title: Nonclinical safety profile of tolvaptan.
abstract: OBJECTIVE
  In the present study, the nonclinical safety profile of tolvaptan was evaluated.
  
  
  METHODS
  A series of safety pharmacology and toxicology studies were performed in vitro and in mice, rats, dogs, rabbits and guinea pigs.
  
  
  RESULTS
  In safety pharmacological studies, tolvaptan had no adverse effects on the central nervous, somatic nervous, autonomic nervous, smooth muscle, respiratory and cardiovascular, or digestive systems. In general toxicity studies, a single dose of tolvaptan up to 2,000 mg/kg was not lethal in rats and dogs. Tolvaptan did not cause any target organ toxicity in rats after treatment for 26 weeks or in dogs after treatment for 52 weeks at oral doses of up to 1,000 mg/kg/day. The toxicities observed in the present studies were generally attributable to the exaggerated pharmacological action of tolvaptan. In reproductive and developmental toxicity studies in rats, fertility was not affected. Suppressed viability or growth observed in the prenatal and postnatal progeny occurred at the maternally toxic dose of 1,000 mg/kg/day. In rabbits, tolvaptan showed teratogenicity at 1,000 mg/kg/day, a dose that was maternally toxic causing abortion. Tolvaptan was not genotoxic or carcinogenic, and did not induce phototoxicity, antigenicity or immunotoxicity.
  
  
  CONCLUSIONS
  Nonclinical toxicity that precludes the safe administration of tolvaptan to humans was not observed. However, appropriate cautions should be taken in women of childbearing potential.
authors: Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd, 463-10 Kagasuno, Kawauchi-cho, Tokushima, 771-0192, Japan. a_oi@research.otsuka.co.jp
authors: Akihide
authors: A
authors: Oi
authors: Katsumi
authors: K
authors: Morishita
authors: Takumi
authors: T
authors: Awogi
authors: Atsushi
authors: A
authors: Ozaki
authors: Masanao
authors: M
authors: Umezato
authors: Shinji
authors: S
authors: Fujita
authors: Eiji
authors: E
authors: Hosoki
authors: Hajime
authors: H
authors: Morimoto
authors: Nobuya
authors: N
authors: Ishiharada
authors: Hironobu
authors: H
authors: Ishiyama
authors: Tohru
authors: T
authors: Uesugi
authors: Masaya
authors: M
authors: Miyatake
authors: Tadashi
authors: T
authors: Senba
authors: Toshiyuki
authors: T
authors: Shiragiku
authors: Naoto
authors: N
authors: Nakagiri
authors: Norio
authors: N
authors: Ito
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000494:pharmacology* / Q000633:toxicity*; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D002490:Central Nervous System / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004232:Diuretics / Q000494:pharmacology* / Q000633:toxicity*; D004285:Dogs; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology; D005260:Female; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects; D017933:Peripheral Nervous System / Q000187:drug effects; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D012119:Respiration / Q000187:drug effects; D013270:Stomach / Q000187:drug effects / Q000502:physiology; D000077602:Tolvaptan
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D004232:Diuretics; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D000077602:Tolvaptan