EFFECTS OF GENETIC POLYMORPHISMS OF CYP2C9/19 AND METABOLIC INHIBITION BY COADMINISTERED DRUGS ON THE INTER- AND INTRA- INDIVIDUAL VARIATIONS IN THE WARFARIN-INDUCED ANTICOAGULATION

Effects of genetic polymorphisms of CYP2C9/19 and metabolic inhibition by coadministered drugs on the inter and intra-individual variations in the warfarin-induced anticoagulation were studied using in vivo pharmacokinetic data obtained from cardiac patients and in vitro enzyme kinetics obtained from human liver microsomes and recombinant CYP2C9 wild type and Leu359 variant. Results indicated that both heterozygous 2C9 Leu359 mutation and the two concomitantly given drugs (i.e., benzbromarone and bucolome) possessing potent inhibitory effect on the in vitro S-warfarin metabolism would be associated with a clinically relevant reduction in the in vivo CLpo, u of pharmacologically more potent S-warfarin in humans. Estimation for changes in in vivo CLpo, u based upon in vitro enzyme kinetic data was considered feasible for warfarin.