Chronic toxicity in monkeys with the thiazolidinedione antidiabetic agent troglitazone.
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 micrograms.hr/ml of troglitazone, 401 to 2060 micrograms.hr/ml of its sulfate conjugate, and 34 to 312 micrograms.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.
Rothwell
Charles
C
Pfizer Global Research and Development, Pfizer Inc., Ann Arbor, Michigan 48105, USA.
McGuire
Edward J
EJ
Altrogge
Douglas M
DM
Masuda
Hiroshi
H
de la Iglesia
Felix A
FA
D000284:Administration, Oral; D000740:Anemia / Q000139:chemically induced / Q000473:pathology; D000818:Animals; D019540:Area Under Curve; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D002839:Chromans / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004906:Erythrocyte Count; D005260:Female; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D009929:Organ Size / Q000187:drug effects; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D045162:Thiazolidinediones; D018675:Toxicity Tests; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D002784:Cholesterol; D000077288:Troglitazone