title: Effects of etravirine on the pharmacokinetics and pharmacodynamics of warfarin in rats.
abstract: OBJECTIVE
  Warfarin is often used with etravirine (ETV) to prevent HIV-related thromboembolic events. As both warfarin and ETV bind to plasma proteins and are metabolized by hepatic cytochrome P450s, they are likely to interact. Hence, we evaluated the effect of ETV on the pharmacokinetics and blood clotting time of racemic warfarin in rats.
  
  
  METHODS
  Two groups of male Sprague-Dawley rats, in which the jugular vein had been cannulated, were studied. The control group (n = 10) received 1 mg·kg(-1) racemic warfarin i.v., and the test group (n = 13) 1 mg·kg(-1) of racemic warfarin followed by 25 mg·kg(-1) ETV i.v. Serial blood samples were collected for up to 144 h and the blood clotting time (calculated as international normalized ratio [INR]) measured in blood plasma at each sample point. Plasma concentrations of R-warfarin, S-warfarin, R-7-hydroxywarfarin and S-7-hydroxywarfarin were measured by a LC/MS/MS method using a chiral lux cellulose-1 column. Pharmacokinetic parameters were analysed using non-compartmental methods.
  
  
  RESULTS
  ETV significantly increased, by threefold, the systemic clearance and volume of distribution of S-warfarin, but not those of R-warfarin. ETV decreased the total AUC of warfarin, but had no effect on its elimination half-life. ETV also increased the systemic clearance of both R-7-hydroxywarfarin and S-7-hydroxywarfarin but only increased the volume of distribution of R-7-hydroxywarfarin. Interestingly, the effect of warfarin on blood clotting time (INR) was significantly increased in the presence of etravirine.
  
  
  CONCLUSIONS
  Our data suggest that etravirine may potentiate the anticoagulant effect of warfarin and this could have clinical significance.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA.
authors.forename: J
authors.initials: J
authors.lastname: John
authors.forename: M
authors.initials: M
authors.lastname: John
authors.forename: L
authors.initials: L
authors.lastname: Wu
authors.forename: C
authors.initials: C
authors.lastname: Hsiao
authors.forename: C V
authors.initials: CV
authors.lastname: Abobo
authors.forename: D
authors.initials: D
authors.lastname: Liang
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001777:Blood Coagulation / Q000187:drug effects*; D004357:Drug Synergism; D008297:Male; D009570:Nitriles; D011724:Pyridazines / Q000008:administration & dosage*; D011743:Pyrimidines; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage*; D014859:Warfarin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; D000082:Acetaminophen; D014859:Warfarin; C087837:7-hydroxywarfarin