Acute, subacute and chronic oral toxicity studies of the new serotonin (5-HT)3-receptor antagonist ramosetron in beagle dogs.

The oral toxicity of ramosetron ((R)-5-[(1-methyl-3-indolyl) carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride, CAS 132907-72-3, YM060), a new compound having serotonin (5-HT)3 receptor antagonist activity was investigated in beagle dogs. To evaluate the acute toxicity, two groups of beagle dogs, each comprised of one male and one female, were given YM060 bulk powder in gelatin capsules at dose of 0, 3 mg/kg or 0, 30 and 60 mg/kg in ascending order in at least 7-day intervals. After the final dose, animals were observed for 2 weeks. No deaths were observed at any dose. At 60 mg/kg, the male exhibited frequent vomiting, salivation and prone position 1-3 h after administration, when the plasma concentration of the unchanged drug reached Cmax or was close to Cmax. The female exhibited no changes except vomiting. No effects on either the male or the female were detected in body weight, food consumption, electrocardiography, hematology, plasma biochemistry or urinalysis. To evaluate the subacute toxicity of YM060, three male and 3 female beagle dogs per group received doses of 0, 1, 3, 10 and 20 mg/kg/d for 13 weeks. YM060 was triturated 10-fold using lactose and filled in gelatin capsules before use. The plasma concentration of unchanged drug increased almost dose-dependently, peaked about 2 h post-dosing and subsequently decreased with time. The plasma concentration-time profile after the final dose at week 13 was not different from that after the initial dose. No treatment-related changes were observed up to 3 mg/kg/d.(ABSTRACT TRUNCATED AT 250 WORDS)