Possible role of CYP2C9 & CYP2C19 single nucleotide polymorphisms in drug refractory epilepsy.

ABSTRACT

Background & objectives Multiple drug resistance in epilepsy is a common problem and one third of epilepsy patients remain non responsive to antiepileptic drug (AED) therapy. In this study we aimed to investigate the relationship between the genetic polymorphism of cytochrome P450 genes, namely CYP2C9 and CYP2C19 with multiple drug resistance in epilepsy patients. Methods: A total of 402 patients with epilepsy were enrolled in this study; 128 were drug resistant and 274 were drug responsive. The peripheral blood samples of the patients with epilepsy were collected. Drug compliance was confirmed in 20 per cent patient population using HPLC. Genotyping of CYP2C9 (*2 and *3), and CYP2C19 (*2 and *3) was carried out by PCR-RFLP. Results: The genotype frequencies of CYP2C9 430 C>T (*2 variant) and CYP2C9 1075 A>C (*3 variant) did not differ significantly in drug resistant versus responsive patients. After combining CYP2C9 *2 and CYP2C9 *3, the frequency of CYP2C9*1/*3 was significantly lower in drug resistant as compared to drug responsive epilepsy patients (P=0.03, OR=0.53, 95%CI=0.30-0.95). Similarly, combined frequency of all the slow and poor metabolizer variants (2C9 *1/*2, *1/*3 and *2/*3) was also lower as compared to drug resistant group (P=0.03, OR=0.60, 95% CI 0.38-0.96). There was no significant differences in genotypic or allelic distribution of CYP2C19*2 while CYP2C19*3 was monomorphic in northern Indian population. Interpretation & conclusions: Our results demonstrated significant involvement of CYP2C9 genetic variants in the modulation of epilepsy pharmacotherapy confirming the important role of CYP2C9 mutants preventing epilepsy patients from developing drug resistance.