[Development of rapid genotyping methods for single nucleotide polymorphisms of cytochrome P450 2C9 (CYP2C9) and cytochrome P450 2C19 (CYP2C19) and their clinical application in pediatric patients with epilepsy]

Abstract

Genetic polymorphism of cytochrome P450 2C9 (CYP2C9) and cytochrome P450 2C19 (CYP2C19) is widely known to contribute to interindividual differences in the pharmacokinetics of some antiepileptic drugs. We developed a rapid detection assay of polymorphisms of CYP2C9 and CYP2C19, using the Light Cycler(®) polymerase chain reaction (PCR) system. Using this assay, we examined polymorphisms in 20 Japanese pediatric patients prescribed phenytoin for the treatment of epilepsy, and classified their polymorphisms into four groups: group I, CYP2C9*1/*1 and CYP2C19*1/*1; group II, CYP2C9*1/*1 and CYP2C19*1/*2 or *1/*3; group III, CYP2C9*1/*1 and CYP2C19*2/*2; and group IV, CYP2C9*1/*3 and CYP2C19*1/*2 or *1/*3. The mean maximal elimination rates (V(max)) in groups I, II, III and IV were 13.1, 11.2, 10.2 and 8.0 mg/day/kg, respectively, with statistically significant differences among groups (p=0.012, Kruskal-Wallis analysis). The intrinsic metabolic activity (V(max)/K(m)) of groups I, II, III and IV were 2.9, 2.2, 1.5 and 1.1 l/day/kg, respectively (p=0.009), again with significant differences among groups. These findings indicate that polymorphism of CYP2C9 and CYP2C19 plays an important role in phenytoin metabolism in children. With a total processing time for this assay of less than 3 hours, prediction of the optimal phenytoin dosage based on the CYP2C9 and CYP2C19 genotypes will be possible before commencement of therapy, resulting in the prevention of phenytoin overdoses in pediatric patients with epilepsy.