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Mechanisms of the stereoselective interaction between miconazole and racemic warfarin in human subjects
Author(s) -
O'Reilly Robert A,
Goulart Darklis A,
Kunze Kent L,
Neal John,
Gibaldi Milo,
Eddy A Craig,
Trager William F
Publication year - 1992
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1992.78
Subject(s) - miconazole , warfarin , hydroxylation , pharmacology , cyp2c9 , chemistry , microsome , drug interaction , in vivo , isozyme , anticoagulant , enzyme , biochemistry , drug , cytochrome p450 , medicine , biology , atrial fibrillation , antifungal , microbiology and biotechnology
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. The 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. Clinical Pharmacology and Therapeutics (1992) 51 , 656–667; doi: 10.1038/clpt.1992.78