Abstract
Phensuximide (PSX), methsuximide (MSX) and ethosuximide (ESX) are succinimide antiepileptic agents used worldwide in the treatment of absence seizures. A previous study from our laboratory demonstrated that PSX (0.3 or 0.6 mmol kg^−1^ day^−1^, i.p.) induced urotoxicity following daily administration for 5–7 days in Fischer 344 rats, but PSX (1.25 mmol kg^−1^, i.p.) induced only minimal urotoxicity following acute administration. The purpose of this study was to determine the acute nephrotoxic potential of MSX and ESX in male Fischer 344 rats and if antiepileptic succinimide‐induced urotoxicity is potentiated by phenobarbital pretreatment. In one set of experiments, rats (four rats per group) were administered a single intraperitoneal (i.p.) injection of a succinimide (0.4 or 1.0 mmol kg^−1^) or vehicle (sesame oil, 2.5 ml kg^−1^), and the renal function was monitored at 24 and 48 h. Neither ESX or MSX induced substantial changes in renal function or morphology, which suggests that neither compound is acutely nephrotoxic. Similar results were obtained with PSX, which supported our earlier findings with this antiepileptic agent. In a second set of experiments, rats (four rats per group) were pretreated for 3 days with phenobarbital (75 mg kg^−1^ day^−1^, i.p.) prior to receiving a succinimide (0.4 or 1.0 mmol kg^−1^, i.p.) or vehicle (sesame oil, 2.5 ml kg^−1^, i.p.). Renal function was monitored at 24 and 48 h after the last injection. Phenobarbital pretreatment had only minor effects on ESX‐ or MSX‐induced renal effects, with no significant morphological changes detected between treated and pair‐fed control groups. However, PSX‐induced urotoxicity was potentiated by phenobarbital. Marked hematuria and proteinuria were observed following PSX (1.0 mmol kg^−1^) administration to phenobarbital‐pretreated rats. Bladders from these animals contained bloody urine and exhibited hemorrhagic areas among the bladder epithelial cells. Proximal tubular cells exhibited mild damage, with some swelling and blebbing at the brush border membrane. These results suggest that phenobarbital potentiates PSX‐induced urotoxicity and that the resulting hemorrhagic cystitis is mediated by one or more PSX metabolites.