MECHANISMS OF THE STEREOSELECTIVE INTERACTION BETWEEN MICONAZOLE AND RACEMIC WARFARIN IN HUMAN-SUBJECTS

Miconazole decreased the total body clearance of both (R)- and (S)-warfarin in normal subjects but did not change volumes of distribution. Miconazole inhibited the oxidation of both (R)- and (S)-warfarin to phenolic metabolites, although (S)-warfarin was inhibited to the greater extent. In particular, (S)-7-hydroxylation, the pathway primarily responsible for termination of the anticoagulant effect, was most strongly inhibited. Inhibition of warfarin hydroxylation by miconazole in human liver microsomes and the in vivo results showed a good rank order correlation. Thc enhanced anticoagulant effect observed when miconazole and warfarin are coadministered may result from inhibition of P4502C9, the isozyme of P450 primarily responsible for the conversion of (S)-warfarin to (S)-7-hydroxywarfarin. Because miconazole inhibits a number of P450 isozymes, in addition to P4502C9, it can be expected to lead to interactions with other drugs whose primary metabolism is controlled by these enzymes.