The mechanism of the warfarin-rifampin drug interaction in humans.
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.
Heimark
L D
LD
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Gibaldi
M
M
Trager
W F
WF
O'Reilly
R A
RA
Goulart
D A
DA
D000328:Adult; D002250:Carbon Radioisotopes; D002849:Chromatography, Gas; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D006900:Hydroxylation; D008297:Male; D013058:Mass Spectrometry; D011517:Prothrombin Time; D012293:Rifampin / Q000494:pharmacology*; D013237:Stereoisomerism; D014859:Warfarin / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*
D002250:Carbon Radioisotopes; D014859:Warfarin; D012293:Rifampin