Renal Toxicity of a Nondopaminergic Antipsychotic Agent, Trimethyl Imidazopyrazolopyrimidine, in Rats

Abstract

A nondopaminergic antipsychotic agent, 5-ethyl-1,3,8-trimethyl-1 H -imidazo[1,2-c]pyrazolo[3,4-e]pyrimidine (TIPP; PD 112488), has been tested for potential toxicity in rats. As part of a preclinical safety evaluation, 10 Wistar rats per sex were administered TIPP as a dietary admixture, receiving doses of 0, 5, 10, 20, 25, 50, 100, and 200 mg/kg for 2 wk. In addition, 3 groups of 6 male Wistar rats were administered TIPP (PD 114877 and PD 117498, acid hydrolysis products of TIPP) at 100 mg/kg by gavage for 5 days. All animals given 200 mg/kg were euthanatized in moribund condition or found dead after 1 wk of treatment. Clinical evidence of renal toxicity was noted and included emaciation, hematuria, urinary incontinence, and enlarged kidneys at doses of 10 mg/kg and higher. Plasma urea levels were higher than those of controls in all TIPP-treated groups. Significant pathologic changes of the urothelium were evident at all doses and were characterized by necrotizing pyelitis and cystitis. Necrosis and inflammation of the urothelium resulted in secondary hydronephrosis. No renal toxicity was noted with the acid hydrolysis products. The urothelial changes with oral administration of TIPP in rats is species-specific, and the specificity may be related to the metabolism and excretion of the drug.