Rodent carcinogenicity with the thiazolidinedione antidiabetic agent troglitazone.
Carcinogenic potential of the thiazolidinedione antidiabetic troglitazone was assessed in 104-week studies in mice and rats. Mice were given 50, 400, or 800 mg/kg, male rats 100, 400, or 800 mg/kg, and female rats 25, 50, or 200 mg/kg. Vehicle and placebo controls were included. Survival was significantly decreased in both sexes of both species at high doses, but was adequate for valid evaluation of carcinogenicity. Hypertrophy and hyperplasia of brown adipose tissue was observed in both species at all doses, and fatty change and hypocellularity of bone marrow was noted in mice at all doses and in female rats at 50 and 200 mg/kg. Hepatocellular vacuolation was observed in mice at 400 and 800 mg/kg, and centrilobular hepatocellular hypertrophy occurred in rats at > or = 200 mg/kg. Ventricular dilatation, myocardial fibrosis, and atrial myocyte karyomegaly in male rats at 400 and 800 mg/kg and female rats at all doses were morphologically similar to spontaneous lesions, but incidence and severity were increased compared with controls. In mice, the incidence of hemangiosarcoma was increased in females at 400 mg/kg and in both sexes at 800 mg/kg. The incidence of hepatocellular carcinoma was increased in female mice at 800 mg/kg. Troglitazone exposure [AUC((0-24))] at the lowest dose associated with increased tumor incidence in mice was 16 times human therapeutic exposure at 400 mg daily. No tumors of any type were increased in rats at exposures up to 47 times therapeutic exposure.
Herman
J R
JR
Pfizer Global Research and Development, Pfizer, Inc., Ann Arbor, Michigan 48105, USA. james.herman@pfizer.com
Dethloff
L A
LA
McGuire
E J
EJ
Parker
R F
RF
Walsh
K M
KM
Gough
A W
AW
Masuda
H
H
de la Iglesia
F A
FA
D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000473:pathology; D002839:Chromans / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects; D006394:Hemangiosarcoma / Q000139:chemically induced / Q000473:pathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000473:pathology; D008136:Longevity / Q000187:drug effects; D051379:Mice; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D016019:Survival Analysis; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D045162:Thiazolidinediones; D000077288:Troglitazone
D002273:Carcinogens; D002839:Chromans; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D000077288:Troglitazone