CYP1A1, CYP1A2, and CYP1B1
(Guengerich and Shimada, 1998; Iwanari et al.,
2002), explained the observations that andrographolide-inducibility of the expression of those
isoenzymes differed: andrographolide extensively
induced CYP-1A1 expression, while it induced
CYP1A2 less markedly, and did not induce CYP1B1
expression (Jaruchotikamol et al., 2007). Andrographolide significantly up-regulated the expression
level of CYP1A1 mRNA, protein, and enzyme in a
concentration-dependent manner in monolayer-cultured hepatocytes. In addition, a robust increased
expression of UGT1A6 mRNA, which belongs to a
battery of AhR-mediated genes by andrographolide
was noted (our unpublished observations). Cotreatment with andrographolide and B[a]A synergistically enhanced the expression of CYP1A1 mRNA, in
which the expression was blocked by resveratrol, an
AhR antagonist (Jaruchotikamol et al., 2007). These
observations hint at the possibility that an AhRmediated transcription activation pathway participates in the synergistic effect of concomitant treatment with andrographolide and B[a]A on CYP1A1
mRNA expression. The increase of luciferase activity
seen in TCDD-treated cells transfected with the
3×(DRE), with no enhancement by co-treatment with
andrographolide, supported a possibility of andrographolide induced CYP1A1 after AhR activation.
Therefore, andrographolide might influence the
expression mechanism of CYP1A1 by enhanced
Jarukamjorn
efficiency of mRNA processing or inhibition of
mRNA turnover.
CONCLUSION AND PERSPECTIVES
As alteration of CYP activities lead in some cases
to severe clinical events, an approach to investigating
the effects of herbal medicines on the regulation of
CYP enzymes and determining critical potential
CYPs interaction with pharmaceuticals are of clear
necessity. For example, reduction of an HIV-1
protease inhibitor indinavir by St John's wort could
lead to the development of drug resistance and
treatment failure (Izzo and Ernst, 2001).
Compared with the typical CYP1A inducers,
andrographolide, a single substance extracted from
Andrographis paniculata, interestingly demonstrated
a marked synergistic modification of the induction of
CYP1A1 mRNA expression (Jaruchotikamol et al.,
2007). The expression of CYP1A1 markedly
influences the activation of human-related chemical
carcinogens (Kimura et al., 1986; Nemoto et al.,
1989; Nemoto and Sakurai, 1992; Iwanari et al.,
2002). Some possible advice for the rational
administration and precautions for using the herbal
medicine Andrographis paniculata, therefore, is
considerably recommended. Moreover some risks
associated with the use of Andrographis paniculata
or andrographolide might be of clear interest, and
further evaluation of andrographolide analogs and/or
their metabolites seems worthwhile. However, since
resveratrol possesses several pharmacological actions, which suggests involvements of several
signaling pathways (Chun et al., 1999; Le Corre et
al., 2006; Park et al., 2007), further investigations not
restricted to the AhR-mediated pathway to reveal the
synergistic mechanism might be of value and awaits
elucidation.
A couple of recent publications concerning
CYP1A induction and drug development testing
stated that a candidate drug, which exhibited CYP1A
inducibility might be generally discontinued for fear
of possible toxic or carcinogenic effects (Nebert et
al., 2004; Uno et al., 2004). However, although
potential induction of drug-drug interactions and
bioactivation of toxic or carcinogenic compounds due
to the induction of CYP1A1/CYP1A2 have been a
concern for safety in drug development, induction of
CYP1A has rarely been the deciding factor to
determine whether a compound should be dropped
for further testing because of its inducibility of
CYP1A (Valles et al., 1995; Gastel, 2001). In the
104
field of drug development, a drug candidate is
dropped only if it has very serious safety issues or
clinically relevant drug-drug interactions (Farrell and
Murray, 1990). According to these controversies,
some advice for the rational administration, risks, and
precautions for using the herbal medicine Andrographis paniculata and/or andrographolide should be
heeded.
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107
© 2008 Los Autores
Interactions between antiepileptic drugs and herbal medicines
[Interacciones entre fármacos antiepilépticos y medicinas herbales]
Cecilie JOHANNESSEN LANDMARK1 and Philip N. PATSALOS2*
1
2
Department of Pharmacy, Faculty of Health Sciences, Oslo University College, Oslo, Norway.
Pharmacology and Therapeutics Unit. Department of Clinical and Experimental Epilepsy, Institute of Neurology, Queen Square, London
and Chalfont Centre for Epilepsy, Chalfont St Peter, Chesham Lane, Buckinghamshire, SL9 ORJ,UK.
Abstract
As a therapeutic class, antiepileptic drugs (AEDs) have a high propensity to interact and many interactions with concomitant medications
have been described. Increasingly, herbal medicines are often used by patients with epilepsy and the risk that these may interact with their
AED medication is now being realised. The purpose of this review is to highlight the interactions that have been reported between AEDs and
herbal medicines. Overall, the published data are sparse and comprise of both pharmacodynamic (preclinical only) and pharmacokinetic
(preclinical and clinical) interactions. Pharmacodynamic interactions between diazepam and the Chinese herb Saiboku-to and with Ginkgo
biloba, and between phenytoin, valproate and gabapentin and Centella asiatica have been described. Pre-clinical studies suggest that the
Japanese herbs Sho-seiryu-to and Sho-saiko-to, the herbal infusion preparation from Cassia auriculata, the traditional Chinese herbal
medicine Paeoniae Radix and the herb Mentat can affect the pharmacokinetics of carbamazepine by various mechanisms. Pharmacokinetic
interactions have also been reported with phenytoin (Paenoniae Radix, Ayurvedic syrup shankhapushpi), phenobarbital (Ginkgo biloba) and
diazepam (the Chinese herbs Angelica dahurica and Salvia miltiorrhiza Bge). Clinical studies have reported a reduction in serum
carbamazepine concentrations when co-administered with the traditional Chinese herb Free and Easy Wanderer Plus and also a reduction in
serum midazolam concentrations by Echinacea and by St John’s Wort. The mechanism of these interactions is considered to be induction of
hepatic metabolism. In contrast, piperine elevates serum phenytoin concentrations, possibly be enhancing the gastrointestinal absorption of
phenytoin. More research and information are required in order to clarify the propensity of AEDs and herbal medicine to interact and
therefore potentially compromise the therapeutics of AEDs.
Keywords: Antiepileptic drugs, interactions, herbal medicines, Carbamazepine, Phenytoin, Valproate.
Resumen
Los fármacos antiepilépticos (FAE), como una clase terapéutica, tienen una alta propensión a interactuar y se han descrito muchas
interacciones concomitantes con medicamentos. El uso de las medicinas herbales es cada vez más frecuente en pacientes con epilepsia y en la
actualidad se investiga el riesgo de que estas puedan interactuar con estos FAE. En general, los datos publicados son escasos y comprometen
tanto interacciones farmacodinámicas (solamente preclínicas) como farmacocinéticas (preclínicas y clínicas). Se han descrito las
interacciones farmacodinámicas entre diazepam y la hierba china Saiboku-to y con Ginkgo biloba y entre fenitoína, valproato y gabapentina y
Centella asiatica. Los estudios preclínicos sugieren que las hierbas japonesas Sho-seiryu-to y Sho-saiko-to, la infusión de Cassia auriculata,
la hierba medicinal tradicional china Paeiniae Radix y la hierba Mentat pueden afectar la farmacocinética de carbamazepina por varios
mecanismos. Las interacciones farmacocinéticas han sido también publicadas con fenitoína (Paenoniae Radix, sirope ayurvédico
shankhapushpi), fenobarbital (Ginkgo biloba) y diazepam (las hierbas chinas Angelica dahurica y Salvia miltiorrhiza Bge). La reducción de
las concentraciones de carbamazepina en suero cuando es co-administrada con la hierba tradicional china Free and Easy Wanderer Plus ha
sido publicada en estudios clínicos. También se ha estudiado la reducción en suero de las concentraciones de midazolam por Echinacea y la
hierba de San Juan. Se considera que el mecanismo de estas interacciones es a través de la inducción del metabolismo hepático. Por el
contrario, piperina eleva las concentraciones de fenitoína en suero, posiblemente por el aumento de la absorción gastrointestinal de la
fenitoína. Se requiere más información e investigación para esclarecer las interacciones entre los FAE y las medicinas herbales.
Palabras clave: Fármacos antiepilépticos, interacciones, medicinas herbales, Carbamazepina, Fenitoína, Valproato.
Antiepileptic drugs and herbal medicine interations
INTRODUCTION
Antiepileptic drug (AED) interactions with drugs
used in the management of non-epilepsy comorbidities are numerous and common (Patsalos and
Perucca, 2003b). Furthermore, over the counter
medications including herbal medicines (plant-based
remedies) are increasingly being used by patients
with epilepsy and the risks that these may interact
with their AED medication is now being realised.
Also, there are various traditions for the use of herbal
medicines in different parts of the world and
consequently in many countries the potential for
clinically relevant interactions is much greater. A
recent cohort study of 400 patients with epilepsy
reported that 34% had used or were using complementary and alternative medicines for general
health purposes and stated that they believed that
these medicines had little or no effect on their
epilepsy, and the majority of patients (63%) had not
informed their doctor (Easterford et al., 2005).
Because patients may often be unaware of the
interaction potential between AEDs and herbal
medicines and because many patients do not consider
such medicines as drugs, most patients do not inform
their doctor that they are taking these additional
potentially interacting medications. It should be emphasized that most herbal preparations are not
included in the regulatory framework, and a complication is that the quality and quantity of the active
ingredients in herbal medicines is often, variable are
often with unknown additional ingredients and thus
potential interactions may be variable and difficult to
predict (Samuels et al., 2008; Skalli et al., 2007). The
clinical consequence of interactions may be lack of
efficacy, toxic reactions, unexpected effects, unforeseen side effects, and non-compliance, and it is
therefore of major importance for patient outcome.
Vulnerable patient groups should be extra cautious
regarding their increased risk of interactions and
toxic effects, and include the elderly, cancer patients
and pregnant women (Skalli et al., 2007). Both
pregnant women and the elderly undergo changes in
physiological and pharmacokinetic para-meters, and
cancer patients and elderly patients are often
prescribed polytherapy. Also these groups may often
choose herbal medicines in addition or as a substitute
for marketed drugs.
Interactions can be divided into two types,
pharmacodynamic and pharmacokinetic. Pharmacodynamic interactions relate to interactions at the site
of action of a drug and may be additive, synergistic
Johannessen Landmark & Patsalos
or antagonistic in nature. AEDs mainly target
proteins involved in neuronal excitation, via modulation of voltage-gated sodium or calcium channels or
ligand-gated receptors for GABA (γ-amino butyric
acid) and glutamate, or by affecting intracellular
pathways, and most AEDs have several mechanisms
of actions (Johannessen Landmark, 2007). Consequently, there are many sites at which a pharmacodynamic interaction could be elicited. In contrast
pharmacokinetic interactions relate to the processes
of absorption, distribution, metabolism and excretion
and by far the most important site of interaction is
that of metabolism involving cytochrome P450
(CYP) and uridine glucuronyl transferases (UGTs) in
the liver (Patsalos and Perucca, 2003a).
Overall, interactions between AEDs and herbal
medicines are poorly described in the literature
although the widely used herbal medicines Ginkgo
biloba and St. John’s Wort have recently been
reviewed with regards to their interactions with commonly used drugs (Hu et al., 2005). The purpose of
this review is to highlight the interactions between
AEDs and commonly used herbal drugs, including
drugs from traditional Chinese and Japanese (Kampo)
medicine, and also Indian Ayurvedic herbal
preparations. The review first describes the putative
pharmacodynamic interactions followed by the
pharmacokinetic interactions and these in turn are
divided into preclinical and clinical observations.
Search strategy and selection criteria
The present review is based on recently published
articles and searches in PubMed November-January
2008. Relevant peer-reviewed articles in recognized
international journals in English (1987-2007) were
included in the review. Primary sources were preferred, but review articles of specific importance
were also included. Relevant published case reports
were included and also abstracts when a complete
published article was not available. Both preclinical
and clinical findings were included. Furthermore,
searches of the various AEDs in combination with
interactions and herbal medicine were used. The
AEDs included were carbamazepine, diazepam, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, midazolam, phenobarbital (pentobarbital), phenytoin, pregabalin, rufinamide, tiagabine,
topiramate, valproate, and zonisamide.
109
I. PHARMACODYNAMIC INTERACTIONS
Preclinical studies
Diazepam
The mechanism of action of diazepam in that it
acts by binding to the GABAA receptor, a receptor
that is well characterized. Consequently, diazepam is
a drug of choice to study pharmacodynamic interactions with herbal drugs that have yet to be
characterized with regards to their cellular mechanisms of action. Diazepam (1.0 mg/kg s.c.) administered in combination with the Chinese herb
Saiboku-to (2 g/kg/day; traditionally used for cold,
inflammation and anxiety disorders) resulted in a
potentiated anxiolytic-like effect in the rat, which
could not be attributed to alteration in diazepam
blood concentrations or metabolism of diazepam
(Yuzurikara et al., 2002). In another study in rats with
the same compounds, it was suggested that Saibokuto (2 g/kg/day) potentiated the pharmacological effect
of diazepam via an action on the GABAA receptor
(Ikarashi et al., 2002). This was ascertained by
measurement of diazepam-mediated acetylcholine
release in striatum and hippocampus using intracerebral microdialysis, as this release is dependent on
GABAergic activity (Ikarashi et al., 2002). As to
exactly what component of Saiboku-to is responsible
for this effect is unknown since the Saiboku-to
preparation contains 10 different herbs (Ikarashi et
al., 2002).
Diazepam (1.0 mg/kg s.c.) in combination with an
extract from Ginkgo biloba (EGb 761, in single doses
of 1-16 mg/kg i.p. and in repeated doses from 24-96
mg/kg/day p.o.) increased a social contact test in a rat
model to a greater extent than with diazepam alone in
a dose-dependent manner, and this effect was explained by a possible interaction at the GABAA
receptor (Chermat et al., 1997). This herb has traditionally been used to improve blood flow, protect
against oxidative cell damage and to enhance
memory and concentration, although the documentation is conflicting (NIH, 2005). Ginkgo biloba has
also been proposed to have pro-convulsive properties,
as it contains a neurotoxin (a vitamin B6 derivative,
Ginkgotoxin, 4-O-methopridoxine) that inhibits
GABA synthesis via competitive antagonism of pyridoxil phosphate, a coenzyme of the enzyme responsible for the conversion of glutamate to GABA,
glutamate decarboxylase (Samuels et al., 2007).
Phenytoin, valproate and gabapentin
An isobolographic study with phenytoin
(13 mg/kg), valproate (104 mg/kg) and gabapentin
(310 mg/kg) in combination with Centella asiatica
(0.2-0.3 ml of the prepared herbal extract/25 g body
weight; traditionally used to improve circulation and
with putative antibacterial effects) in mice demonstrated additive anticonvulsant activity and a significant decrease in the effective dose of the AEDs
needed for seizure protection, by 62% for phenytoin,
72% for valproate and 75% for gabapentin
(Vattanajun et al., 2005). The pentylenetetrazole test
was used to determine the effective dose, and the
rotarod test was used to determine neurotoxicity, but
blood or brain concentrations of phenytoin, valproate
and gabapentin were not measured (Vattanajun et al.,
2005). The exact mechanism of the pharmacodynamic anticonvulsant potentiation was unknown, a
possible pharmacokinetic contribution at the level of
absorption was excluded since the herb was administered orally and the AEDs intraperitoneally.
Nevertheless, the findings suggest that Centella
asiatica may be used with potential favourable
outcome as an adjunctive medication for patients
with epilepsy (Vattanajun et al., 2005).
Clinical studies
Pharmacodynamic interactions between AEDs and
herbal medicines have not been reported in patients,
and they may be difficult to document and evaluate.
II. PHARMACOKINETIC INTERACTIONS
Preclinical studies
Carbamazepine
Two commonly used Japanese herbs (Sho-seiryuto and Sho-saiko-to) (traditionally used for the
management of inflammation and cold symptoms)
affect the pharmacokinetics of carbamazepine, as
studied in rats (Ohnishi et al., 1999; 2002).
Simultaneous administration of carbamazepine (50
mg/kg) and Sho-seiryu-to (TJ-19, 1 g/kg) lengthened
the time to reach the peak plasma concentration
(Tmax), but did not influence the maximal plasma
concentration (Cmax), the area under the plasma concentration-time curve (AUC) or elimination half-life
(t1/2). Carbamazepine Tmax values and the elimination
rate constant were increased after 1-week daily
pretreatment with Sho-seiryu-to, by 83% and 88%,
respectively; while the t1/2 and the mean residence
110
time (MRT) decreased by 52% and 34%, respectively
(Ohnishi et al., 1999). These results indicate that in
rats oral administration of Sho-seiryu-to delays the
oral absorption of carbamazepine, while 1-week
pretreatment with Sho-seiryu-to induces the
metabolism of carbamazepine (Ohnishi et al., 1999).
When the herb Sho-saiko-to (TJ-9, 1 g/kg) was
administered orally in combination with carbamazepine (50 mg/kg) a 50% reduction in carbamazepine Cmax and a tendency for Tmax to increase
was observed and this was accompanied by a 40%
reduction in gastric emptying (Ohnishi et al., 2002).
Using hepatic microsomes it was observed that Shosaiko-to was associated with a concentrationdependent inhibition of epoxide hydrolase, with a Ki
of 540 µg/ml (Ohnishi et al., 2002). However,
following 1-week pre-treatment with Sho-saiko-to,
there were no differences in these pharmacokinetic
parameters (Ohnishi et al., 2002).
The Japanese herb Saiko-ka-ryukotsu-borei-to
(1 g/kg; traditionally used to treat a variety of neurological symptoms) in combination with carbamazepine (50 mg/kg) in rats was not associated with any
pharmacokinetic interactions as measured by the
same parameters as described above (Ohnishi et al.,
2001).
Concomitant
use
of
carbamazepine
(100 mg/kg/day) and the herbal infusion preparation
from Cassia auriculata (an extract corresponding to
20 g fresh plant material/kg p.o) (traditionally used
for the treatment of diabetes, inflammation and
infections and considered to have antioxidant properties) in rats resulted in a 63 ± 10% increase in
carbamazepine blood concentrations after four weeks
(Thabrew et al., 2004). No concurrent increase in
toxicity was observed, as measured by general
behaviour, liver function, haematological parameters
and kidney function. Although the dose of the herb
used in this study was approximately 10 times higher
than that typically ingested by humans, the authors
concluded that this infusion preparation has the
potential to inhibit the metabolism of carbamazepine,
probably via an action on CYP3A4, and therefore
patients should avoid the infusion (Thabrew et al.,
2004).
The traditional Chinese herbal medicine Paeoniae
Radix (300 mg/kg p.o. of the herbal extract;
traditionally used to relieve pain and inflammation)
in combination with carbamazepine (100 mg/kg)
decreased carbamazepine Tmax by 55% in rats, but no
statistically significant changes were found in carbamazepine plasma concentrations, t1/2, Cmax, AUC,
MRT, oral clearance (Cl/F) or oral volume of
distribution (Vd/F) (Chen et al., 2002). The authors
explained these findings by increased absorption, but
an interaction involving metabolism was also
suggested despite the reported data (which were
highly variable in a small number of animals; n =6).
A small decrease (8%) in carbamazepine protein
binding was also observed but the potential clinical
significance of this is uncertain (Chen et al., 2002).
Carbamazepine (50 mg/kg) and phenytoin
(50 mg/kg) in combination with the herb Mentat
(500 mg/kg p.o.; traditionally used for its psychotropic effects) in rabbits was associated with a 35%
and 55% increase in AUC for carbamazepine and
phenytoin, respectively, and the changes were
explained on the basis of an increase in absorption or
a decrease in carbamazepine and phenytoin
metabolism (Tripathi et al., 2000).
Phenytoin
The administration of phenytoin (100 mg/kg) in
combination with Paenoniae Radix (300 mg/kg of the
herb extract) increased phenytoin Tmax 3-fold in a rat
model and this was attributed to a delay in phenytoin
absorption (Chen et al., 2001). There were no significant changes in other pharmacokinetic parameters,
except for a 44% reduction in Vd/F.
A study of Ayurvedic syrup shankhapushpi
(0.5 ml, containing six different herbs; traditionally
used to treat seizures) in combination with phenytoin,
which was administered using a multiple dosing
regimen (40 mg/kg/day for five days) reported a 50%
reduction in phenytoin plasma concentrations and a
concurrent lowering of seizure threshold by >50%
(Dandekar et al., 1992). It was suggested by the
authors that both a pharmacodynamic and a pharmacokinetic interaction is occurring.
Diazepam
The Chinese herb Angelica dahurica (1 g/kg p.o.;
traditionally used to treat pain, headache,
inflammation and fever) increased the first pass
metabolism of diazepam (10 mg/kg) in rats, as
measured by a four-fold increase in Cmax (Ishihara et
al., 2000). The herb inhibited the activity of CYP2C,
CYP3A and CYP2D1 but since diazepam was
associated with a high clearance, underwent hepatic
blood flow rate-limited metabolism and a change of
intrinsic clearance; hepatic clearance was therefore
unaffected (Ishihara et al., 2000). It has also been
suggested that the herb may modulate GABAA
111
receptors and thus result in a pharmacodynamic
interaction with diazepam as well (Hu et al., 2005).
In a study of diazepam (15 mg/kg) and the
Chinese herb Salvia miltiorrhiza Bge (100 mg/kg/day
p.o.; traditionally used to treat cardiovascular
diseases) administered in combination to rats,
diazepam clearance was increased two-fold and Cmax
and AUC were decreased by 27% and 55%,
respectively. These findings were accompanied by an
increase in microsomal protein content and nonspecific CYP enzyme levels (Jinping et al., 2003).
Sho-saiko-to (used for the treatment of
inflammation), a traditional Chinese and Japanese
herbal medicine, and Saiko-keisi-to (used to treat a
variety of neurological symptoms) a traditional
Japanese herbal medicine, shortened the pentobarbital-induced sleeping time in mice by 35% for
both herbs, following their administration (0.55 and
0.5 g/kg, respectively) for four weeks and the
administration of 60 mg/kg pentobarbital 48 hours
after the final dose of the herbal preparation (Nose et
al., 2003). The administration of Sho-saiko-to
(0.55 g/kg) for two weeks reduced the pentobarbitalinduced sleeping time in rats slightly (14%)
following administration of 30 mg/kg pentobarbital
48 hours after the final dose of the herbal preparation
(Nose et al., 2003). Administration of Sho-saiko-to
for two weeks also up-regulated mRNA expression of
CYP2B, CYP3A1, CYP2E1 and CYP4A1 from two
to eight-fold in rats, and the administration of Saikokeishi-to (0.5 g/kg) for two weeks also up-regulated
the mRNA expression of CYP2B, CYP3A1 and
CYP4A1 two to four-fold (Nose et al., 2003). The
doses used in these experiments equals about five
times the therapeutic dose used in man (Nose et al.,
2003). Sho-saiko-to also increased the expression of
CYP P-450 mRNA16α levels in rats by about 30%
following chronic administration of 0.46 g/kg/day of
the herb for three months (Kojma et al., 1998). These
data suggest that the two herbs may have the
potential to influence the pharmacokinetics of AEDs
in man.
Phenobarbital
An extract from Ginkgo biloba (an enhancer of
memory and concentration) has been demonstrated to
induce the activity of CYP2B (Umegaki et al., 2002)
and since phenobarbital is a substrate for CYP2B in
rats, the potential interaction between the two was
investigated. Ginkgo biloba (0.1, 0.5 and 1.0% G.
biloba extract) reduced the hypnotic potency of
phenobarbital (50 mg/kg) in rats, as measured by the
duration of sleep (from loss to recovery of righting
reflex; Kubota et al., 2004). A 40% decrease in
phenobarbital Cmax and 20% reduction in phenobarbital AUC0-24 were observed and these changes
were possibly due to an enhancement of CYP2B
expression, since liver weight was increased by 35%
with the highest dose of concentration of Ginkgo
biloba (Kubota et al 2004).
Clinical studies
Carbamazepine
St. John’s Wort (Hypericum perforatum), is a
commonly used herbal drug, and in one study, more
than 5% of patients with epilepsy used the herbal
drug for mood disturbance (mild to moderate
depression) and fatigue (Patsalos et al., 2002). St.
John’s Wort has the potential to increase the
metabolism of AEDs, since it induces CYP3A4,
CYP2C9 and CYP2C19 and possibly by affecting
drug transporter activity in the gastrointestinal tract
(Roby et al., 2000; Wang et al., 2004; Zhou et al.,
2004). St. John’s Wort (300 mg tablet with 0.3%
hypericin) did not, however, alter the plasma
concentration of carbamazepine at steady state in an
open cross over study of eight volunteers (5 men and
3 women aged 24-43 years old; Burstein et al., 2000).
The subjects received carbamazepine daily titrated
from 200 mg to 400 mg for 20 days, and then the
combination of drug and herb for 14 days. No
differences were seen in carbamazepine peak or
trough concentrations, AUC or oral clearance values
(Burstein et al., 2000). These data suggested that
CYP3A4 was not further induced by St. John’s Wort
over and above that consequent to carbamazepine
autoinduction, but careful monitoring of carbamazepine was recommended, as carbamazepine
clearance was increased by 24% in one patient
(Burstein et al., 2000).
In another study, the opposite interaction effect
was studied, namely the induction effect of carbamazepine (200 mg/day, days 1-12 and 400 mg/day,
days 13-18) upon the metabolism of hypericin and
pseudohypericin (300 mg extract of Hypericum with
92 µg hypericin and 262 µg pseudohypericin) from
St. John’s Wort. The study entailed 33 healthy male
volunteers (18-50 years old; Johne et al., 2004) and
although it demonstrated a 30% reduction in pseudohypericin AUC, which was attributed to induction of
CYP3A4 by carbamazepine, the interaction was not
regarded as clinical significant with regards to the use
of St. John’s Wort (Johne et al., 2004). Because of
112
the extensive use of St. John’s Wort, its interaction
with carbamazepine and other AEDs requires further
study.
In a randomized controlled study of 188 patients
(86 men and 102 women aged 18-65 years old) with
bipolar disorder, the use of the traditional Chinese
herb Free and Easy Wanderer Plus (FEWP, 36 g/day;
used in mood disorders) and carbamazepine (mean
dose 460 mg/day) in combination demonstrated lower
discontinuation rate and fewer side effects compared
to placebo plus carbamazepine (Zhang et al., 2007). It
was concluded that FEWP improves tolerability of
carbamazepine in long-term use and may be
attributed to the observed 75% decrease in mean
serum carbamazepine concentrations (5.6 ± 5.8 µg/ml
versus 2.4 ± 2.9 µg/ml) consequent to possibly multiple mechanisms including enzyme induction of
CYP3A4, a delay in oral absorption, and a reduction
in protein binding, caused by FEWP (Zhang et al.,
2007). However, based on these data an increase in
oral clearance of 56% could be calculated and
enzyme induction is the most reasonable explanation,
since a limitation in absorption is rarely a problem
with carbamazepine (0.88 ml/kg/min, assuming an
average weight of 70 kg). Because the FEWP
formulation used contained 11 different herbs, it was
not possible to ascertain which constituent(s)
was/were responsible for the pharmacological effect
and the interaction (Zhang et al., 2007). It seems
reasonable to assume that this same interaction could
occur in patients with epilepsy.
Midazolam
In an open-label study of 12 healthy volunteers
(six women and six men aged 31 years old on
average), the interaction between midazolam
(0.05 mg/kg i.v.), a known CYP3A substrate, and the
herb Echinacea (400 mg Echinacea purpurea root)
was investigated (Gorski et al., 2004). This herb is
traditionally used for the management of colds and
inflammation. A pharmacokinetic interaction was
demonstrated, as the systemic clearance of midazolam was increased by 34% and AUC reduced by
23%. It was suspected that the herb induced CYP3A
by acting as a ligand for the pregnane X receptor,
which also may affect other enzymes and transporters
in the intestine and liver (Gorski et al., 2004). It was,
however, pointed out by Gurley et al. (2004) that the
oral clearance may not be altered, and that the herb
affects CYP3A4 activity in opposite ways, by
induction in the liver and inhibition in the intestine,
and that there may be a multiplicity of biologically
active phytochemicals in Echinacea.
The metabolism of midazolam was also affected
by St. John’s Wort in a study of 21 young healthy
volunteers (10 men 19-31 years old and 11 nonpregnant women aged 20-55 years old; Dresser et al.,
2003). The study was a two-way open-label cross
over study, and midazolam was administered 4 mg
orally and 1 mg [3N15]midazolam i.v., and 300 mg of
extract from St. John’s Wort (with 0.3% hypericin)
was administered three times a day from day three to
14 of the study (Dresser et al., 2003). Blood samples
were taken after 1-24 hours following administration
of midazolam, and the results demonstrated a 2.7-fold
increase in oral clearance, a 50% reduction in Cmax
and a 44% reduction in t1/2 of midazolam, possibly
caused by induction of CYP3A4 activity in the
intestine and in the liver (Dresser et al., 2003).
Valproate
In a randomized, open-label, two-way crossover
study of 6 healthy volunteers (3 men and 3 women,
aged 30-40 years old), the traditional Chinese
medicine Paenoiae Radix (traditionally used as a
spasmolytic and pain-relieving agent; 1.2 g powder of
herb extract) in combination with valproate (200 mg)
was studied (Chen et al., 2000). Serial plasma
samples were obtained after seven days, in addition
to clinical biochemistry analyses and adverse event
monitoring, and no differences were observed in t1/2,
Cmax, Tmax, AUC, MRT, CL/F, Vd/F, protein binding
or overall safety (Chen et al., 2000).
Phenytoin
In a series of 20 patients (males and females aged
20-45 years) with uncontrolled epilepsy prescribed
phenytoin (either 150mg bd – 10 patients or 200 mg
bd – 10 patients), the effect of a single dose of
piperine (20 mg; the active component of Piper
longum, Piper nigrum, and Zingiber officinalis) on
the pharmacokinetics of phenytoin was investigated
(Pattanaik et al., 2006). It was observed that at seadystate piperine significantly increased mean phenytoin
serum concentrations and this was associated in
significant increases in phenytoin AUC (9% versus
17%), and Cmax (10% versus 22%) values for the 300
mg and 400 mg phenytoin groups respectively. The
mechanism of interaction is considered to be
enhancement of phenytoin absorption by piperine
(Pattanaik et al., 2006; Bano et el., 1987).
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Potential AED interactions
Ginkgo
biloba
induces
CYP2C19,
as
demonstrated in a pharmacogenetic study with 18
volunteers (male Chinese aged 20-24, 54-71 kg and
previously genotyped for CYP2C19), (Yin et al.,
2004). Of the subjects, there were six homozygous
extensive metabolizers, five heterozygous extensive
metabolizers, and seven poor metabolizers (Yin et al.,
2004). Omeprazole was used as a substrate and an
index of CYP2C9 activity. The results demonstrated
that Ginkgo biloba (70 mg Ginkgo biloba leaf
extract) decreased the AUC of omeprazole by 41%,
27%, and 40% in the homozygote and heterozygote
extensive metabolizers, and the poor metabolizers,
respectively (Yin et al., 2004). The plasma
concentrations of omeprazole and its sulfone
metabolite were reduced by approximately 30%
compared to controls. Based on these data, it is
possible that Ginkgo biloba would reduce serum
concentrations of AEDs that are substrates for
CYP2C19, such as phenytoin, phenobarbital and
diazepam (Patsalos and Perucca, 2003b).
Anthranoid-containing plants with laxative
properties, including senna (Cassia senna) and
cascara (Rhamnus purshiana) and soluble fibres
(including Guar gum and Psyllium) increase the
intestinal transit time and may decrease the absorption of most intestinally absorbed drugs (FughBerman, 2000), and potential interactions between
these products and AEDs (Figure 1 and Table 1) need
more close consideration (Patsalos and Perucca,
2003a).
CONCLUSION
The use of herbal medicines by patients with
epilepsy is increasing and most patients consider
herbal medicines as safe because they are of natural
origin. However, these medicines, which may vary in
quality and ingredient content, have the potential to
interact with AEDs and therefore affect seizure
control or induction AED-related adverse effects. Todate the literature describing these interactions is
limited and most relate to pre-clinical studies. Clearly
more research is required.
.
Figure 1. Schematic illustration showing the possible pharmacodynamic or pharmacokinetic sites of interactions between antiepileptic
drugs and herbal drugs.
Altererd
pharmacodynamic
sensitivity
ABSORPTION
BOUND DRUG
(blood/tissue)
EFFECT
(brain)
UNBOUND DRUG
(blood)
Decreased plasma
concentration due to altered
bioavailability or elimination
METABOLISM
(liver, other tissues)
EXCRETION
Altered metabolic
capacity by induction
or inhibition of CYPs
or UGTs
Abbreviations: CYPs = cytochrome P450 isoenzymes, UGTs = uridine glucuronyl transferases
114
PK
PK
St. John’s Wort
Salvia miltiorrhiza Bge
PK
St. John’s Wort
PD
PK
Sho-seiryu-to
Saiboku-to
PK
Sho-saiko-to
PD
PK
Saiko-ka-ryukotsu-to
Ginkgo biloba
PK
Paenoiae Radix
PK
PK
Mentat
Angelica dahurica
PK
FEWP
Diazepam
PK
Cassia auriculata
Carbamazepine
Interaction
Herbal drug
AED
Preclinical
Preclinical
Preclinical
Preclinical
Clinical, healthy
Clinical, healthy
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Clinical, RCT
Preclinical
Type of study
Table 1. Interactions between antiepileptic drugs (AED) and herbal drugs.
CYP induction
Potentiation of GABA
Potentiation of GABA
CYP2C/D,3A inhibition
CYP3A4 induction by
carbamazepine
No CYP3A4 induction
Decreased absorption
Decreased absorption
No interaction
Increased absorption?
CYP inhibition?
CYP3A4 induction
CYP3A4 inhibition?
Mechanism
Chermat et al., 1997
↑ increased social contact
Jinping et al., 2003
Ishihara et al., 2000
↑ Cmax, ↓ CLint (but not CLtot)
↑ CL, ↓ AUC, ↓ Cmax
Johne et al., 2004
↓ AUC of hypericin
Ikarashi et al., 2002 +
Yuzurikara et al., 2002
Burnstein et al., 2000
↑CL in 1 subject
A ”diazepam sparing” effect
Ohnishi et al., 1999
↑ Tmax
Chen et al., 2002
↓ Tmax
Tripathi et al., 2000
↑ AUC
↓ Cp
Zhang et al., 2007
↓ Cp ↑ CL
Thabrew et al., 2004
↑ Cp
No changes
Reference
Consequence
115
PK
PK
Echinacea purpurea
St. John’s Wort
Midazolam
No PK
PK +
PD
Shankhapushpi
Paeoniae Radix
PK
Piperine
PD?
PK
Paenoiae Radix
Centella asiatica
PK
Mentat
Clinical, healthy
Preclinical
Preclinical
Clinical, healthy
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Clinical, healthy
Clinical, healthy
Preclinical
Type of study
Synergistic effect?
CYP induction?
Synergistic effect?
Decreased absorption?
CYP inhibition?
Synergistic effect?
CYP2B,3A1,2E1,4A1 induction
CYP2B,3A1,2E1,4A1 induction
CYP2B induction
CYP3A4 induction
CYP3A induction
Synergistic effect?
Mechanism
Dandekar et al., 1992
↓ Cp, ↑ seizure protection
No change (Cp-PK parameters)
Chen et al., 2000
Vattanajun et al., 2005
Pattanaik et al., 2006
↑ AUC, ↑ Cmax
Reduced effective AED dose
Chen et al., 2001
Nose et al., 2003
↓ induced sleeping time
↑ Tmax
Nose et al., 2003
↓ induced sleeping time
Tripathi et al., 2000
Kubota et al., 2004
↓ Cmax and AUC
↑ AUC
Dresser et al., 2003
↑ CL, ↓ Cmax↓ t1/2
Gorski et al., 2004
↑ CL, ↓ AUC
Reference
Consequence
Abbreviations: FEWP = Free and Easy Wanderer Plus, RCT = randomized controlled trial, PK = pharmacokinetic; PD = pharmacodynamic, AUC = area under the curve,
CL = clearance, CLint = intrinsic clearance, CL tot = total clearance, Cp = plasma concentration, Css = plasma concentration at steady state, t1/2 = elimination half-life, Tmax = time to
reach maximum plasma concentration, Cmax = maximum plasma concentration
Valproate
PD?
Centella asiatica
PK
Saiko-keisi-to
Phenytoin
PK
Sho-saiko-to
(Pentobarbital)
PK
Ginkgo biloba
Phenobarbital
PD?
Centella asiatica
Gabapentin
Interaction
Herbal drug
AED
116
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118
© 2008 Los Autores
Influence of menthol on first pass elimination
[Influencia del mentol sobre la eliminación de primer paso]
Ayse GELAL
Dokuz Eylul University Medical Faculty, Department of Pharmacology. Inciralti, 35340 Izmir Turkey.
Abstract
Menthol is one of the most widely consumed essential oils. In vitro and in vivo studies indicate that menthol induces or inhibits drug
metabolizing activities of liver or gut; thus it could decrease or increase serum drug concentrations. In vitro studies demonstrate that menthol
has a relaxant effect on the gastrointestinal tract, thus it could influence the rate of drug absorption. Also in vitro Caco-2 model study results
suggest that peppermint oil (30-55% of which is menthol) has inhibitory effect on the functionality of intestinal P-glycoprotein related efflux
carriers, which could affect the amount of absorbed drug. This paper will focus on the effect of menthol on the first pass elimination of drugs.
This issue is stressed, because it could change pharmacological responses of various drugs.
Keywords: Menthol, Essential oils, Metabolism, Drug-interactions.
Resumen
El mentol es uno de los aceites esenciales más consumidos. Estudios in vitro e in vivo indican que algunos aceites esenciales inducen o
inhiben la actividad metabolizadora de los fármacos que realizan el hígado o el intestino, lo cual podría disminuir o incrementar las
concentraciones de fármaco en suero. En estudios in vitro se demuestra que el mentol tiene un efecto relajante sobre el tracto gastrointestinal,
lo que podría influenciar la velocidad de absorción de los fármacos. También en estudios in vitro que utilizan el modelo de células Caco-2 se
demuestra que el aceite de menta (constituido por 30-55% de mentol) tiene efecto inhibitorio sobre la funcionalidad de la glicoproteína P que
está relacionado con el flujo de transportadores, el cual podría afectar la cantidad de fármaco absorbido. Este artículo tratará los efectos del
mentol sobre la eliminación de primer paso de fármacos. Se enfatiza en este problema, porque pudiera cambiar las respuestas farmacológicas
de varios medicamentos.
Palabras clave: Mentol, Aceites esenciales, Metabolismo, Interacción de fármacos.
INTRODUCTION
Menthol (C10H20O; mol. wt 156.27) is a
monocyclic terpene alcohol present as a major
constituent of peppermint oil (Mentha piperita) and
cornmint oil (Mentha arvensis). Menthol has three
asymmetric carbon atoms in its cyclohexane ring (Fig.
1), and therefore occurs as four pairs of optical isomers: (-)- and (+)-menthol, (-)- and (+)-neomenthol,
(-)- and (+)- isomenthol, and (-)- and (+)-neoisomenthol (Eccles, 1994). (-)-menthol (also called lmenthol or (1R,2S,5R)-menthol) is the main form of
menthol occurring in nature and one of the most
important flavoring chemicals. The majority of natural
(-)-menthol is obtained by freezing the oil of Mentha
arvensis to crystallize the menthol present
(Anonymous, 2007).
Menthol is used extensively in many commercial
products (pharmaceuticals, cosmetics, toothpastes,
chewing gum, and other toilet goods as well as in
cigarettes) and foods. In 2007, worldwide consumption of (-)-menthol, by product area, was estimated to
be (Clark, 2007): Oral hygiene, 28.0%; pharmaceuticals, 26.6%; tobacco, 25.3%; confectionaries, 11.0%;
shaving products, 7.0%; miscellaneous, 2.1%. With
regard to its medicinal purposes, menthol is currently
available in both prescribed and over-the-counter
Menthol and drug metabolism
(OTC) medications for gastrointestinal disorders,
common cold and respiratory conditions, musculoskeletal pain and dermatological problems. The current annual world production of menthol is estimated
to be in excess of 19 000 metric tons (natural menthol
at 12 870 metric tons and synthetic menthol at 6 300
metric tons for a total of 19.170 metric tons)
(Anonymous, 2007).
Figure 1. Chemical structure of (-)-menthol
Bioavailability of an orally administered drug is
comprised of the individual fractions that survive the
various barriers encountered by the drug during its
first passage from the gut lumen to the sampling site
(Kwan, 1997):
F’= FX. FG. FH
F’ is oral bioavailability fraction. FX is the fraction
absorbed (i.e. net transport of unchanged drug into and
around the absorptive cells of the gastrointestinal
tract), FG is the fraction that is not metabolized in a
single passage through the gut wall, FH is the fraction
that is not extracted during the first passage through
the liver.
F’ is less than 100% of the active ingredient in the
oral dose for four reasons (Benet et al, 1998):
(1) drug is not absorbed out of the gut lumen
into the cells of the intestine and is eliminated
in the feces
(2) drug is absorbed into the cells of the intestine
but back-transported into the gut lumen
(3) drug is biotransformed by the cells of the
intestine (to an inactive metabolite)
(4) drug is eliminated by the cells of the liver,
either by biotransformation and/or by
transport into the bile.
The main topic of this paper is the effect of
menthol on the bioavailability of the coadministered
drugs through the above mentioned first pass
elimination mechanisms. The studies investigating
whether or not menthol, which is consumed
Gelal
widespreadly all over the world, causes natural
product-drug interaction will be discussed.
Effects of menthol on gastrointestinal motility
As mentioned above peppermint oil is obtained
from the fresh leaves of Mentha piperita. The major
constituents of the oil are (-)-menthol (30-55%),
(-)-menthone (14-32%), (+)- isomenthone (1.5-10%),
(-)-menthyl acetate (2.8-10%), (+)-menthofuran (1.09.0%) and 1.8 cineol (3.5-14%). Peppermint oil has
been used for many years in herbal remedies for the
treatment of digestive disorders since it has spasmolytic effect on gastrointestinal tract. Grigoleit’s review
shows that peppermint oil is used in an enteric coated
form in irritable bowel syndrome, and that it is a safe,
efficacius and cost effective symptomatic short term
treatment in reducing global symptoms and pain due
to its spasmolytic and antiflatulent effects. The antispasmodic effect of peppermint oil is due to
(-)-menthol, which acts as a calcium antagonist;
however, its antiflatulent effects are currently unexplained (Grigoleit and Grigoleit, 2005a, 2005b).
Menthol has been shown to inhibit histamine and
acethylcholine-induced contractions of guinea-pig
isolated Taenia coli. The inhibitory effect depends on
its antagonistic effect on L type calcium channels
(Hawthorn et al., 1988; Grigoleit and Grigoleit,
2005c). In vitro studies on guinea-pig and human gut
smooth muscle indicate that menthol exerts an
inhibitory effect on gut smooth muscle by decreasing
the influx of extracellular calcium through potentialdependent channels, whilst having no effect on the
intracellular mobilization of calcium (Eccles, 1994).
The relaxant effect of menthol on the gastrointestinal
tract could influence the rate of drug absorption.
Menthol is highly lipid-soluble and is rapidly
absorbed from the small intestine when taken orally.
We had determined the disposition kinetics of 100 mg
menthol capsule and 10 mg menthol containing mint
candy or mint infusion (Gelal et al., 1999). Average
peak plasma concentrations of menthol (Cmax) were
2610±862 ng/ml and 368±115 ng/ml; the time to reach
Cmax (tmax) were 61±26 min and 30±12 min in the
menthol capsule group and mint candy lozenge/mint
infusion group, respectively. In our menthol-caffeine
interaction study, eleven healthy female subjects
participated in a randomized, double-blind, two-way
crossover study, comparing the kinetics and effects of
a single oral dose of caffeine (200 mg) in coffee taken
together with a single oral dose of menthol (100 mg)
or placebo capsules, coadministration of menthol
caused a significant increase in caffeine tmax and slight
120
decrease of caffeine Cmax. We suggested that the
relaxant effect of menthol on the gastrointestinal tract
could influence the rate of drug absorption by decreasing gastric emptying, which most likely accounts
for the slowing of caffeine absorption in our study
(Gelal et al., 2003). However, in our other study
undertaken to determine whether or not menthol
affects the metabolism and pharmacological responses
of the calcium channel antagonist felodipine in people,
felodipine tmax value did not change in presence of
menthol. This indicates that the rate of felodipine
absorption into the systemic circulation is unaffected
by the coadministration of menthol (Gelal et al.,
2005). The lack of effect by menthol on felodipine
absorption rate in our study could be related to
competitive antagonism between l-menthol and [3H]nitrendipine or the dihydropyridine radioligand [3H](+)-PN200-110 binding to intestinal smooth muscle
(Hawthorn et al., 1988).
Effects of menthol on drug metabolism
(biotransformation)
The liver contains many isoforms of cytochrome
P450 (CYP) and can biotransform a large variety of
substances. The enterocytes lining the lumen of the
intestine also have significant CYP activity and this
activity is dominated by a single family of isozymes,
CYP3A, the most important isoforms in drug
metabolism (Benet et al., 1998). Despite widespread
human exposure to menthol and other monoterpenes
found in essential oils, the effects of these substances
on drug metabolism are not well characterized. The
effects can be estimated using in vitro and in vivo drug
biotransformation measurements.
Some of the terpenoids used in pharmaceutical
preparations and as constituents of food induce or
inhibit drug metabolizing activities of liver in vitro.
Madyastha and Srivastan (1988), for estabilishing the
effect of l-menthol on hepatic drug-metabolizing
enzymes, administered 800 mg/kg l-menthol (as a
suspension in 1% methyl cellulose solution, once daily
up to 7 days) by gastric intubation to the adult male
rats. In this study it was observed that both CYP and
NADPH-cytochrome c reductase activity were induced to significant levels. Maximal induction of CYP
and its reductase was observed upon 3 days of
repeated treatment with l-menthol. Further treatment
(for 7 days total) reduced their levels considerably,
although the levels were still higher than the control
values.
Austin et al., designed the study to investigate the
effects of five terpenoids, including menthol, on the
Gelal
expression of genes coding for components of the
CYP2B subfamily of rat liver microsomal membranes.
Their research arised from the previous findings that
various terpenoids increase the rate of metabolism of
penta- and hexabarbital, and decrease the sleeptime
induced by these barbiturates suggesting that the
action of the terpenoids may be mediated through an
increase in the activity of a member of the major
phenobarbital-inducible CYP subfamily CYP2B. In
their study, the rats were given intraperitoneal
injections of menthol or other terpenes at a dose of 40
mg/kg for 3 days. The induction of hepatic CYP2B
subfamily was confirmed by radioimmunuassay,
Western blotting and by nucleic acid hybridization
after in vivo treatment of rats with menthol. None of
the terpenoids had an effect on the amount of mRNA
coding for CYP1A2 (Austin et al., 1988).
De-Oliveira et al. (1999) investigated the inhibitory
effects of menthol and some monoterpenoid alcohols
on liver microsomal enzymes involved in the biotransfomation of xenobiotic substances. They found
that (-)-menthol inhibited CYP2B1 activity in vitro, as
opposed to previous in vivo studies. They also showed
that (-)-menthol had weak inhibitory effect on
CYP1A2 activity. In their study, 40 µM menthol
decreased rate of O-dealkylation by 20%. However,
this in vitro finding may not be extrapolated to in vivo
results, because menthol is rapidly but incompletely
metabolized to menthol glucuronide in vivo and the
remainder of menthol is metabolised by hydroxylation
(Yamaguchi et al., 1994; Bell et al., 1981). For that
reason we carried out a clinical research to determine
whether a single oral dose of menthol affects the
metabolism of caffeine, a CYP1A2 substrate, and the
pharmacological responses of caffeine in people
(Gelal et al., 2003). Co-administration of menthol
resulted in an increase of caffeine tmax values (as
mentioned above) from 43.6±20.6 min (mean ± SD) to
76.4±28.0 min (p<0.05). The Cmax values of caffeine
were lower in the menthol phase than in the placebo
phase, but this effect was not statistically significant
(p=0.06). Area under the curve [(AUC)0-24, (AUC)0-∞],
terminal half-life and oral clearance were not affected
by menthol. We concluded that 100 mg menthol did
not alter caffeine metabolism in healthy female
volunteers.
Some essential oils reduce CYP3A drug
biotransformation by acting as an inhibitor of CYP3A
activity or as a substrate of CYP3A (Bennet et al.,
1998). One of the inhibitors identified in this work
was peppermint oil. Cyclosporine (CyA) is a potent
immunosupressive agent. It has poor oral bioavaila121
bility, which can be attributed to presystemic elimination by CYP3A and active efflux of drug by P-glycoprotein (P-gp) to intestinal lumen. The impact of
peppermint oil as a bioavailability enhancer on CyA
oral bioavailability in male rats was evaluated by
Wacher et al. (2002). They compared peppermint oil
efficacy with CYP3A inhibitor ketoconazole and the
solubility enhancer and Pgp inhibitor D-α-tocopheryl
poly (ethylene glycol 1000) succinate (TPGS).
Additionaly, the in vivo effects of peppermint oil and
ketoconazole were compared with their relative
activities as CYP3A inhibitors in vitro using liver
microsomes. Peppermint oil and TPGS enhanced CyA
oral bioavailability. However ketoconazole, a potent
CYP3A inhibitor in vitro, was ineffective. They
concluded that inhibition of CYP3A may not be the
only means by which peppermint oil exerts its effect.
Gastrointestinal muscle relaxant effects (which
may account for the significant increase in CyA tmax)
and permeability enhancer effects of peppermint oil
and menthol may also contribute to the effect of
peppermint oil as an enhancer of CyA absorption.
Following the Wacher’s study, Dresser et al.,
(2002) published the study which investigated the
effect of peppermint oil and ascorbyl palminate on
CYP3A4 activity in vitro and oral bioavailability of
felodipine in humans. Felodipine is a dihydropyridine
calcium antagonist. CYP3A4 is the major enzyme for
its biotransformation and it is not a substrate for P-gp.
So felodipine is the most extensively studied probe for
CYP3A4 enzyme activity. Peppermint oil augmented
the oral bioavailability of felodipine in this study. The
mechanism may involve inhibition of presystemic
drug metabolism mediated by CYP3A4. Dresser et al.
(2002), suggested that the concentration of menthol in
peppermint oil accounts for some portion of the
inhibitory effect of the oil on CYP3A4-mediated
metabolism in vitro and in vivo. Thereafter, in order to
explore the suggestion of Dresser et al.; we planned a
study to evaluate the interaction of menthol and
felodipine (Plendil®) in healthy subjects. Eleven
healthy subjects (10 female, 1 male) participated in a
randomized, double-blind, two-way crossover study,
comparing the kinetics and effects of a single oral
dose of felodipine ER tablet (Plendil®, 10 mg) with
menthol or placebo capsules. Menthol was given in
divided doses. At the beginning of the study, 100 mg
menthol or placebo capsule were given and then in the
2nd, 5th and 7th h of the study, 50 mg, 25 mg and 25 mg
menthol or placebo capsules were given, respectively.
The results showed that there were no differences in
the dehydrofelodipine and felodipine Cmax and AUC0Bol. Latinoam. Caribe Plant. Med. Aromaticas Vol. 7 (2) 2008
Gelal
24 values when coadministered with menthol or
placebo, indicating that neither the formation nor the
elimination of felodipine and dehydrofelodipine (the
primary metabolite of felodipine) were affected by the
presence of menthol, and also that there was no presystemic interaction. Dresser et al. had used 600 mg
peppermint oil in their study. Acoordingly, subjects
received approximately 180 to 300 mg single dose of
menthol in this study. We found that pharmacokinetics
of felodipine were not altered by 200 mg menthol in
divided doses. Divided dose of 200 mg menthol may
not constitute an adequate concentration-time profile
of menthol at CYP3A4 during the period of absorption
or metabolism. However, to conclude that menthol
does not affect felodipine pharmacokinetics, further
studies are required.
Effects of menthol and other monoterpene alcohols
on propofol induced anesthesia time in mice were
investigated (Li et al., 2006). They found that duration
of anesthesia was prolonged, primarily due to the
inhibition of propofol’s metabolism. Aminopyrine has
similar CYP isozyme specificity (CYP2B and
CYP2C) with propofol. The effects of menthol on
aminopyrine N-demethylation was also tested by Li et
al., who showed that menthol significantly inhibited
aminopyrine N-demethylation activity preincubated
with the microsomes.
In a case report, concomitant ingestion of mentholcontaining cough drops (approximately 6 drops/day
over 4 days; estimated menthol dose of 42 mg daily)
reduced the international normalized ratio (INR) to
subtherapeutic range in a patient receiving anticoagulation therapy with warfarin. Clinically available
warfarin is a racemic mixture of (R)- and (S)-warfarin,
both enantiomers are eliminated extensively via
hepatic metabolism. CYP2C9 is almost exclusively
responsible for the metabolism of the pharmacologically more active (S)-enantiomer. The Naranjo
probability scale was used to assess the causal
relationship between the medication and the adverse
reaction in the report and was rated 'possible'
(Kassebaum et al., 2005).
Menthol is used extensively in cigarettes and one
of its major consumption areas is tobacco industry.
Benowitz et al. (2004) showed that mentholeted
cigarette smoking inhibits the metabolism of nicotine.
Their data suggest that mentholated cigarette smoking
was associated with both a decrease in CYP2A6
activity, as evidenced by a trend towards reduced
nicotine clearance via the cotinine pathway, and a
significant reduction in glucuronidation, as evidenced
by the lower nicotine-glucuronide/nicotine ratio in the
122
urine. Their study results also support the in vitro
studies showing that menthol inhibits nicotine metabolism in human microsomes and cDNA-expressed
CYP2A6 (MacDougall et al., 2003; Benowitz et al.,
2004)
Effects of menthol on P-glycoprotein
P-glycoprotein (Pgp) is a 170 kDa transport protein
belonging to the superfamily of the ABC transporters.
Drug extrusion is mediated by this active transporter.
The efflux mechanism plays a major role in the
occurence of multidrug resistance in the treatment of
cancer; it also has an important physiological role in
the protection of the body against xenobiotics. Pgp is
functionally expressed in the small intestine, renal
epithelium, the blood-brain barrier and several other
tissues in the human body (Deferme et al., 2002). The
essential oil can have properties of being a ligand for
Pgp or CYP or a ligand for either proteins (Bennet et
al., 1998). Deferme et al. screened standardized food
extract, including mint, to their possible inhibitory
effect on the Pgp mediated efflux of 3H-cyclosporine
A (CsA) using the in vitro Caco-2 model. Their results
included a significantly increased absorptive transport
of CsA, together with a significantly decreased
secretory transport. The results suggest that the
absorption enhancing effect of mint might be due to
an inhibitory effect of peppermint oil on the
functionality of intestinal Pgp related efflux carriers.
CONCLUSION
Human beings are exposed to menthol, which is
commonly used in food, cosmetics, cigarettes and
herbal medicinal products. However, our knowledge
about this compound is still limited despite its
widespread consumption. Research on this natural
product-drug interactions is important, since its
coadministration with drugs may result in drug
toxicity or ineffectivenes.
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124
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