Chronic toxicity of zatosetron, a 5-HT3 receptor antagonist, in rhesus monkeys

A 1-year chronic toxicity study was conducted in which rhesus monkeys (4/sex/dose) were given daily doses of 0, 3, 10, or 25 mg zatosetron/kg by nasogastric intubation. Clinical signs of toxicity characterized by salivation, diarrhea or soft stools, and/or emesis occurred in animals that received 10 or 25 mg/kg of zatosetron. One monkey in the high-dose group and one in the middle-dose group died as a result of intratracheal administration of the compound. The death of another monkey in the high-dose group was associated with an unexpectedly high (3-fold the mean plasma Cmax value in surviving females in this group) plasma level of zatosetron as indicated by postmortem analysis of heart blood. Animals of both sexes in all treatment groups gained weight at a slightly reduced rate when compared to control monkeys. Depressed appetite occurred in some monkeys in all treatment groups but was most evident in those receiving 25 mg/kg. Evaluation of ECG's indicated that treatment with zatosetron did not produce any rhythm or conduction disturbances. However, there was a mild increase in the Q-Tc interval throughout the treatment period at 4 hours postdosing in monkeys in the middle- and high-dose groups and a slight increase prior to dosing in animals in the high-dose group. Mean plasma Cmax and AUC(0-24 hr) values on Day 360 were dose proportional for zatosetron and for the N-demethylated metabolite in both sexes over the dose range tested. The mean t1/2 (elimination phase) for the plasma disappearance of zatosetron ranged from 3.4 to 7.2 hr in males and from 2.3 to 6.8 hr in females. Hematology, urinalysis, and clinical chemistry parameters were unaffected by treatment. There were no treatment-related gross or microscopic alterations or changes in organ weights. With the exception of mild effects on body weight gain, there was no evidence of chronic toxicity in monkeys given 3 mg/kg zatosetron daily for 1 year.