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ToxSci Advance Access published online on November 28, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl176
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received September 27, 2006
Accepted November 21, 2006

Carcinogenicity

Subchronic Urinary Bladder Effects of Muraglitazar in Male Rats

Terry R. Van Vleet 1, M. Randy White 1, Thomas P. Sanderson 1, Samuel M. Cohen 2, Martin Cano 2, Lora L. Arnold 2, C. Robbie Waites 1, Beth E. Schilling 1, James Mitroka 3, and Mark A. Dominick 1 *

1 Department of Drug Safety Evaluation, Bristol-Myers Squibb Company, Mt. Vernon, IN
2 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
3 Department of Nonclinical Pharmacokinetics, Lawrenceville, NJ

* To whom correspondence should be addressed.
Mark A. Dominick, E-mail: mark.dominick{at}bms.com


  Abstract

Muraglitazar, a PPAR{alpha}/{gamma} 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/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 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.


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