The clinical impact of cytochrome P450 polymorphisms on anti-epileptic drug therapy

Abstract

The goal of pharmacogenetics is to deliver safe and effective drug therapy. Genetic polymorphisms in cytochrome P450 (CYP) enzyme genes are implicated in the inter-individual variability in pharmacokinetics of anti-epileptic drugs (AEDs). However, the clinical impact of CYP polymorphisms on AED therapy remains controversial. Previous studies have shown that the defective CYP2C9 alleles affect the required dose of phenytoin and the risk of its toxicity. We have reported that the CYP2C19-deficient genotype is associated with the serum concentration of an active metabolite of clobazam, N-desmethylclobazam, and with the clinical efficacy of clobazam therapy. We determined also the influence of polymorphisms in CYP genes on the population pharmacokinetic parameters of AEDs using a non-linear mixed effect modeling program, which enables us to define relevant genetic factors together with other factors, and the magnitude of the effect on variation in pharmacokinetics in patients. The defective alleles of CYP2C9 and CYP2C19 were found to have significant effects on the inter-individual differences in clearance of phenobarbital and zonisamide, respectively. Based on these recent findings, we discuss the clinical significance of AED dose adjustment according to both genetic and non-genetic factors that affect CYP activity.