Muraglitazar, a
PPARalpha/gamma agonist, dose-dependently increased urinary bladder
tumors in male Harlan Sprague-Dawley (HSD) rats administered 5, 30, or 50 mg/kg/day for up to 2 years. To determine the mode of
tumor development, male HSD rats were treated daily for up to 21 months at doses of 0, 1, or 50 mg/kg while being fed either a normal or 1% NH4Cl-acidified diet.
Muraglitazar-associated, time-dependent changes in urine composition, urothelial mitogenesis and apoptosis, and urothelial morphology were assessed. In control and treated rats fed a normal diet, urine pH was generally > or = 6.5, which facilitates formation of
calcium-and
magnesium-containing solids, particularly in the presence of other prolithogenic changes in rat urine. Urinary
citrate, an inhibitor of lithogenesis, and soluble
calcium concentrations were dose dependently decreased in association with increased
calcium phosphate precipitate, crystals and/or microcalculi;
magnesium ammonium phosphate crystals and aggregates; and
calcium oxalate-containing thin, rod-like crystals. Morphologically, sustained urothelial cytotoxicity and proliferation with a ventral bladder predilection were noted in treated rats by month 1 and urinary
carcinomas with a similar distribution occurred by month 9. Urothelial apoptotic rates were unaffected by
muraglitazar treatment or diet. In
muraglitazar-treated rats fed an acidified diet, urine pH was invariably < 6.5, which inhibited formation of
calcium-and
magnesium-containing solids. Moreover, dietary acidification prevented the urothelial cytotoxic, proliferative, and tumorigenic responses. Collectively, these data support an indirect pharmacologic mode of urinary bladder
tumor development involving alterations in urine composition that predispose to
urolithiasis and associated decreases in urine-soluble
calcium concentrations.