WARFARIN-FLUCONAZOLE .1. INHIBITION OF THE HUMAN CYTOCHROME-P450-DEPENDENT METABOLISM OF WARFARIN BY FLUCONAZOLE - IN-VITRO STUDIES

The antifungal agent fluconazole was found to be a potent inhibitor of cytochrome P450 (P450) 2C9 (K-i = 7-8 mu M), the principal enzyme res ponsible for the clearance (85%) of the more potent anticoagulant (S)- warfarin to the inactive (S)-7- and (S)-6-hydroxywarfarin metabolites in vivo, Fluconazole was also found to be a potent inhibitor of the P4 503A4-catalyzed formation of (R)-10-hydroxywarfarin (K-i, = 15-18 mu M ) as well as the low K-m P450 enzymes responsible for the formation of (R)-6-, (R)-7-, and (R)-8-hydroxywarfarin (K-i = 2-6 mu M). By contra st, experiments with the P4501A2 inhibitor furafylline and cDNA-expres sed P4501A2 indicate that fluconazole is a weak inhibitor of this enzy me (K-i > 800 mu M), as measured by the inability of fluconazole to si gnificantly suppress the P4501A2-dependent 6-hydroxylation of (R)-warf arin. The prediction generated from these studies, that fluconazole is a potent in vivo inhibitor of warfarin metabolism, is tested in compl ementary studies reported in the accompanying article, ''Warfarin-Fluc onazole II.''