Document 6429458

Transcription

Document 6429458
CHEMOTHERAPY
16
JAN. 19987
PHARMACOKINETIC
STUDIES OF CEFOPERAZONE AFTER
BOLUS INJECTION IN PATIENTS WITH BENIGN
PROSTATIC HYPERTROPHY
SYUJIFUKUSHIMA,
TAKESHI
MIURAand TOSHIMICHI
SUGAWARA
Department of Urology, YokohamaMunicipalCitizens Hospital
IICHIRO
KONGO
and HIROSHIFUJII
Department of Urology, KanagawaPrefectural HospitalCenter for the Adult
MAKOTO
HIROKAWA
and AKIRAIWASAKI
Department of Urology, Fujisawa MunicipalHospital
EIICHIISHIEUKA
and NAOTOKITAHMA
Department of Urology, YokohamaRed Cross Hospital
(ReceivedSeptember 2, 1985)
We
measured
intravenous
and
to 53
concentrations
(T1/ 2ƒÀ) was
who
and
after
administration.
tained
left
patient
In
In
patients
maximum
of
with
cefoperazone
benign
sustained
groups,
the
According
into
detected
maximum
the
in
prostatic
serum.
(CPZ)
following
its
hyperplasia.
The
39.8 ƒÊg/
to our
CPZ
in urine
of
findings
may
after
and
the
drug's
biological
transurethral
g
at
CPZ
2.3
in
effective
operation
INTRODUCTION
In general, an antibiotic is administered according
to its antimicrobial spectrum and ability to penetrate the affected organ. Recently,
there have
been many reports concerning the penetration
of
various antibiotics into specific tissues.
ADACHI1),
SAKURAI2),and RISTUCCIA3)measured the concentrations of several antibiotics in the prostates of patients with benign prostatic hypertrophy
(BPH).
We previously reported that in the presence of
BPH cefoperazone(CPZ) appears in high concentration in prostatic tissue and suggested that this agent is suitable for the treatment of bacterial prostatitis4).
In the study reported here, we performed a pharmacokinetic evaluation of CPZ's penetrability into prostate.
g,
half-life
after
the
declined
bacterial
In
in
bacteria
prostatic
medical
Municipal
pital
ages
saline
for
was
thral
Blood
tration
For
was
1 g
60
in
of
53
patients.
dissolved
procedures
(TUR)
or
determination
drawn
determination
only
of
the
once
serum
after
intraprostatic
1983.
(70.4•}5.7,
and
in
prior
retropubic
of
Hos-
March,
Kidney
injected
operative
Cross
years
1.
The
Ka-
Fujisawa
Red
83
all
CPZ
admitted
Hospital,
and
to
in Fig.
normal
BPH
Adult,
intravenously
resection
for
1982
from
shown
of
with
the
Yokohama
January,
were
BPH.
METHODS
Citizens
for
and
ranged
solution
its
prostatitis
males
Center
as
functions
A
53
Hospital,
mean•}SD),
that
and
cause
Municipal
between
Their
with
capacity
AND
were
nagawa
three
hyperplasia.
subjects
Yokohama
g
at-
all
parallel
that
PATIENTS
The
to the
the
min
34.3 ƒÊg/
concentration
inhibitory
the
benign
the
in
at 8.6
was
administration.
prostate
its
of CPZ
respectively,
concentration
resection,
min
against
for
concentrations
30.5 ƒÊg/
maximum
concerning
be
the
of 33.3
capsule,
underwent
of
concentration
prostate,
prostatectomy,
values
surgical
who
value
penetration
are
concentrations
patients
were
retropubic
reached
in serum.
and/ or
CPZ
underwent
lobes
min.
a
of
133 min.
patients
right
at 10.3
prostate
administration
High
In
serum
to
were
liver
20ml
of
surgery
transure-
prostatectomy.
CPZ
concen-
prostatectomy.
concentrations
VOL.35
Fig. 1
NO,1
Age distribution
CHEMOTHERAPY
and surgical
Mean age
17
procedure
Fig. 2
Two-compartment
CPZ concentration
open model of serum
70.4 yrs.
√V:5.7
but
of CPZ, we used a fragments
of prostatic tissue
obtained by TUR or specimens from the prostatic
capsule and each of the lateral lobes removed by
open prostatectomy.
The prostatic
tissue was
washed in a saline solution to eliminate blood and
urine and frozen until the analysis was performed.
The prostatic tissue CPZ concentration
was determined from the degree of inhibition of Micrococcus luteus (strain ATCC 9341) on a thin-layer
disc containing nutrient fluid. The prostatic tissue
was homogenized in a 1/ 15M phosphate buffer (pH
7.0) and centrifuged at 3,000 rpm for 30 min. Using the supernatant,
we measured the intraprostatic
CPZ concentration by the same method as that used
for serum.
In the pharmacokinetic
studies of the
serum and intraprostatic CPZ concentrations obtained were from a single determination
of each sample. The pharmacokinetic
data were analyzed with
a NEC ACOS 250 computer by the simulation and
simplex method.
Serum CPZ concentration
was
measured by a two-compartment
model according to
the calculation shown in Fig. 2. We employed the
model in Fig. 3 to estimate the penetration of CPZ
into prostatic tissue, which we considered to be related to its concentration in serum.
We then applied a constant so that the square
sum of the difference between the obtained value
and the theoretical value would be minimal.
In
addition, the duration of serum and prostatic CPZ
concentrations at each stage were computed in
terms of the bacterial inhibitory concentration
by
the Newton- Raphson method.
The area under the
curve (AUC) was also computed by numerical integration according to Simpson's rule.
The dose required to sustain a given concentration in serum and in prostate for 1.5 hours was
calculated by the golden section method.
C1 : Serum
concentration
(ƒÊg/ ml)
V: Distributionvolume of compartment 1(1)
K01 : Elimination
K12. K21 : Transition
W : Dose(mg)
t : Time (hr)
rate
constant
(hr-1)
rate constant (hr-1)
Fig. 3
Model of drug transport
and nrostatic tissue
C3
Ki3, K31:
between
serum
Drug concentration
(ƒÊg/ g)
Transition rate constant (hr-1)
RESULTS
1.
Serum
The
ble
CPZ
1.
The
biological
CPZ
values
of 105.5 ƒÊg/
point)
and
time
parameters
distribution
half-life
serum
space
133 min.
concentration,
ml
26.0 ƒÊg/
are
was
shown
at 9 min
ml
at
listed
5.7
L
in
(the
360 min
in
Ta-
and
A simulation
the
curve
Fig.
of
4,
yielded
minimum
time
(the
maximum
point).
2.
CPZ
In
Table
subdivided
ple
concentration
pharmacokinetic
concentration
1 the
in prostatic
prostatic
according
tissue
pharmacokinetic
to preparation
data
and
tissue
are
sam-
site.
With
tration
open
in
prostatectomy,
the
right
lobe,
the
maximum
33.3 ƒÊg/
g,
was
concenattained
CHEMOTHERAPY
18
Table
I
Pharinacokinetic
JAN,
1987
parameters
Serum
Cw=
A1e-
α1+
Prostatic
Cw=
A2β1
tissue
B1ek31- 1+
B2eα1+
B3e.-β1
Fig. 4
at 8.6
was
Simulated mean serum
CPZ after 1 g intravenous
concentration
injection
min
The
after
3.52.
administration.
The
concentration
ed a maximum
ministration.
surgical
The
capsule,
was
also
the
highest
left
lobe
at 8.6
K31/ K13 ratio
μg/ g at 10. 3 min.
which
g,
Fig. 5
Simulated mean right lobe concentration
of CPZ after 1 g intravenous injection
K31/ K13 ratio
in the
of 30.5 ƒÊg/
of
was
min
reach-
concentration
Fig. 6
Simulated mean left lobe concentration
of CPZ after I g intravenous
injection
(64.2)
postad-
3.85.
In
was
the
34.3
The K31/ K13 ratio was 3.29,
smaller
than
that
for
the
adenomatous
lobes.
In
the
case
of
tration,
39.8 ƒÊg/
occurred
very
The
K31/ K13
The
after
ratio
tissue
shown
similar
g,
in
course,
reaching
the
in
with
the
CPZ
concen-
adenomatous
min-after
tissue
administration.
3.69.
curves
were
Figs.
maximum
resected
was
simulation
prostatic
are
TUR,
soon-2.3
for
CPZ
derived
5-8.
All
concentrations
maximum.
concentration
in
from
these
four
curves
data
depict
and
slowly
declining
a
VOL.35
Fig.7
3.
Duration
of
(MIC)
The
are
and
33
lobe
min.
4.
The
AUC
μg/ml
which
the
prostatic
in
prQstate,
concentration
A level
2.
was
of
12.5
for
remained
peg
over
was
of
above
A concentration
maintained
2
of 25.0ƒÊg/
duration
concentrations
tissue
Table
in serum
regions
the
surgical
inhibitory
Simulated mean TUR tissue concentration
of CPZ after 1g intravenous injection
was
g was
In
AUC
sustained
58 min- in
for
prostatic
for
and
serum
5.
for
trations
the
In
was
concentrations
is given
large:
160. 9ƒÊg/ hr/ ml
in
314.5ƒÊg/
at
25.0ƒÊg/
in
Table
3.
Table
In
2
Duration
25.0ƒÊg/
to
of
for
1.5 hours
drug
1.18g
g
was
and
the
hr/ g,
of
61.40
AUC
was
g,
the
MIC
maintain
a concentration
In
in
average
for
1.5
4)
to
drug.
iarge
of 75.22μg/
maintain
required
of
was
an
are
listed
concen-
in
Table
4.
of 100ƒÊg/ ml necessitated
the
surgical
required
2.35g
various
for
capsule
for
a level
a
of
the
pros-
concentration
of
of
50ƒÊg/ g.
DISCUSSION
3.13
the
at
(Table
serum,
25.0ƒÊg/
AUC
average
with
dosages
The
hr/ ml at
ml.
se-
the
an
required
hours
The
tate,
CPZ
tissue
g,
with
ieft lobe,
Dosage
left
3)
several
in
μg/ hr/ g.
However,
srnall in all sites.
in
the
3.13μg/
capsule,
small
1.44g
(Table
AUC
and
2 hrs
detected
hrs.
longer-
of
for
capsule.
and
at
surgical
a concentration
28min;
rum
or
listed
of CPZ
prostatic
minimal
19
Fig. 8
CPZ
during
in serum
MIC
50 ƒÊg/ ml
all
of
intervals
CPZ
the
CHEMOTHERAPY
NO.1
Simulated mean surgical capsule concentration of CPZ after 1g intravenous injection
Inflammation
of the
prostate
clinicians.
Patients
with
by
of MIC
maintenance
is often
prostatitis
encountered
range
wide-
CHEMOTHERAPY
20
JAN. 1987
Table 3
The area under the concentration/time curve
Table
Dose required
4
to maintain
ly in age, from adolescents to the elderly.
If detected early, acute inflammation can be controlled
with antibiotics.
However, in some cases the inflammation is not cured but advances to a chronic
state, and the treatment period may be prolonged,
to no effect. The main problem is that few antibiotics reach the prostate in high enough concentration to exert a bacteriocidal effect on the prostatitis-causing organisms.
Newly developed antibiotics are always studied for their efficacy against
prostatitis,
particularly in terms of their ability to
penetrate the prostate. Their penetrative capacities
should be evaluated in patients with prostatic inflammation, but in fact have generally been assessed
in patients with prostatic adenoma, following drug
MIC
for
1.5
administration
and
vestigation
we
trations
tatic
of
tive.
lished
in
and
et al5).
into
results',
and
surgical
excision.
simultaneously
CPZ
capsule,
MIYATA
factorily
hours
However,
to
on
that
prostate.
suggested
reports
this
the
tissue,
in-
concenthe
pros-
serum.
reported
the
In
measured
adenomatous
the
data
CPZ
We
that
diffused
satis-
presented
CPZ
similar
is clinically
there
have
been
pharmacokinetics
effecno
of
CPZ
pubwith-
in prostate.
Our
1)
nomatous
g and
travenous
results
The
are
CPZ
lobes
summarized
concentration
reached
33. 3 ƒÊg/ g,
respectively,
administration.
as
in
maximum
follows.
right
and
levels
at 8.6
min
left
ade-
of 30 .5ƒÊg/
after
in-
VOL.35
2)
sule
CPZ
concentration
required
attain
its
than
more
in
the
surgical
time-
of 34.3ƒÊg/
that
g,
10.3
which
adenomatous
In adenomatous
maximum
in
somewhat
maximum
ly higher
3)
CHEMOTHERAPY
NO.1
The
tissue
concentration
min-
was
by
higher,
1. cephalexin,
to
zole-
slight-
TUR,
39.8ƒÊg/
in
reached
earlier,
istration,
than
When
tic
the
at
in
tissue
currently
efficacy,
min
after
resected
were
with
penicillin-
G by
from
the
of
drug
by
accepted
which
study
2.3
open
criteria
derived
et
al7),
EAGLE6)
are
and
associates
and
applied
to
this
tis.
by
cause
effectiveness
against
inflammation,
50ƒÊg/ ml
Table
since
is sustained
2.
This
rum
antibiotic
tant
element
a serum
for
theory,
over
drug
bacteria
2 hrs,
as
that
ignores
in
only
se-
concentration
the
impor-
within
in
tissue-
20:
the
tissue
a factor
that
tration
of
can
as
the
impossible
was
addressed
an
antibiotic
in
concentration
that
achived
However,
be
in
acute
increase
to
by
measure
benign
prostatic
inflammation
vascular
perfusion
be
antibiotics
tissue.
med
Therefore,
prostate,
against
than
greater
we
bacteria
02.5ƒÊg/
that
for
J.
may
per-
7)
which
the
data
to
CPZ
MIC
prostatic
the
is
of
and
reported
infla-
be
for
Serratia,
bacter,
calis
and
are
often
benign
prostatic
of CPZ
against
μg/ml
in
Pseudomonas,
Klebsiella
every
species
detected
in urine
hyperplasiam.
these
Proteus,
and
bacteria
is less
case12),
CPZ
after
Med.
lower
seems
capable
&
N.
M. HI-
Y. KATAYAMA:
Entero-
the
for
and
based
10)
MIC
with
between
N. Engl.
1953
Dosage
in
schedule
in
sepsis
proposed
vitro-
in
results.
Saishin-
Prostatitis.
Urol.
dosage
vivo
experi-
Igaku
32:
1977
2:
3•`27,
Clin.
N.
1975
Problems
prostatitis;
and
mixed
in diagnosis
gram-
negative,
infection.
J.
of bactegram-
Urol.
posi-
111:
630
1974
OHKAWA,
M.;
M. SHIMAMURA,
MIYAZAKI&
chronic
of
ganisms.
con-
interval
efficacy.
the
clinical
"Con-
therapy
of
cephaloridine
on
Nishi
1981
M. LEVY
T. INAMATSU:
DRACH, G. W..
636,
cefoperazone.
481•`488,
between
and
than 12.5
trolling the majority of these organisms and is considered clinically useful.
Acknowledgments:
The authors are grateful to
Mt. MASASHINOGUCHI, Department of Technology,
Toyama Chemical Industry Co., Ltd. for his helpful suggestions in the pharmacokinetic
analysis of
CPZ.
References
1) ADACHI,B.: Study of prostatic tissue and seminal plasma levels of chemotherapy agents.
248:
MEARES, E. M.:
tive
fae-
of
"discontinuous"
cephalothin
Am.
operation
Although
87•`93,
MATSUMURA,
414•`418,
The
effect
on
therapeutic
1497•`1504,
9)
prostati-
Streptococcus
is not
29:
gland
H. TAKAMOTO,
K. NANBA
43:
SHIMADA, K.&
rial
tis8•`10).
N.
the
Jpn.
Y.
R. FLEISCHMAN&
vs
ments
epidermidis
responsible
FUJII,
prostatic
between
Urol.
levels
Urol.
schedule
effective
CPZ
Staphylococcus
to
prostatiH.
E. ISHIZUKA&
T. ARAKI,
relationship
8)
coli
been
our
Acta.
tissue
J.
penicillin.
injections
ml.
Escherichia
have
applying
conclude
of
1982
Difference
K.;
EAGLE, H.;
tinuous"
prostate
to
70:
Current
cefoperazone
T. TANAHASHI,
same
permeability,
access
of
A. KONDO,
; nor
hyperplasia.
of the
and
the
6)
of
mitting
Urol.
I. KONDO,
A. IWASAKI,
capsule.
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ISHITO,
in-
concen-
prostate
to
J.
CUNHA
SHIMA-
the
inflamed
assumed
ery-
sulfame-
1983
Nihon
is clinically
fluid
of
therapy
MIURA,
study
levels:
and
5)
al7).
It
Jpn.
338•`345,
T.
A
Prostatic
DA et
prostatic
methylch-
B. A.
antimicrobial
Urology
FUKUSHIMA, S.;
RANO,
flamed
and
Concentrations
and
A. M.&
KITAJIMA:
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shown
concerns
and
596•`
de-
concentration
however,
concentration
of
many
2.
trimethoprim.
M. HIROKAWA,
monstrates
69:
of chemothera-
1979
RISTUCCIA,
concepts
and
agent
Urol.
aminobenzylpenicillin,
403•`409,
3)
cephalothin
CPZ,
levels
tissue
plasma.
thoxazole-
antibio-
experiments
4)
SHIMADA
J.
of
sulfamethoxa-
lorophenylisoxazolylpenicillin,
surgery.
for
from
cephaloridine
admin-
Jpn.
Study
prostatic
or seminal
g, and
thromycin,
was
and
1978
SAKURAGI, T.:
peutics
the
doxycycline
trimethoprim.
603,
2)
tissue.
resected
was
21
cap-
K. KURODA:
prostatitis,
T. MISAKI,
Clinical
especially
Rinsho
Hinyokika
K.
studies
of
of
isolated
29
or-
771•`776,
1976
11)
SAITO,
& I. KONDO:
of surgery
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Nishi
996,
12)
K.
prognosis
N.&
antibacterial
ous
als.
infection
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J.
and
prostatic
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44:
hy989•`
1982
KOSAKAI,
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Urinary
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with
T. OGURI:
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Comparison
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CHEMOTHERAPY
22
JAN.
前 立 腺 肥 大症 患 者にCefoperazone(CPZ)one
shot静
1987
注後の血中
お よび 前 立 腺 組 織 移 行 濃 度 の 薬 動 力学 的 解 析
福島
修 司 ・三 浦
猛 ・菅 原
横浜市立市民病院泌尿器科
敏道
近 藤 猪 一 郎 ・藤
井
浩
神奈川県立成人病センター泌尿器科
広
石
川
信 ・岩
崎
藤沢市民病院泌尿 器科
塚
栄
一 ・北
島
晧
直
登
横浜赤十字病院泌尿器科
CPZ
1gを 前立腺肥大症患 者53名 の手術前に静注 し,血 清および摘 出前立腺 組織内濃度を測定し,薬 動力学
的解析を試みた。
血 清濃度は高 く維持 され,生 物学的半減期(T1/2β)は133分 であ った。 恥骨 後式前 立腺摘出術施 行例の 前立
腺組織は 左右両葉 とも8.6分 で最高濃度に達し,そ の濃度は30.5μg/g,33.3μg/gで
あった。被膜は10.3分
で最高濃度に達 し,そ の濃度は34.3μg/gで あった。経尿道的 切除例では2.3分 で最高濃 度39.8μg/gに 達 し
ていた。 どの部位 も血清濃度の低下とともに下降 し,同 様な濃度推移を示した。
時 間曲線下面積お よび各部位の濃度の推 移をみ ると,前 立腺炎の起炎菌や前立腺 肥大症 の術後に検 出され る細
菌に対して有効性が高いと判断された。