CHRONIC TOXICITY IN MONKEYS WITH THE THIAZOLIDINEDIONE ANTIDIABETIC AGENT TROGLITAZONE

概要

論文の詳細を見る
The antidiabetic agent troglitazone was given to groups of 4 cynomolgus monkeys per sex at 300, 600, or 1200 mg/kg daily by gavage for 52 weeks. A group of 4 monkeys per sex received vehicle alone and served as controls. Emesis and soft stool or diarrhea occurred sporadically in all troglitazone-treated groups, but did not compromise animal health. There were no effects on body weight or food consumption, or ophthalmologic, electrocardiographic, or echocardiographic parameters. Erythrocyte count, hemoglobin, and hematocrit decreased 8% to 16% in males at all doses and serum cholesterol decreased 30% to 46% in both sexes at all doses. Urinary ketones were increased in several animals at 600 and 1200 mg/kg. Absolute and relative liver weights increased at all doses in both sexes by 40% to 71 % . The only microscopic change attributable to troglitazone treatment was minimal to mild bile duct hyperplasia in males at all doses and in females at 600 and 1200 mg/kg. No differences in systemic exposure were apparent between sexes. Over the dose range tested, AUC_<(0-24)> values were 27 to 102 μg.hr/ml of troglitazone, 401 to 2060 μg.hr/ml of its sulfate conjugate, and 34 to 312 μg.hr/ ml of its quinone metabolite. Therefore, oral administration of troglitazone to monkeys at 300, 600, and 1200 mg/kg for 52 weeks resulted in significant systemic exposure, with only minimal gastrointestinal, hematologic, and hepatic effects.
2002-02-25