The effects of acetaminophen on pharmacokinetics and pharmacodynamics of warfarin.
The oral anticoagulant warfarin is clinically administered as a racemic mixture of two enantiomers, (R) and (S). Many relevant drug interactions with warfarin have been attributed to the specific metabolic inhibition of the elimination of the more pharmacologically active (S)-enantiomer. To investigate reports that acetaminophen can potentiate the anticoagulant effect of warfarin, 20 healthy male volunteers were each given single oral 20 mg doses of racemic warfarin on three separate occasions: (1) alone, (2) after 1 day of acetaminophen (4 g/d), and (3) after 2 weeks of acetaminophen (4 g/d). The urinary excretion pattern of acetaminophen and its metabolites was not significantly altered over its course of administration. The (R)- and (S)-enantiomers of warfarin exhibited significantly different pharmacokinetic properties. However, acetaminophen did not alter the disposition of either (R)- or (S)-warfarin. All subjects exhibited a pharmacodynamic response to racemic warfarin. The response was not significantly altered in the presence of acute or chronic acetaminophen dosing, as assessed by prothrombin time and factor VII concentrations.
Kwan
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Department of Pharmacy, Sunnybrook Health Science Centre, North York, Ontario, Canada.
Bartle
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Walker
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D000082:Acetaminophen / Q000378:metabolism / Q000494:pharmacology* / Q000652:urine; D000284:Administration, Oral; D000293:Adolescent; D000410:Alanine Transaminase / Q000187:drug effects / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000704:Analysis of Variance; D000925:Anticoagulants / Q000493:pharmacokinetics*; D001219:Aspartate Aminotransferases / Q000187:drug effects / Q000378:metabolism; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005167:Factor VII / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011517:Prothrombin Time; D013237:Stereoisomerism; D013997:Time Factors; D014859:Warfarin / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*