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 K(i) 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 K(i) 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.
Iwakawa
Seigo
S
Department of Pharmaceutics, Kobe Pharmaceutical University, Kobe, Japan. iwakawa@kobepharma-u.ac.jp
Miyashita
Kenji
K
Hashimoto
Yasuaki
Y
Kuroda
Tsutomu
T
D001189:Aryl Hydrocarbon Hydroxylases / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D065729:Cytochrome P-450 CYP2C9; D005905:Glyburide / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D008862:Microsomes, Liver / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D014859:Warfarin / Q000378:metabolism*
D011994:Recombinant Proteins; D013453:Sulfonylurea Compounds; D014859:Warfarin; C057619:glimepiride; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D005905:Glyburide