Effect of Glimepiride and Glibenclamide on S-Warfarin 7-Hydroxylation by Human Liver Microsomes, Recombinant Human CYP2C9.1 and CYP2C9.3

The effect of glimepiride on metabolism of S-warfarin to 7-hydroxywarfarin was studied using human liver microsomes and recombinant cytochrome P450 2C9 microsomes (CYP2C9.1 and CYP2C9.3), and was compared with the results from the experiments using glibenclamide as an inhibitor. S-Warfarin 7-hydroxylation by recombinant CYP2C9.1 and CYP2C9.3 was inhibited by glimepiride competitively. The apparent Ki value of glimepiride was lower at CYP2C9.3 than at CYP2C9.1. Glimepiride also inhibited 7-hydroxylation of S-warfarin in a competitive manner by microsomes from human liver which showed the genotypes of CYP2C9, as CYP2C9*1/*1 or CYP2C9*1/*3. The apparent Ki value of glimepiride was lower than that of glibenclamide. These results may provide valuable information for optimizing the anticoagulant activity of warfarin when glimepiride is co-administered to patients. Warfarin is an anti-coagulation drug as administered as racemate. S-Enantiomer of warfarin has 3 to 5 times higher anticoagulant activity than the R-enantiomer. l, 2) Therefore, changes in the disposition of S-warfarin will affect more significantly to its anti-coagulation activity of warfarin than that of R-warfarin. S-Warfarin is mainly metabolized to 7-hydroxylated metabolite by cytochrome P450 2C9 (CYP2C9). 2) More than 10 genotypes of CYP2C9 are demonstrated, and major genotypes of CYP2C9 are CYP2C9* 1 and CYP2C9*3 in Asian people. 3-9)