Impact Of CYP450 Gene Variants On Warfarin Dosing In the Indian Population

Abstract

Warfarin is a common oral anticoagulant that has narrow therapeutic index and high inter-individual variability in dose response and is primarily determined by the genetic polymorphisms of drug-metabolizing enzymes. This paper explores the effects of gene variants CYP2C9 and CYP4F2, typical of Indian population, on the pharmacokinetics and pharmacodynamics of warfarin in genetically simulated Wistar rat models. The forty-eight rats were divided into six groups according to their genotypes and received warfarin at 0.2 mg/kg/day during five days. Metabolic clearance and anticoagulant response were measured by the determination of the plasma warfarin levels and prothrombin time (PT). The findings indicated that rats with CYP2C9 *1/*2 and *3/*3 genotype had a significantly greater concentration of warfarin in the plasma and PT that was extended compared to the wild-type, which are indications of reduced clearance and sensitivity to anticoagulants. In the same way, CYP4F2 *1/*3 and *3/*3 genotypes had significant but moderate alterations in both parameters. The results are reflective of clinical data in human beings and the usefulness of preclinical genetic models in the study of pharmacogenetic variation. The research supports the possibility of genotype-specific personalized dosing of warfarin with an emphasis on a genetically diverse population like India.