The role of pharmacogenetics in the metabolism of antiepileptic drugs: pharmacokinetic and therapeutic implications.

Several different factors, including pharmacogenetics, contribute to interindividual variability in drug response. Like most other agents, many antiepileptic drugs (AEDs) are metabolised by a variety of enzymatic reactions, and the cytochrome P450 (CYP) superfamily has attracted considerable attention. Some of those CYPs exist in the form of genetic (allelic) variants, which may also affect the plasma concentrations or drug exposure (area under the plasma concentration-time curve [AUC]) of AEDs. With regard to the metabolism of AEDs, the polymorphic CYP2C9 and CYP2C19 are of interest. This review summarises the evidence as to whether such polymorphisms affect the clinical action of AEDs. In the case of mephenytoin, defects in its metabolism may be attributable to >10 mutated alleles (designated as *2, *3 and others) of the gene expressing CYP2C19. Consequently, poor metabolisers (PMs) and extensive metabolisers (EMs) could be differentiated, whose frequencies vary among ethnic populations. CYP2C19 contributes to the metabolism of diazepam and phenytoin, the latter drug also representing a substrate of CYP2C9, with its predominant variants being defined as *2 and *3. For both AEDs, there is maximally a 2-fold difference in the hepatic elimination rate (e.g. clearance) or the AUC between the extremes of EMs and PMs which, in the case of phenytoin (an AED with a narrow 'therapeutic window'), would suggest a dosage reduction only for patients who are carriers of mutated alleles of both CYP2C19 and CYP2C9, a subgroup that is very rare among Caucasians (about 1% of the population) but more frequent in Asians (about 10%). The minor contribution of CYP2C19 to the metabolism of phenobarbital (phenobarbitone) can be overlooked. In rare cases, valproic acid can be metabolised to the reactive (hepatotoxic) metabolite, 4-ene-valproic acid. It is not yet clear whether genetic variants of the involved enzyme (CYP2C9) are responsible for this problem. Likewise, the active metabolite of carbamazepine, carbamazepine-10,11-epoxide, is transformed by the microsomal epoxide hydrolase, an enzyme that is also highly polymorphic, but the pharmacokinetic and clinical consequences still need to be evaluated. Pharmacogenetic investigations have increased our general knowledge of drug disposition and action. As for old and especially new AEDs the pharmacogenetic influence on their metabolism is not very striking, it is not surprising that there are no treatment guidelines taking pharmacogenetic data into account. Therefore, the traditional and validated therapeutic drug monitoring approach, representing a direct 'phenotype' assessment, still remains the method of choice when an individualised dosing regimen is anticipated. Nevertheless, pharmacogenetics and pharmacogenomics can offer some novel contributions when attempts are made to maximise drug efficacy and enhance drug safety.