Warfarin-fluconazole. I. Inhibition of the human cytochrome P450-dependent metabolism of warfarin by fluconazole: in vitro studies.

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Kunze KL, Wienkers LC, Thummel KE, Trager WF

Warfarin-fluconazole. I. Inhibition of the human cytochrome P450-dependent metabolism of warfarin by fluconazole: in vitro studies.

Drug Metab Dispos. 1996 Apr;24(4):414-21.

PubMed ID

8801056 [ View in PubMed

]

Abstract

The antifungal agent fluconazole was found to be a potent inhibitor of cytochrome P450 (P450) 2C9 (Ki = 7-8 microM), the principal enzyme responsible 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 P4503A4-catalyzed formation of (R)-10-hydroxywarfarin (Ki = 15-18 microM) as well as the low KM P450 enzymes responsible for the formation of (R)-6-, (R)-7-, and (R)-8-hydroxywarfarin (Ki = 2-6 microM). By contrast, experiments with the P4501A2 inhibitor furafylline and cDNA-expressed P4501A2 indicate that fluconazole is a weak inhibitor of this enzyme (Ki > 800 microM), as measured by the inability of fluconazole to significantly suppress the P4501A2-dependent 6-hydroxylation of (R)-warfarin. The prediction generated from these studies, that fluconazole is a potent in vivo inhibitor of warfarin metabolism, , is tested in complementary studies reported in the accompanying article, "Warfarin-Fluconazole II".

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Fluconazole	Cytochrome P450 2C9	Protein	Humans	Unknown	Inhibitor	Details
Fluconazole	Cytochrome P450 3A4	Protein	Humans	Unknown	Inhibitor	Details