title: Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of racemic warfarin in healthy subjects.
abstract: OBJECTIVE
  Case reports suggest that gemfobrozil can increase the anticoagulant effect of warfarin. Because gemfibrozil inhibits CYP2C9 in vitro, we studied its effects on the pharmacokinetics and pharmacodynamics of racemic warfarin.
  
  
  METHODS
  In a randomized cross-over study, 10 healthy subjects ingested 600 mg gemfibrozil or placebo twice daily for 8 days. On day 3, they were administered a single dose of 10 mg racemic R-S-warfarin orally. The concentrations of R- and S-warfarin in plasma and thromboplastin time were monitored up to 168 h.
  
  
  RESULTS
  Gemfibrozil decreased the mean (+/-SD) area under the plasma concentration-time curve [AUC((0-infinity))] of S-warfarin by 11%, from 19.9 +/- 5.2 mg l(-1) h to 17.6 +/- 4.7 mg l(-1) h (95% CI on the difference -3.7, -0.78; P < 0.01) and that of R-warfarin by 6% from 31.3 +/- 7.5 mg l(-1) h during the gemfibrozil phase to 29.5 +/- 6.9 mg l(-1) h during the placebo phase (95% CI -3.3, -0.33; P < 0.05). There were no significant differences in the elimination half-lives of S- or R-warfarin between the phases. Gemfibrozil did not alter the anticoagulant effect of warfarin.
  
  
  CONCLUSIONS
  Unexpectedly, gemfibrozil slightly decreased the plasma concentrations of R- and S-warfarin. Displacement of warfarin from plasma albumin by gemfibrozil or its interference with the absorption of warfarin could explain the present findings. Usual therapeutic doses of gemfibrozil seem to have limited effects on the pharmacokinetics and pharmacodynamics of single dose warfarin in healthy subjects.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. jari.lilja@hus.fi
authors.forename: Jari J
authors.initials: JJ
authors.lastname: Lilja
authors.forename: Janne T
authors.initials: JT
authors.lastname: Backman
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001777:Blood Coagulation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D005260:Female; D015248:Gemfibrozil / Q000494:pharmacology*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008297:Male; D010314:Partial Thromboplastin Time; D014859:Warfarin / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D000960:Hypolipidemic Agents; D014859:Warfarin; D015248:Gemfibrozil