Role of para-hydroxylation in phensuximide-induced urotoxicity in the Fischer 344 rat.

Phensuximide (PSX) is an antiepileptic agent which has been shown to induce hemorrhagic cystitis and mild nephrotoxicity following repeated administration in man or rats or when acutely administered to phenobarbital-pretreated rats. The purpose of this study was to explore the role of para-hydroxylation of the phenyl group of PSX in PSX-induced urotoxicity. Two PSX derivatives, 2-(4-fluorophenyl)-N-methylsuccinimide (FMPS) and N-methyl-2-(4-methylphenyl)succinimide (MMPS), were synthesized and evaluated for urotoxic potential. Male Fischer 344 rats (four rats/group) were administered intraperitoneally (i.p.) a succinimide (0.4 or 1.0 mmol/kg) or vehicle and renal function monitored for 48 h. In a separate experiment, rats were pretreated with phenobarbital (75 mg/kg/day; 3 days, i.p.) prior to succinimide or succinimide vehicle. In non-phenobarbital pretreated rats, acute FMPS or MMPS treatment had little effect on renal function or morphology at the doses tested. Hematuria (+) was noted in the FMPS (1.0 mmol/kg) group on post-treatment day 2. However, in the phenobarbital-pretreated rats, FMPS (0.4 or 1.0 mmol/kg) induced marked hematuria (++) and increased proteinuria while having little or no effect on other renal functional parameters or renal morphology. At killing, bladders of treated rats were distended with bloody urine and exhibited hemorrhagic areas within the bladder wall. In phenobarbital-pretreated rats, MMPS administration had little effect on any renal functional parameter measured or urological morphology. These results suggest that para-hydroxylation does not contribute to the hemorrhagic cystitis induced by PSX.