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Acute toxicity induced by 2‐aryl‐N‐methylsuccinimides

Phensuximide (PSX) is a 2‐arylsuccinimide useful in the treatment of absence seizures. PSX is a mild urotoxicant and is structurally related to N‐phenylsuccinimide (NPS) and its antifungal derivatives. Since substitution of the phenyl ring of NPS with chloro or tert‐butyl groups can produce compounds with enhanced nephrotoxic potential, it was felt that similar substitutions on the phenyl ring of PSX also might produce derivatives with enhanced nephrotoxic potential. Three derivatives of PSX were prepared and tested: 2‐(3‐chlorophenyl)‐N‐methylsuccinimide (CPMS); 2‐(4‐tert‐butylphenyl)‐N‐methylsuccinimide (BPMS) and 2‐(3,5‐dichlorophenyl)‐N‐methylsuccinimide (DPMS). In one set of experiments, male Fischer 344 rats 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 renal function monitored at 24 and 48 h. Only minor changes in renal function were noted with the PSX derivatives. BPMS and DPMS (1.0 mmol kg−1) treatment induced mild renal tubular necrosis and thickening of the glomerular membranes. However, no significant morphological changes were noted in ureters, bladder or liver in any treatment group. In a second set of experiments, rats were pretreated with phenobarbital (75 mg kg−1 day−1, i.p., 3 days) followed by a single i.p. injection of DPMS (0.4 or 1.0 mmol kg−1) or DPMS vehicle. Renal function was monitored as before. Phenobarbital pretreatment did not markedly enhance the functional nephrotoxicity induced by DPMS (0.4 mmol), but tubular necrosis was greater than observed in non‐phenobarbital‐pretreated rats receiving DPMS (1.0 mmol kg−1). In addition, hepatotoxicity was observed as the appearance of numerous non‐staining vacuoles in hypertrophied hepatocytes. In the phenobarbital plus DPMS (1.0 mmol kg−1) treatment group, all rats died by 48 h. Prior to death, rats exhibited increased proteinuria (+3), hematuria (+3) and blood urea nitrogen concentration. At 24 h, kidneys from rats treated with phenobarbital plus DPMS (1.0 mmol kg−1) exhibited extensive proximal tubular necrosis and numerous glomeruli with thickened membranes. Hepatotoxicity was more pronounced than with phenobarbital plus DPMS (0.4 mmol kg−1) at 48 h and urinary bladders had focal areas of erythrocytes pooling below the epithelial lining. These results demonstrate that although NPS and PSX are structural analogs, chemical substitutions that enhance the nephrotoxic potential of NPS do not have a similar effect on PSX. In addition, DPMS can induce urotoxicity in a manner similar to that observed for PSX and probably induces toxicity via one or more metabolites.