Evaluation of Phenytoin Dosage Regimens Based on Genotyping of CYP2C Subfamily in Routinely Treated Japanese Patients

Abstract

Two research groups have reported the effect of genetic polymorphisms of CYP2C9 and CYP2C19 on the pharmacokinetic parameters of phenytoin in Japanese epileptic patients. We measured the plasma phenytoin concentrations at steady-state in 20 routinely treated Japanese patients, and evaluated the usefulness of genotyping the CYP2C subfamily in predicting plasma concentrations and determining the dosage regimens of phenytoin. The plasma phenytoin concentrations predicted by genotypes of the CYP2C subfamily were well correlated with the observed concentrations in some patients, but not in some patients. The pharmacokinetic parameters (Vmax and Km) in individual patients, which were obtained from population estimates according to Bayes' theorem, showed considerable interindividual variability even among patients with the same genotype. In addition, we assessed the effect of plasma protein binding on the residual interindividual variability in the clearance of phenytoin; however, there was no significant correlation between the unbound fraction and the intrinsic metabolic activity (Vmax/Km). These findings suggested that the mechanism responsible for the large variability in the clearance of phenytoin is not completely resolved, and that we should not overestimate the usefulness of genotyping the CYP2C subfamily in determining the dosage regimens of the drug.