title: Effect of grapefruit juice on the pharmacokinetics of tolvaptan, a non-peptide arginine vasopressin antagonist, in healthy subjects.
abstract: OBJECTIVE
  Tolvaptan is a selective vasopressin V2 receptor antagonist that can be given orally once daily for treatment of clinically significant hypervolemic and euvolemic hyponatremia (US and Europe) or extracellular volume expansion despite taking other diuretics (Japan). In vitro studies indicated that tolvaptan was a CYP3A4 substrate.
  
  
  METHODS
  A single-center, randomized, crossover trial of 60-mg tolvaptan with 240 mL of water or with 240 mL of reconstituted grapefruit juice (washout period of 72 h between doses) was conducted in 20 healthy subjects. Blood samples for tolvaptan plasma concentrations were obtained for 48 h postdose.
  
  
  RESULTS
  All subjects completed the trial. Following co-administration with grapefruit juice, tolvaptan concentrations were elevated compared with tolvaptan alone for only 16 h postdose; consequently, the mean elimination half-life of tolvaptan was unchanged, 5.7 vs 5.1 h respectively. The mean maximal plasma concentration (C(max)) and the area under the curve (AUC(∞)) of tolvaptan were increased 1.86- and 1.56-fold respectively when co-administered with grapefruit juice.
  
  
  CONCLUSIONS
  It appears that grapefruit juice increases the bioavailability of tolvaptan, but does not affect its systemic elimination. The adverse event profile was consistent with the aquaretic effect of tolvaptan as urinary frequency, thirst, and dry mouth were the most frequently reported events.
authors.affiliation: Clinical Pharmacology, Otsuka Pharmaceutical Development & Commercialization, Inc., 2440 Research Boulevard, Rockville, MD 20850, USA. susan.shoaf@otsuka-us.com
authors.forename: Susan E
authors.initials: SE
authors.lastname: Shoaf
authors.forename: Suresh
authors.initials: S
authors.lastname: Mallikaarjun
authors.forename: Patricia
authors.initials: P
authors.lastname: Bricmont
mesh_terms: D000293:Adolescent; D000328:Adult; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000097:blood / Q000493:pharmacokinetics*; D001628:Beverages; D001682:Biological Availability; D032083:Citrus paradisi; D018592:Cross-Over Studies; D004232:Diuretics / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077602:Tolvaptan; D055815:Young Adult
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D004232:Diuretics; D000077602:Tolvaptan