Effect of Four‐Day Treatment with Carbamazepine at Different Dose Levels on Microsomal Enzyme Induction, Drug Metabolism and Drug Toxicity

Regnaud, L.; Sirois, G; Chakrabarti, Swapan

doi:10.1111/j.1600-0773.1988.tb01834.x

Cited by 22 publications

(3 citation statements)

References 11 publications

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“…We have shown that term perfused human placenta from a normal pregnancy does not metabolize CBZ. Although CBZ induces its own metabolism in vivo (mediated by CYP3A4) (5,6,(32)(33)(34), and there are indications that AEDs induce CYP1 Amediated AHH activity in the placenta (35), our results suggest that CBZ does not affect placental CYP enzymes. This was reflected both in the perfusion and in the in vitro studies by the lack of detectable CYP enzyme induction in placentas from mothers receiving CBZ therapy.…”

Section: Discussionmentioning

confidence: 61%

Pharmacokinetics of Oxcarbazepine and Carbamazepine in Human Placenta

et al. 1997

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Summary:Purpose: To study the transfer and metabolism of oxcarbazepine (OCBZ) and 10-hydroxy-10,l l-dihydrocarbamazepine (10-OH-CBZ) and carbamazepine (CBZ) metabolism and its possible induction in human placenta.Methods: A dual recirculating human placental perfusion system, blood sampling, high performance liquid chromatography (HPLC), reverse transcriptase-polymerase chain reaction (RT-PCR), and enzyme assays.Results: OCBZ was metabolized into 10-OH-CBZ in five human placental cotyledons perfused for 2 h in a dual recirculating perfusion system. The same metabolite was found by HPLC in three sample pairs of maternal and cord blood taken during delivery from patients on OCBZ therapy. In all of the clinical samples, 10,1l-trans-dihydroxy-l0,1 l-dihydrocarbamazepine (l0,ll-D) was also found, but not in the perfusions. In addition, 10-OH-CBZ was not metabolized in the placental perfusions. The transfer of OCBZ through the perfused placentas was quicker than the transfer of antipyrine, while the transIt has been known for some time that the placenta is able to metabolize drugs (1,2). Interspecies differences in the placental structure are so significant that results obtained from animal experiments cannot be directly generalized to apply to humans (3). For ethical reasons, in vitro placental perfusion is the only way for thorough investigation of pharmacokinetics in the human placenta.Pregnant women are frequently treated with carbamazepine (CBZ). CBZ undergoes almost complete biotransformation (4), and it induces its own metabolism (5,6), as do many other antiepileptic drugs (AEDs) (7).CBZ is metabolized mainly (40%) through oxidation into CBZ-10,ll-epoxide (CBZ-E), which is thought to be responsible for the side effects of CBZ, including teratogenicity (8,9). However, this epoxide is not reactive and does not bind significantly to macromolecules (10,ll). The principal catalyst of CBZ-E formation in human liver is cytochrome P-450 (CYP3A4) (12).Accepted October 28, 1996. Address correspondence and reprint requests to Dr. P. Pienimiiki at Department of Pharmacology and Toxicology, University of Oulu, Kajaanintie 52 D, Finland. fer of 10-OH-CBZ was slower. Both OCBZ and 10-OH-CBZ also accumulated in placental tissue. CBZ metabolism was studied in three perfusions using placentas from mothers on CBZ therapy. No metabolism could be detected in the perfused placentas, while metabolites were found in both maternal and cord blood of the same mothers. Another series of placentas of mothers on CBZ therapy did not differ significantly from the placenta of a healthy mother as to CYP activities or the level of CYP3A4 mRNA.Conclusions: OCBZ is metabolized into 10-OH-CBZ to some extent in human placenta in vitro, suggesting that the placenta also participates in the metabolism of OCBZ in vivo. On the contrary, the placenta does not participate in the metabolism of CBZ. No induction of placental CBZ metabolism in vitro can be detected after maternal CBZ treatment during pregnancy. Key Words: Carbamazepine metabolites-Oxcarb...

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Section: Discussionmentioning

confidence: 61%

Pharmacokinetics of Oxcarbazepine and Carbamazepine in Human Placenta

et al. 1997

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“…The major pathway is the enzymes, including CYP3A [5,6], the isoform resequential epoxidation and hydrolysis of CBZ to sponsible for the epoxidation of CBZ [7,8]. The form the stable 10,11-epoxide and trans-dihydrodiol, further metabolism of epoxides to diols is dependent on microsomal epoxide hydrolase (mEH) [4]; animal studies [9] and indirect pharmacokinetic evidence in man [10,11] suggest that hepatic mEH is inducible by CBZ. A more recent study which used carbamazepine-10,1 -epoxide as an in vivo probe for mEH has provided more direct evidence for the inducibility (by phenytoin and phenobarbitone) of the hepatic enzyme [12].…”

Section: Introductionmentioning

confidence: 99%

Lymphocyte microsomal epoxide hydrolase in patients on carbamazepine therapy.

Pirmohamed

Allott

Green

et al. 1994

Brit J Clinical Pharma

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1. In order to determine whether carbamazepine is an inducer of lymphocyte microsomal epoxide hydrolase, the activity of the enzyme has been measured in the lymphocytes of 40 patients on continuous drug therapy using [3H]‐cis stilbene oxide as a substrate. 2. Induction of the cytochrome P450 isoform, CYP3A, has been assessed in the same patients by measurement of the 24 h urinary excretion of 6 beta‐ hydroxycortisol by radioimmunoassay. The urinary concentrations of carbamazepine and its two metabolites, the 10,11‐epoxide and trans‐ dihydrodiol, have also been measured by h.p.l.c. 3. The 24 h urinary 6 beta‐hydroxycortisol excretion in the patients increased with the dose of carbamazepine (r = 0.57, P < 0.001) indicating induction of CYP3A. 4. The total amount of trans‐dihydrodiol excreted in the urine increased with the dose of carbamazepine, and it was the most abundant urinary metabolite in all patients and at all dose‐levels. There was no relationship between the dose of carbamazepine and the diol to epoxide ratio (r = 0.01, NS). 5. Lymphocyte microsomal epoxide hydrolase activity was marginally, but significantly (P = 0.02) higher in the patients (28.4 pmol diol min‐1 mg‐1 protein) than in drug‐free controls (23.4 pmol diol min‐1 mg‐1 protein (95% CI for difference ‐9 to ‐0.8)). 6. The results indicate that at concentrations of carbamazepine which produce marked induction of hepatic CYP3A, an enzyme involved in the metabolism and bioactivation of carbamazepine, there is only a slight increase in lymphocyte microsomal epoxide hydrolase.

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“…It has for a very long time been known that the classical antiepileptic drugs, phenobarbital and phenytoin are dangerous to porphyria patients. There is also evidence against the safety of carbamazepine and valproate (Bonkowsky et al 1980;McGuire et al 1988;Regnaud et al 1988). Treatment of epileptic seizures in patients with suspected or diagnosed porphyria thus represents a difficult problem.…”

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Effect of Tiagabine and Topiramate on Porphyrin Metabolism in an in vivo Model of Porphyria

Krijt

Krijtová

Sanitrák

2001

Pharmacology & Toxicology

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Administration of many antiepileptic drugs to patients with porphyria can precipitate an acute porphyric crisis. Information on the porphyrogenic activity of new antiepileptic drugs is still limited. In the presented study, the effects of tiagabine and topiramate on porphyrin metabolism were evaluated in an in vivo model of porphyria. Administration of the protoporphyrinogen oxidase inhibitor oxadiazon (12.5 mg/kg/day) for four days to male Wistar rats caused a partial block of porphyrin biosynthesis, thus mimicking the condition of quiescent variegate porphyria. Administration of phenobarbital (75 mg/kg/day) to oxadiazon-pretreated rats increased liver porphyrin content, liver porphobilinogen content (means 480 nmol/g, control less than 20 nmol/g) and urinary excretion of porphobilinogen (means 1000 mmol/l, control less than 20 mmol/l). Tiagabine (75 mg/kg/day) and topiramate (75 mg/kg/day) increased liver porphobilinogen content (means 33 and 53 nmol/g respectively) and urinary porphobilinogen concentration (240 and 490 mmol/l respectively). Similar results were obtained in oxadiazon-treated BALB/c mice. In untreated rats, tiagabine and topiramate caused a moderate increase of hepatic pentoxyresorufin-O-dealkylase activity (approximately 100 and 200 pmol/min./mg respectively, controls 15 pmol/min./mg). These data demonstrate that administration of tiagabine or topiramate to oxadiazontreated animals can provoke a condition resembling an acute porphyric attack and suggest that administration of these drugs to patients with suspected porphyria should be avoided. However, 5-day administration of both tiagabine and topiramate (75 mg/kg) is considerably less porphyrogenic than phenobarbital administered at the same dose.

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Effect of Four‐Day Treatment with Carbamazepine at Different Dose Levels on Microsomal Enzyme Induction, Drug Metabolism and Drug Toxicity

Cited by 22 publications

References 11 publications

Pharmacokinetics of Oxcarbazepine and Carbamazepine in Human Placenta

Pharmacokinetics of Oxcarbazepine and Carbamazepine in Human Placenta

Lymphocyte microsomal epoxide hydrolase in patients on carbamazepine therapy.

Effect of Tiagabine and Topiramate on Porphyrin Metabolism in an in vivo Model of Porphyria

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