Carbamazepine induces multiple cytochrome P450 subfamilies in rats

Abstract

We compared the effect of three different doses (30, 60, and 100 mg/kg) of carbamazepine (CBZ) administered intraperitoneally for 1, 3, and 7 days on the activity and protein content of hepatic cytochrome P450 (CYP) subfamilies in Sprague–Dawley rats. After 3-day- and 7-day administration with CBZ, the total CYP content had increased in a dose-dependent fashion. Among six enzyme activities examined, only aniline hydroxylase activity remained unchanged after 7-day treatment with CBZ. Pentoxyresorufin O-deethylase activity showed the most significant increase and was induced up to 7 days in a time-dependent fashion. Pretreatment of rats with cycloheximide significantly suppressed the pentoxyresorufin O-deethylase induction by one dose of 100 mg/day CBZ. Immunoblot analysis showed a significant correlation between the protein content of each isoenzyme examined and its activity except CYP2E1 after 7-day treatment with CBZ. Similar results were obtained in the mRNA levels of CYP subfamilies. These results suggested that CBZ may induce multiple CYP subfamilies, except CYP2E1, and the activity and the protein content of CYP2B showed the greatest increase with increased CYP2B mRNA.

Introduction

Carbamazepine (CBZ) is used for the treatment of partial and tonic-clonic seizures and trigeminal neuralgia [1]. Since both therapeutic and adverse effects, such as drowsiness, diplopia, and ataxia, are related to the plasma concentration of CBZ [2], therapeutic drug monitoring is essential to obtain efficacy and avoid toxicity. The therapeutic plasma concentration is considered between 6 and 10 μg/ml.

CBZ undergoes hepatic metabolism consisting of epoxide, aromatic hydroxylation, and conjugation pathways [3]. CBZ has a low systemic clearance at the start of therapy, but its clearance increases during long-term therapy [3]. The change in clearance is attributable to the drug's enzyme-inducing property [3]. CBZ is known to induce the metabolism of a number of drugs [4], [5], [6], [7], [8] as well as its own metabolism. For example, CBZ reportedly induces CYP3A and CYP2B in humans and rats [7], [8], [9]. CBZ epoxide, a major metabolite of CBZ, also reported to induce these CYP subfamilies in rats [9]. However, previous case reports suggested co-administration of CBZ induces the metabolism of warfarin, phenytoin, and theophylline. Warfarin and phenytoin are substrates for CYP2C9 [10], [11] and theophylline is for CYP1A2 [12]. These clinical observations imply that CBZ may induce more CYP subfamilies than CYP2B and CYP3A. We, therefore, investigated which CYP subfamilies were induced in hepatic microsomes of rats treated with CBZ and how the dose and the duration of CBZ treatment affected the enzyme induction. The present data clearly indicate that CBZ induces several CYP subfamilies with increased mRNA levels and most significant induction is found in CYP2B.