WARFARIN-FLUCONAZOLE .2. A METABOLICALLY BASED DRUG-INTERACTION - IN-VIVO STUDIES

Consistent with expectations based on human in vitro microsomal experi ments, administration of fluconazole (400 mg/day) for 6 days to six hu man volunteers significantly reduced the cytochrome P450 (P450)-depend ent metabolic clearance of the warfarin enantiomers. In particular, P4 502C9 catalyzed 6- and 7-hydroxyIation of (S)-warfarin, the pathway pr imarily responsible for termination of warfarin's anticoagulant effect , was inhibited by similar to 70%, The change in (S)-warfarin pharmaco kinetics caused by fluconazole dramatically increased the magnitude an d duration of warfarin's hypoprothrombinemic effect. These observation s indicate that coadministration of fluconazole and warfarin will resu lt in a clinically significant metabolically based interaction. The ma jor P450-dependent in vivo pathways of (R)-warfarin clearance were als o strongly inhibited by fluconazole. 10-Hydroxylation, a metabolic pat hway catalyzed exclusively by P4503A4, was inhibited by 45%, whereas 6 -, 7-, and 8-hydroxylations were inhibited by 61, 73, and 88%, respect ively. The potent inhibition of the phenolic metabolites suggests that enzymes other than P4501A2 (weakly inhibited by fluconazole in vitro) are primarily responsible for the formation of these metabolites in v ivo as predicted from in vitro kinetic studies. These data suggest tha t fluconazole can be expected to interact with any drug whose clearanc e is dominated by P450s 2C9, 3A4, and other as yet undefined isoforms. Overall, the results strongly support the hypothesis that metabolical ly based in vivo drug interactions may be predicted from human in vitr o microsomal data.