title: Effects of torsemide on pharmacodynamics and pharmacokinetics of warfarin in humans and rats.
abstract: OBJECTIVE
  This study aimed to evaluate the effects of torsemide on warfarin therapy in humans and rats.
  
  
  METHODS
  For the animal study, rats were orally dosed with warfarin (0.13 mg/kg, control group) or warfarin (0.13 mg/kg) with torsemide (2 mg/kg, low dose group and 10 mg/kg, high dose group). The pharmacodynamic response of warfarin was assessed by measuring the international normalized ratio (INR) for 5 consecutive days following drug administration. For the human study, 191 patients on warfarin with mechanical heart valves were followed up retrospectively. The stable dose was calculated as the mean dose in INR levels of 2-3 for 3 consecutive times.
  
  
  RESULTS
  In the animal study, the INR, maximum plasma concentration (Cmax ) and area under the plasma drug concentration-time curve (AUC0-∞ ) of (S)-warfarin in the high dose group were significantly higher than in other groups (P < 0.05). Compared with the control group, Cmax and AUC0-∞ of (R)-warfarin in the high and low dose groups were higher, whereas the volume of distribution/bioavailability and clearance/bioavailability were significantly lower (P < 0.05). In the univariate analysis of the clinical study, diuretics significantly lowered stable warfarin doses (P = 0.016) (5.07 ± 1.78 mg/day vs 5.77 ± 1.81 mg/day). After controlling confounding variables, the effects of diuretics were found to lower the warfarin dose by 0.464 mg.
  
  
  CONCLUSIONS
  It was concluded that warfarin dose needs to be lowered when it is used concomitantly with diuretics.
authors.affiliation: College of Pharmacy & Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.
authors.forename: Han Oll
authors.initials: HO
authors.lastname: Kim
authors.forename: Kyung Eun
authors.initials: KE
authors.lastname: Lee
authors.forename: Hee Yoon
authors.initials: HY
authors.lastname: Park
authors.forename: Na Ra
authors.initials: NR
authors.lastname: Lee
authors.forename: Byeou Ree
authors.initials: BR
authors.lastname: Oh
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Chang
authors.forename: Hye Sun
authors.initials: HS
authors.lastname: Gwak
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D004232:Diuretics / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000077786:Torsemide; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D004232:Diuretics; D013449:Sulfonamides; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000077786:Torsemide
keywords: diuretics; pharmacodynamics; pharmacokinetics; torsemide; warfarin