ToxSci Advance Access originally published online on April 10, 2007
Toxicological Sciences 2007 98(1):258-270; doi:10.1093/toxsci/kfm083
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Rodent Carcinogenicity Profile of the Antidiabetic Dual PPAR 
and 
Agonist Muraglitazar
* Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Drug Safety Evaluation Mt. Vernon, Indiana 47721
Covance Laboratories, Vienna, Virginia 22182
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198
1 To whom all correspondence should be addressed at Department of Drug Safety Evaluation, Bristol-Myers Squibb Pharmaceutical Research Institute, 2400 West Lloyd Expressway, P3, Evansville, IN 47721-0001. Fax: (812) 429-8469. E-mail: sarah.tannehill-gregg{at}bms.com.
Received November 30, 2006; accepted March 23, 2007
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Abstract |
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The carcinogenic potential of muraglitazar, a dual human peroxisome proliferator–activated receptor 
/
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 
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 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 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).
Key Words: muraglitazar; rodent carcinogenicity; peroxisome proliferator–activated receptor (PPAR) agonist; gallbladder adenoma; urinary bladder carcinogenesis; urolithiasis; liposarcoma; lipoma.
Portions of this report were presented at the 45th annual meeting of the Society of Toxicology, San Diego, CA, March 2006 (Abstract # 2095).
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