Rodent carcinogenicity profile of the antidiabetic dual PPAR alpha and gamma agonist muraglitazar.
The carcinogenic potential of muraglitazar, a dual human peroxisome proliferator-activated receptor alpha/gamma agonist, was evaluated in 2-year studies in mice (1, 5, 20, and 40 mg/kg) and rats (1, 5, 30, and 50 mg/kg). Benign gallbladder adenomas occurred at low incidences in male mice at 20 and 40 mg/kg (area under the curve [AUC] exposures > or = 62 times human exposure at 5 mg/day) and were considered drug related due to an increased incidence of gallbladder mucosal hyperplasia at these doses. There was a dose-related increased incidence of transitional cell papilloma and carcinoma of the urinary bladder in male rats at 5, 30, and 50 mg/kg (AUC exposures > or = 8 times human exposure at 5 mg/day). At 30 and 50 mg/kg, the urinary bladder tumors were accompanied by evidence of increased urine solids. Subsequent investigative studies established that the urinary bladder carcinogenic effect was mediated by urolithiasis rather than a direct pharmacologic effect on urothelium. Incidences of subcutaneous liposarcoma in male rats and subcutaneous lipoma in female rats were increased at 50 mg/kg (AUC exposures > or = 48 times human exposure at 5 mg/day) and attributed, in part, to persistent pharmacologic stimulation of preadipocytes. Toxicologically relevant nonneoplastic changes in target tissues included thinning of cortical bone in mice and hyperplastic and metaplastic adipocyte changes in mice and rats. Considering that muraglitazar is nongenotoxic, the observed tumorigenic effects in mice and rats have no established clinical relevance since they occurred at either clinically nonrelevant exposures (gallbladder and adipose tumors) or by a species-specific mechanism (urinary bladder tumors).
Tannehill-Gregg
Sarah H
SH
Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Drug Safety Evaluation Mt. Vernon, Indiana 47721, USA. sarah.tannehill-gregg@bms.com
Sanderson
Thomas P
TP
Minnema
Daniel
D
Voelker
Richard
R
Ulland
Borge
B
Cohen
Samuel M
SM
Arnold
Lora L
LL
Schilling
Beth E
BE
Waites
C Robbie
CR
Dominick
Mark A
MA
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens; D004305:Dose-Response Relationship, Drug; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009369:Neoplasms / Q000139:chemically induced / Q000453:epidemiology / Q000473:pathology; D010080:Oxazoles / Q000493:pharmacokinetics / Q000633:toxicity*; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016019:Survival Analysis; D016482:Urinalysis
D002273:Carcinogens; D007004:Hypoglycemic Agents; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D005998:Glycine; C500085:muraglitazar