ToxSci Advance Access originally published online on November 28, 2006
Toxicological Sciences 2007 96(1):58-71; doi:10.1093/toxsci/kfl176
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Subchronic Urinary Bladder Effects of Muraglitazar in Male Rats1
* Departments of Drug Safety Evaluation, Bristol–Myers Squibb Company, Mt Vernon, Indiana 47721;
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198; and
Department of Nonclinical Pharmacokinetics, Bristol–Myers Squibb Company, Lawrenceville, New Jersey 08543
2 To whom correspondence should be addressed at Drug Safety Evaluation, Bristol-Myers Squibb, 2400 West Lloyd Expressway, P3 Evansville, IN 47721-0001. Fax: 812-429-8474. E-mail: mark.dominick{at}bms.com.
Received September 27, 2006; accepted November 21, 2006
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Abstract |
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Muraglitazar, a PPAR
/
dual agonist, was dosed orally to rats once daily for 13 weeks to evaluate urinary and urothelial changes of potential relevance to urinary bladder tumorigenesis. Groups of 17 young or aged rats per sex were fed a normal or 1% NH4Cl-supplemented diet and were dosed with 0, 1, or 50 mg/kg muraglitazar. Lithogenic ions and sediment were profiled from freshly voided urine samples collected 24 h after dosing, and drug exposures were measured. Urinary citrate, oxalate, and epidermal growth factor (EGF) were assayed from 18-h urine collections. Urothelium was assessed by light microscopy, scanning electron microscopy, and BrdU and TUNEL immunohistochemistry. When fed a normal diet, urine pH was higher in males (above 6.5). Urine volume/body weight was greater in females. Urine soluble/total calcium and magnesium and phosphorus/creatinine ratios were lower in male rats fed a normal diet. Urine citrate levels were decreased and oxalate was increased in young male rats treated with 50 mg/kg muraglitazar compared to age/sex/diet-matched controls. No changes in urine sediment were detected 24 h after dosing. In young male rats treated with 50 mg/kg on normal diet, multifocal urothelial necrosis and proliferation were observed, whereas urothelial apoptosis and urine EGF levels were unchanged compared to age/sex/diet-matched controls. Urothelial necrosis and proliferation were not correlated to systemic or urinary drug exposures and were prevented by dietary acidification. These data suggest that muraglitazar-associated changes in urine composition predispose to urothelial cytotoxicity and proliferation in the urinary bladder of young male rats and that urine sediment must be profiled at multiple daily timepoints to fully qualify drug-induced changes in urine composition.
Key Words: PPAR agonist; urinary bladder; tumorigenesis; crystalluria; citrate.
1 Portions of this report were presented at the 45th annual meeting of the Society of Toxicology, San Diego, CA, March 2006 (Abstract # 982).