Acute, subacute and chronic oral toxicity studies of the new serotonin (5-HT) 3-receptor antagonist ramosetron in beagle dogs
Tabata, H.; Matsuzawa, T.; Hanada, T.; Ishikawa, A.; Yamada, M.; Ozaki, H.; Izumisawa, N.; Barker, M.H.; Cox, R.A.; Buist, D.P.
Arzneimittel-Forschung 45(7): 760-766
1995
ISSN/ISBN: 0004-4172 PMID: 8573218 Document Number: 440466
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 C-max or was close to C-max. 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. In the 10 mg/kg group, soft stools and mucous stools were sporadically observed in one male and one female. In the 20 mg/kg group, stool abnormalities were more frequent than those in the 10 mg/kg group, and almost all animals had sporadic episodes of soft, mucous or liquid stools throughout the treatment period The frequencies of vomiting and salivation also increased During the early treatment period, vomiting was observed almost daily in 2 males and 2 females, with salivation occurring at the time of dosing almost daily from weeks 1-2. Most of these abnormalities were observed for several hours after dosing. In the chronic toxicity study, 4 male and 4 female beagle dogs per group received doses of 0 (control), 1, 3 and 10 mg/kg/d for 52 weeks. There were no treatment-related findings at any dose level investigated. In conclusion, YM060 has a low toxicity when administered repeatedly to dogs at doses far in excess of the therapeutic dose in humans.