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Antimicrobial Agents and Chemotherapy, December 1998, p. 3136-3140, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Possible Mechanism by Which the Carbapenem
Antibiotic Panipenem Decreases the Concentration of Valproic Acid
in Plasma in Rats
Saori
Kojima,1
Masayuki
Nadai,2
Kiyoyuki
Kitaichi,3
Li
Wang,4
Toshitaka
Nabeshima,1 and
Takaaki
Hasegawa3,*
Department of Hospital Pharmacy, Nagoya
University School of Medicine, Nagoya 466,1
Laboratory of Clinical Pharmacology and Therapeutics, Gifu
Pharmaceutical University, Gifu 502,2 and
Department of Medical Technology, Nagoya University School
of Health Sciences, Nagoya 461,3, Japan, and
Department of Pharmacology, School of Pharmacy, West China
University of Medical Sciences, Chengdu 610041, Sichuan,
China4
Received 1 December 1997/Returned for modification 2 August
1998/Accepted 1 September 1998
 |
ABSTRACT |
There is evidence indicating that the carbapenem antibiotic
panipenem decreases plasma concentrations of valproic acid (VPA) in
epileptic patients during VPA therapy. The mechanism for
panipenem-induced changes in the pharmacokinetics of VPA was
investigated in rats with and without bile duct cannulation. The effect
of panipenem on the pharmacokinetics of diclofenac, which undergoes
extensive enterohepatic recirculation, was also examined. VPA (50 mg/kg of body weight) or diclofenac (10 mg/kg of body weight) was
administered intravenously under the steady-state plasma panipenem
concentration of 4 µg/ml, which had been achieved by a constant
infusion rate. Panipenem decreased the plasma VPA concentrations in
rats without bile duct cannulation but did not change the volume of the
initial space and protein binding of VPA. However, panipenem had no
effect on the plasma VPA concentrations and the biliary excretion of VPA in rats with bile duct cannulation. The secondary increase in
plasma diclofenac concentration observed in the absence of panipenem
was diminished in the presence of panipenem. These findings suggest
that panipenem decreases plasma VPA concentrations by suppressing its
enterohepatic recirculation, probably due to a panipenem-induced
decrease in the numbers of enteric bacteria.
| |
INTRODUCTION |
The antiepileptic valproic acid
(VPA) is widely used as a drug of first choice in the treatment of
epileptic patients with generalized tonic-clonic and partial seizures.
Its therapeutic range of 50 to 150 µg/ml is widely accepted (2,
3, 16, 21, 25). Since a concentration in plasma above 200 µg/ml
appears to be commonly associated with adverse reactions, it is
important in clinical therapy with VPA to maintain its therapeutic
concentration range. VPA, therefore, is one of the drugs requiring the
routine monitoring of concentrations in plasma in order to avoid
subtherapeutic or toxic doses. It is well known that VPA is rapidly
absorbed through the gastrointestinal tract, distributed throughout the body, and extensively metabolized in the liver, and it is primarily excreted into the bile in a glucuronide conjugate form (4, 16).
A large number of developed carbapenem antibiotics are widely used in
the treatment of patients with various infectious diseases. One of
these antibiotics is panipenem, which possesses potent activity against
both gram-positive and gram-negative bacteria and is important for the
effective treatment of patients afflicted with serious infections
(7). There is a possibility that panipenem may be
administered to epileptic patients undergoing VPA therapy when these
patients present with serious bacterial infections. Indeed, it has
recently been reported that seizures were induced when panipenem was
administered to epileptic patients during chronic VPA therapy; these
seizures were coincident with decreased concentrations of VPA in
plasma, which continued to decrease with increasing duration of
panipenem treatment (23a). To our knowledge, no data is available on
the precise mechanism by which coadministration of panipenem produces a
decreased concentration of VPA in plasma.
As part of a program for the development of guidelines for the safe use
of antibiotics in patients receiving VPA treatment, the goal of the
present study was first to clarify the possible mechanism of the
pharmacokinetic interaction between VPA and panipenem by using rats.
Secondly, the nonsteroidal anti-inflammatory agent diclofenac was
studied as a model drug, since it is excreted into the bile in a
primarily glucuronide conjugate form more often than other well-known
drugs in rats (8, 11, 18). Thus, the effect of panipenem on
the enterohepatic recirculation of diclofenac was also investigated.
| |
MATERIALS AND METHODS |
Chemicals.
Panipenem, which consists of
N-benzoyl-
-alanine (betamipron), was used in this study
in the form of a commercial preparation for injection (Carbenin; Sankyo
Co. Ltd., Tokyo, Japan). VPA sodium salt, diclofenac sodium salt, and
the internal standard, mefenamic acid, were purchased from Sigma
Chemicals (St. Louis, Mo.). All other chemicals were commercially
available and were of analytical grade. Panipenem, VPA sodium salt, and
diclofenac sodium salt were dissolved in isotonic saline solution for
intravenous administration.
Animals and experiments.
Eight- to 9-week-old male Wistar
rats (Japan SLC, Hamamatsu, Japan) weighing 280 to 300 g were used
for all experiments. The rats were housed under controlled
environmental conditions (approximately 25°C) with a commercial food
diet and water freely available.
To elucidate the pharmacokinetic interactions between panipenem and VPA
or diclofenac, the rats were cannulated under light anesthesia with
pentobarbital (25 mg/kg of body weight) with polyethylene tubes in the
right jugular vein for drug administration and blood sampling and in
the left femoral vein for infusion of panipenem (these rats are
hereafter referred to as rats without bile duct cannulation). Panipenem
was injected in a bolus loading dose of 250 µg/kg followed by a
constant-rate infusion maintained at a dose of 8.3 µg/min through the
femoral vein to achieve the desired steady-state concentration of 4 µg/ml, which was observed clinically. This dosage of panipenem was
calculated by using pharmacokinetic parameters described previously
(13). After 60 min of panipenem infusion, VPA sodium salt
(50 mg/kg as VPA) or diclofenac sodium salt (10 mg/kg as diclofenac)
was injected. To elucidate the effects of panipenem on the biliary
excretion of VPA, the right jugular vein (for drug administration and
blood sampling), the left femoral vein (for infusion of panipenem), and
the bile duct (for bile collection) were cannulated (these rats are
hereafter referred to as rats with bile duct cannulation). To
investigate the effect of panipenem on the enterohepatic circulation of
VPA, panipenem was directly injected into the duodenum. VPA (50 mg/kg)
was administered intravenously 1 h after a single intraduodenal
administration of panipenem (1.9 mg/kg) in rats without bile duct
cannulation. The dose of panipenem is equivalent to that (loading dose
plus maintenance dose administered for 1 h) used in experiments
with panipenem infusion.
In all experiments, the rats were placed in plastic metabolic cages
(Natsume, Tokyo, Japan) under anesthesia with pentobarbital. Body
temperatures were maintained at 37°C throughout the experiments with
the assistance of heat lamps. The control group was treated with
isotonic saline in place of panipenem. Blood samples of approximately 0.25 ml were collected at appropriate intervals after the
administration of VPA or diclofenac and were immediately centrifuged at
6,000 × g for 5 min to yield plasma samples. Bile
samples were collected in preweighed tubes at three consecutive 30-min
time points. The volume of bile was measured gravimetrically, with
specific gravity assumed to be 1.0. Plasma and bile samples were stored
at 
40°C.
Protein binding experiments.
The effect of panipenem on the
plasma protein binding of VPA was examined by the micropartition
equilibrium dialysis method by using a cellulose membrane (Visking
sheet; Samplatec Corp., Osaka, Japan) with a molecular cutoff of 10,000 to 20,000. Blood samples were obtained from the rats in the presence
and absence of panipenem by exsanguination from the abdominal aorta
under light ether anesthesia, and plasma samples were obtained.
VPA-spiked isotonic phosphate buffer (pH 7.4) samples of various
concentrations (25 and 50 µg/ml) were immediately dialyzed against an
equal volume of plasma at 37°C for 6 h.
Drug analysis.
The concentration of VPA was measured by the
fluorescence polarization immunoassay (FPIA) method with a TDX analyzer
(Abbott Laboratories, North Chicago, Ill.). The concentration of VPA in plasma and on both sides of the dialysis membrane was measured directly
by the FPIA method. The concentration of VPA in the bile was measured
by appropriate dilution with phosphate buffer (pH 7.4). Free VPA,
released by hydrolysis of conjugate in the bile, was measured according
to the method described previously (4). Briefly, bile
samples were hydrolyzed with 5N-NaOH for 30 min at 80°C to completely
hydrolyze the conjugate. The solution was neutralized with 5N-HCl and
was then diluted in phosphate buffer solution (pH 7.4). The resultant
solution was mixed with normal plasma (1:1 [vol/vol]) for FPIA assay.
The recovery rate of VPA from the bile was 98%. The intra- and
interassay coefficients of variation ranged from 4 to 6% in plasma and
bile samples with the desired concentrations of VPA added.
The concentration of diclofenac in plasma was measured by
high-performance liquid chromatography (HPLC), with a minor
modification
of the method described previously (
5).
Briefly, the HPLC apparatus
was a Shimadzu (Kyoto, Japan) LC-6A system
consisting of an LC-6A
liquid pump, an SPD-6A UV spectrophotometric
detector, and an
SIL-6A autoinjector. The UV detector was set at 279 nm, and a
Cosmosil 5C
18 column (Nacalai Tesque, Kyoto,
Japan) was used with
a column oven (OTC-6A) heated to 40°C. The
mobile phase consisted
of 1/15 M acetic acid solution-acetonitrile
(1:1 [vol/vol]), and
the flow rate was 1.5 ml/min. One hundred fifty
microliters of
acetonitrile containing mefenamic acid (1 µg/ml) as an
internal
standard was added to 50 µl of plasma sample and vortexed.
After
centrifugation at 6,000 ×
g for 5 min, 150 µl
of the supernatant
was evaporated to dryness under a nitrogen gas
stream at 40°C.
The residue was reconstituted with 200 µl of the
mobile phase
and injected into the HPLC system. The assay was shown to
be linear
for the concentrations studied, with a correlation
coefficient
of 0.999. The within-day and between-day coefficients of
variation
for the assay were less than 7%.
Data analysis.
The data concerning concentrations of VPA in
plasma over time were analyzed individually for each rat by
noncompartmental methods. The area under the plasma VPA
concentration-time curve (AUC) was calculated by the trapezoidal rule
method. The volume of the initial distribution space
(VC) was calculated by dividing the dose by the
concentration in plasma at zero time. The biliary clearance
(CLBILE) was calculated by dividing the total amount of VPA
excreted into the bile within the collection period by the
corresponding AUC. All computer analyses were performed by the
nonlinear least-squares regression program MULTI, written by Yamaoka et
al. (24).
Statistical analysis.
Results are expressed as the
means ± standard deviations for the indicated numbers of
experiments. Statistical analysis was performed by analysis of
variance, with a P value of <0.05 taken as the limit of
statistical significance.
| |
RESULTS |
The present study focused on whether panipenem influences the
protein binding, biliary excretion, and enterohepatic circulation of
VPA in rats. First, the effect of panipenem on concentrations of VPA in
plasma was examined in rats without bile duct cannulation. Mean
semilogarithmic plasma VPA concentration-time curves after a single
intravenous administration at a dose of 50 mg/kg in the presence or
absence of panipenem are illustrated in Fig.
1. Concentrations of VPA in plasma after
30 min of the single injection were significantly lower in the presence
of panipenem than in the absence of panipenem. The estimated
model-independent pharmacokinetic parameters of VPA can be summarized
as follows: AUC (up to the last measured concentration of VPA),
4.51 ± 0.33 and 3.62 ± 0.66 (significantly different
[P < 0.05]) mg · min/ml in the absence and
presence of panipenem, respectively; and VC,
0.333 ± 0.023 and 0.325 ± 0.035 liters/kg in the absence
and presence of panipenem, respectively (each value represents the
mean ± standard deviation [n = 6]). In parallel
with these changes, the AUC up to the last measured concentration of
VPA in plasma was decreased by 20% in the presence of panipenem
compared with that in the absence of panipenem whereas no significant
differences between the Vcs of the two groups
were observed.
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FIG. 1.
Semilogarithmic plots of plasma VPA concentration-time
data after a single intravenous administration in the presence (solid
circles) or absence (open circles) of panipenem in rats without bile
duct cannulation. Each plot represents the mean ± standard
deviation (n = 6). a, significantly different from the
concentration in the absence of panipenem (P < 0.05).
|
|
In the second set of experiments, the effect of panipenem on the
biliary excretion of VPA was investigated by using rats with bile duct
cannulation. There were no significant differences between the plasma
VPA concentration-time curves in the presence and absence of panipenem
(Fig. 2). As summarized in Table
1, no significant panipenem-dependent
differences between any pharmacokinetic parameters in the two groups
were observed. There was also no significant difference in the
percentage of VPA (unchanged plus conjugated) recovered from bile over
the 90-min experimental period with or without panipenem (Fig.
3).
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FIG. 2.
Semilogarithmic plots of plasma VPA concentration-time
data after a single intravenous administration in the presence (solid
circles) or absence (open circles) of panipenem in rats with bile duct
cannulation. Each plot represents the mean ± standard deviation
(n = 5 to 6).
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TABLE 1.
Pharmacokinetic parameters of VPA after a single
intravenous administration in the presence or absence of panipenem in
rats with bile duct cannulationa
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FIG. 3.
Biliary excretion of VPA after a single intravenous
administration in the presence (solid bars) or absence (open bars) of
panipenem in rats with bile duct cannulation. Each bar represents
the mean ± standard deviation (n = 6 to 7).
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|
As it is thought that panipenem may influence the numbers of
enterohepatic bacteria, the effect of panipenem on the enterohepatic circulation of VPA was also investigated in rats pretreated with a
single intraduodenal administration of panipenem. As shown in Fig.
4, concentrations of VPA in plasma were
decreased by a single intraduodenal administration of panipenem, and
the corresponding AUC was also decreased by about 20% (4.11 ± 0.81 versus 5.31 ± 1.03 mg · min/ml) but did not reach
statistical significance.
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FIG. 4.
Semilogarithmic plots of plasma VPA concentration-time
data after a single intravenous administration in rats pretreated with
intraduodenal administration of saline (open circles) or panipenem
(solid circles). Each plot represents the mean ± standard
deviation (n = 3).
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|
In the third set of experiments, the effect of panipenem on the
enterohepatic recirculation of diclofenac, used as a model drug, was
further investigated. Figure 5 shows that
concentrations of diclofenac in plasma at 90 and 120 min after a single
intravenous administration were significantly lower in the presence of
panipenem than in the absence of panipenem and that the secondary
increase in the concentration of diclofenac in plasma, which represents enterohepatic recirculation, was diminished by panipenem. Also, there
were no significant differences between the Vcs
of diclofenac in the presence (0.324 ± 0.075 liters/kg) and
absence (0.335 ± 0.064 liters/kg) of panipenem, as was seen with
VPA.
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FIG. 5.
Semilogarithmic plots of plasma diclofenac
concentration-time data after a single intravenous administration in
the presence (solid circles) or absence (open circles) of panipenem in
rats without bile duct cannulation. Each plot represents the mean ± standard deviation (n = 6). a, significantly
different from the concentration in the absence of panipenem
(P < 0.05).
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| |
DISCUSSION |
It is generally accepted that plasma protein binding is the
limiting factor in drug disposition, since only the unbound portion of
a drug is capable of diffusing across various biological membranes to
be distributed in the body and therefore subject to metabolism and
renal excretion. Indeed, the pharmacological activity of a drug is
closely related to the concentration in the blood of the drug which is
unbound to protein. The protein binding potency of VPA in rats is
moderate (approximately 60%), whereas panipenem consists of the
organic transport inhibitor N-benzoyl--alanine (betamipron), which exhibits much stronger protein binding than panipenem (13, 23). Previous studies in our laboratory have demonstrated that the presence of high concentrations of betamipron (400 µg/ml) inhibits the protein binding of enprofylline, which is
highly bound to plasma proteins (>90%) and increases the volume of
distribution (23). Therefore, the effect of panipenem and/or betamipron on the protein binding of VPA was examined. The estimated steady-state plasma betamipron concentration in this study was very low
(<1 µg/ml) compared with that in our previous studies (23), and indeed, the present study confirmed that there
were also no significant differences in the protein binding of VPA after panipenem treatment (data not shown). These results suggest that
panipenem-induced decreases in plasma VPA concentrations are not caused
by changes in the protein binding behavior of VPA.
Several studies have shown that about 50% of the administered dose of
VPA is glucuronidated and the glucuronide is excreted in the bile,
undergoing enterohepatic recirculation in rats (4, 12, 14,
15). The percentages of VPA and its conjugated form excreted in
the bile (approximately 2 and 55% of the VPA dose, respectively) are
in agreement with the results of Dickinson and coworkers
(4). These results suggest that panipenem had no effect on
the biliary excretion and metabolism of VPA.
In general, carbapenem antibiotics cannot be absorbed from the
gastrointestinal tract. A minor part of the panipenem administered is
excreted into the bile (20), whereas the majority is
excreted into the urine by glomerular filtration and an active
tubular-secretion mechanism (13). A number of strains of
anaerobic genera, including Clostridium sp. and
Bacteroides sp., and aerobic genera, including Enterococcus faecalis and Staphylococcus
epidermidis, are well known to be able to deconjugate bile salts.
On the basis of these findings and the evidence that the main
metabolite excreted into the bile is valproate glucuronide conjugate
(4, 9, 15), we propose that panipenem may suppress the
enterohepatic recirculation of VPA.
It is well known that diclofenac is primarily excreted into the bile
and that the major portion of diclofenac administered is converted to
its glucuronide conjugate in the liver and excreted into the bile duct;
diclofenac deconjugated by enteric bacteria is reabsorbed from the gut
(17, 19). In the present study, panipenem tended to decrease
the AUC of diclofenac from 60 to 150 min (AUC60-150),
although the difference found between these measures under the
panipenem (22.8 ± 11.9 mg · min/ml) and control
(50.8 ± 21.3 mg · min/ml) conditions was not
statistically significant. This lack of statistical significance is
probably due to interindividual differences in enterohepatic
recirculation. The lack of significant differences between the
VCs of diclofenac in the presence and absence of
panipenem suggests that panipenem did not change the protein binding
behavior of diclofenac, which is highly bound to plasma protein
(6, 10, 11). The results reported here are thus consistent
with the suggestion that the enterohepatic recirculation of VPA and
diclofenac is suppressed by panipenem-induced decreases in the numbers
of enteric bacteria, which are closely related to the production of
-glucuronidase. This suggestion could be confirmed in future
experiments measuring -glucuronidase activity in the small
intestines of rats.
In conclusion, panipenem decreased the plasma concentrations of both
VPA and diclofenac after a single intravenous administration in rats
without bile duct cannulation but did not change these measures in rats
with bile duct cannulation. The possible mechanism responsible for
panipenem-induced pharmacokinetic changes may involve the suppression
of the enterohepatic recirculation of VPA. On the basis of these
observations, further studies are needed to examine the possibility
that VPA interacts with the other carbapenems, which possess potent
activity against both gram-positive and gram-negative bacteria. It
should be noted that whereas VPA has been shown to undergo extensive
hepatic metabolism and enterohepatic recirculation in rats, this is not
the case in humans, due to species differences in hepatic metabolism
(4, 9, 22). Thus, although the data obtained in this study
cannot be extrapolated directly to humans, the results of the current
study should nonetheless provide useful information for designing drug
regimens in epileptic patients during VPA therapy. This study
demonstrates that care should be taken in prescribing potent
antibiotics to patients receiving chronic VPA therapy.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Medical Technology, Nagoya University School of Health Sciences,
1-1-20 Daikominami, Higashi-ku, Nagoya 461-8673, Japan.
Phone: 81-52-719-1558. Fax: 81-52-719-1506 or 1509. E-mail:
hasegawa{at}met.nagoya-u.ac.jp.
| |
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Abstract
Introduction
