Clinical relevance of genetic polymorphism in the CYP2C9 gene to pharmacodynamics and pharmacokinetics of phenytoin in epileptic patients: validatory pharmacogenomic approach to pharmacovigilance

摘要

Aims and objectives: Variations in drug metabolizing genes are known to have a clinical impact on AED therapy. We genotyped normal and epileptic patient cohorts of monoethnic population of Kashmir valley for CYP2C9 gene and allelic polymorphism and investigated the effect of CYP2C9*2 and *3 polymorphism on the Pharmacokinetic and therapeutic and/or adverse pharmacodynamic responses to phenytoin in the idiopathic epilepsy patients. Methods: PCR-RFLP methods were used for genotyping of 121 normal controls and 92 idiopathic epilepsy patients for CYP2C9*2 and *3 polymorphism, the results were validated by direct sequencing. Phenytoin pharmacokinetic (PK) analysis in idiopathic epilepsy patients was done using a validated EMIT assay technique. Pharmacodynamic analysis was done by evaluating clinical response to phenytoin therapy and ADR monitoring. Results: The respective frequencies of CYP2C9 *1, *2, and *3 alleles were 64%, 6.6%, 29.3%, and 58%, 9.8%, 32.6% in controls and idiopathic epilepsy patients from Kashmir valley. PK analysis revealed that AUC_(0-4) was a better surrogate biomarker of CYP2C9 metabolizer status compared to C4 and C_0 concentrations alone. A comparison of "phenytoin response categories" among CYP2C9 Wild and Heterozygous groups did not reveal any significant difference between the groups (p = 0.3800). Conclusion: CYP2C9*3 was the most frequent mutant allele found in healthy controls and idiopathic epilepsy patients of ethnic Kashmiri population. CYP2C9 genotype based phenytoin therapy is highly relevant in Kashmiri population due to a high incidence of genetic variations associated with therapeutic and adverse responses to phenytoin. Phenytoin AUC_(0-4) tends to correlate better with genetic polymorphism of CYP2C9.