Implications of cytochrome P4502C9 polymorphism on Warfarin metabolism anddosing

Warfarin is an anticoagulant available as a racemic mixture. The R- and S- isomers differ with respect to relative plasma concentrations, clearance, p otency, sites of metabolism, and cytochrome P450 (CYP) isoenzymes responsib le for metabolism. S-Warfarin, the more potent isomer, is metabolized prima rily by CYP2C9. Genetic polymorphisms resulting from single amino acid subs titutions reduce the metabolic capability of 2C9. A reduction in warfarin m etabolism due to genetic polymorphism may explain the increased warfarin re sponse and bleeding episodes in some patients. Clinical studies showed an i ncreased plasma level of S-warfarin, decreased clearance of S-warfarin, inc reased frequency of bleeding, and prolongation of hospitalization in patien ts with variant CYP2C9 alleles. Adverse outcomes associated with warfarin p ossibly could be avoided by identifying patients with variant alleles befor e therapy and starting therapy at low dosages.