Subchronic urinary bladder effects of muraglitazar in male rats

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

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Muraglitazar, a PPARα/γ 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% NH4 Cl-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.

Original languageEnglish (US)
Pages (from-to)58-71
Number of pages14
JournalToxicological Sciences
Volume96
Issue number1
DOIs
StatePublished - Mar 15 2007

Fingerprint

Nutrition
Rats
Urinary Bladder
Urine
Sediments
Diet
Oxalates
Epidermal Growth Factor
Citric Acid
Pharmaceutical Preparations
Peroxisome Proliferator-Activated Receptors
Acidification
Bromodeoxyuridine
Cytotoxicity
Chemical analysis
Necrosis
Phosphorus
Magnesium
Optical microscopy
muraglitazar

Keywords

  • Citrate
  • Crystalluria
  • PPAR agonist
  • Tumorigenesis
  • Urinary bladder

ASJC Scopus subject areas

  • Toxicology

Cite this

Van Vleet, T. R., White, M. R., Sanderson, T. P., Cohen, S. M., Cano, M., Arnold, L. L., ... Dominick, M. A. (2007). Subchronic urinary bladder effects of muraglitazar in male rats. Toxicological Sciences, 96(1), 58-71. https://doi.org/10.1093/toxsci/kfl176

Subchronic urinary bladder effects of muraglitazar in male rats. / Van Vleet, Terry R.; White, M. Randy; Sanderson, Thomas P.; Cohen, Samuel Monroe; Cano, Martin; Arnold, Lora L; Waites, C. Robbie; Schilling, Beth E.; Mitroka, James; Dominick, Mark A.

In: Toxicological Sciences, Vol. 96, No. 1, 15.03.2007, p. 58-71.

Research output: Contribution to journalArticle

Van Vleet, TR, White, MR, Sanderson, TP, Cohen, SM, Cano, M, Arnold, LL, Waites, CR, Schilling, BE, Mitroka, J & Dominick, MA 2007, 'Subchronic urinary bladder effects of muraglitazar in male rats', Toxicological Sciences, vol. 96, no. 1, pp. 58-71. https://doi.org/10.1093/toxsci/kfl176
Van Vleet, Terry R. ; White, M. Randy ; Sanderson, Thomas P. ; Cohen, Samuel Monroe ; Cano, Martin ; Arnold, Lora L ; Waites, C. Robbie ; Schilling, Beth E. ; Mitroka, James ; Dominick, Mark A. / Subchronic urinary bladder effects of muraglitazar in male rats. In: Toxicological Sciences. 2007 ; Vol. 96, No. 1. pp. 58-71.
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