Metabolic Characteristics of Oxcarbazepine (^®Trileptal) and their Beneficial Implications for Enzyme Induction and Drug Interactions

Abstract

Hepatic oxygenases of the cytochrome P-450 family play a major role in the clearance of various anti-epileptic drugs. These enzymes are susceptible both to induction and to inhibition. Phenytoin, carbamazepine (CBZ), primidone, and phenobarbitone, for instance, are potent enzyme inducers. Other drugs, such as chloramphenicol, propoxyphene, verapamil, and viloxazine, inhibit cytochrome P-450. Pharmacokinetic behaviour is thus often altered, especially in combined medication, so that the dosage has to be re-adjusted if an optimum therapeutic outcome is to be ensured.Oxcarbazepine (OXC) is a keto analogue of CBZ. In the human liver the keto group is readily reduced, and the resulting monohydroxy metabolite is cleared by glucuronidation. The two enzymes mediating these reactions, i.e. aldo-keto reductase and UDP-glucuronyltransferase, do not depend on cytochrome P-450. The monohydroxy metabolite is the major active substance in plasma. Its elimination is not enhanced by OXC. Moreover, OXC seems to have little effect on cytochrome P-450. Aldo-keto reductases and glucuronyltransferases are in general less sensitive to induction and inhibition than are P-450 dependent enzymes. On the whole, OXC possesses very little potential for metabolic drug interactions, and thus differs favourably from other anti-epileptic drugs.

Development and validation of a high performance liquid chromatographic method for the determination of oxcarbazepine and its main metabolites in human plasma and cerebrospinal fluid and its application to pharmacokinetic study

“…Following oral administration, oxcarbazepine is completely absorbed and extensively reduced by a non inducible aldo-keto reductase to its pharmacologically active metabolite 10-hydroxy-10,11-dihydrocarbamazepine [9,10], which is further metabolized by glucuronidation and excreted into urine [11]. A small percentage of 10-hydroxy-10,11-dihydrocarbamazepine is oxidized through hepatic CYP3A4/5 isoenzymes to the inactive metabolite 10,11-dihydroxy-trans-10,11-dihydrocarbamazepine [12].…”

Oxcarbazepine Placebo‐Controlled, Dose‐Ranging Trial in Refractory Partial Epilepsy

“…To investigate potential interactions with plasma MHD concentrations, ratios of mean steady-state (visits [6][7][8][9][10][11][12] to mean baseline (visits 1-3) plasma concentrations were calculated for each of the following concomitant AEDs: CBZ, valproic acid, phenobarbital, PHT, vigabatrin, clobazam, lamotrigine, clonazepam, primidone, diazepam, and gabapentin. Blood samples to determine trough plasma MHD concentrations were collected before the morning drug dose at visits 3, 6, 7, 9, 11, and 12. Approximately 7 mL of venous blood were collected and centrifuged at room temperature immediately after collection.…”

“…Although OXC is pharmacologically active, MHD is believed to be largely responsible for the pharmacologic effect (11,12). OXC has several distinct characteristics that are highly relevant to the clinical management of epilepsy.…”

“…OXC has several distinct characteristics that are highly relevant to the clinical management of epilepsy. Unlike standard AEDs (e.g., PHT, CBZ, valproic acid), OXC is not oxidatively metabolized and therefore has an extremely low potential for the induction of hepatic enzymes (11,13,14). In an in vitro study, OXC and MHD were shown to have a low potential to inhibit the major human cytochrome P450 (CYP450) enzymes responsible for the metabolism of other drugs, with the exception of CYP2C19, which metabolizes drugs such as phenobarbital and PHT (15).…”

Development and validation of a LC/MS/MS method for simultaneous quantification of oxcarbazepine and its main metabolites in human serum

“…The predominant one is the MHD-glucuronide conjugation mediated by the UDPglucuronyltransferase, while a minor amount (approximately 4%) is oxidised into its pharmacologically inactive metabolite, the 10,11-trans-hydroxycarbazepine (DHD), 10,11-dihydro-10,11-trans-dihydroxy-5H-dibenz [b,f] azepine-5-carboxamide [4]. Both OXC and MHD do not show self-induction characteristics and, moreover, do not seem to influence, by inhibition or by induction, the P450 cytochrome system, catalyst for the metabolic ways of many drugs, avoiding problems of interactions with other substances in eventual multiple therapies [5]. Because the OXC has a minor tendency to interact with other drugs it can be administered both as monotherapy and 1570-0232/$ -see front matter © 2007 Elsevier B.V. All rights reserved.…”