ABSTRACT
Mitochondrial uncouplers (mUncouplers) are known to exhibit a variety of toxic effects in animals. Here we report a safety profile of an mUncoupler, OPC-163493, recently synthesized at Otsuka Pharmaceutical Co, Ltd, and its development as a therapeutic agent for treating diabetes. To understand the acute and subchronic toxicity of OPC-163493, single and repeated oral dose studies in rats, dogs, and monkeys were performed. In the rat studies, rigor mortis and increased body temperatures were observed in the high dose group. Focal necrosis, fatty change, and granular eosinophilic cytoplasm of the hepatocytes were also observed in the high dose group. In the dog studies, gastrointestinal manifestations were observed with decreased body weight and decreased food consumption in the high dose group. Necrotizing arteritis was observed in multiple organs as well as meningitis with hemorrhage in the brain. In the monkey studies, vomiting, decreased food consumption, and decreased locomotor activity were observed in the high dose group. Degeneration of the proximal convoluted tubules and the straight tubular epithelium, regeneration of the proximal tubular epithelium, and degeneration of the collecting tubular epithelium were observed. The target organs of OPC-163493 were liver, blood vessels, and kidney in rats, dogs, and monkeys, respectively. In rats, dogs, and monkeys, safety ratios were 100:1, 13:1, and 20:1, respectively, in terms of total exposure (AUC24h). These safety ratios showed clear separation between exposure to OPC-163493 in animals at NOAEL and the exposure at the effective dose in ZDF rats. This information should contribute to the drug development of new and effective mUncoupler candidates.
ABSTRACT
PURPOSE: 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. CONCLUSION: 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.
