INVESTIGATING THE BIOCHEMICAL REASONS FOR SENSITIVITY OF SOME PATIENTS TO ANTICOAGULANT WARFARIN

摘要

Warfarin is the most widely prescribed anticoagulant drag for the prevention and treatment of arterial and venous thromboembolic disorders. Because of large interpatients variability in the dose-anticoagulant effect relationship and a narrow therapeutic index careful dosage adjustment based on INR (International Normalized Ratio) is essential 1. Warfarin is available as a racemic mixture of two enantiomers, (S)-and (R)-warfarin. In contrast to (R)-warfarin, which is metabolized by multiple cytochrome P450s (CYPs), including CYP1A2 and CYP3A4,(S)-warfarin, is predominantly metabolized to 7-hydroxywarfarin by polymorphic CYP2C9. Since the potency of (S)-warfarin is much higher than that of (R)-warfarin, about 3-to 5-fold,any change in the activity of CYP2C9 gene is likely to have a significant influence on the anticoagulant response. Previous in vitro findings revealed that certain variants in the CYP2C9 gene are associated with large interindividual differences in the pharmacokinetic and pharmacodynamic outcomes of warfarin therapy. Three major alleles have been found to date in humans: Arg144/Ile359, and Cys144/Ile359 and Arg144/Leu359, which have been designated CYP2C9~*1 (wild-type), CYP2C9~*2, and CYP2C9~*3, respectively. The aim of this study was to determine the pharmacogenetic effect of CYP2C9 polymorphisms on warfarin sensitivity in some Iranian patients.