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The mechanism of the warfarin‐rifampin drug interaction in humans
Author(s) -
Heimark Larry D,
Gibaldi Milo,
Trager William F,
O'Reilly Robert A,
Goulart Darklis A
Publication year - 1987
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.1987.168
Subject(s) - warfarin , pharmacology , drug interaction , metabolite , drug , pharmacokinetics , chemistry , in vivo , hypoprothrombinemia , urine , medicine , biology , biochemistry , microbiology and biotechnology , vitamin k , atrial fibrillation
The mechanism of the drug interaction in humans between warfarin and rifampin was investigated by monitoring the elimination kinetics and metabolic disposition of a single oral dose of pseudoracemic warfarin by GC/MS. The decrease in hypoprothrombinemia observed with concomitant administration of therapeutic doses of rifampin was accompanied by a substantial decrease in the elimination half‐lives of both warfarin enantiomers. Rifampin increased the clearance of (R)‐warfarin threefold and the clearance of (S)‐warfarin twofold. The excretion profiles for warfarin and its metabolites in urine and feces were similar for both control and treated subjects with the exception that 4′‐hydroxywarfarin (stereoselective for the (S)‐enantiomer) was observed when rifampin was administered. 4′‐Hydroxywarfarin is a metabolite of the drug hitherto undetected in vivo in humans. Based on formation clearance values estimated for 6‐, 7‐, and 8‐hydroxywarfarin, rifampin appears to increase the clearance of the parent drug by induction of the cytochrome P‐450 isozyme(s) responsible for aromatic hydroxylation. Clinical Pharmacology and Therapeutics (1987) 42, 388–394; doi: 10.1038/clpt.1987.168