Nephrotoxic potential of N-(3,5-dichloro-4-fluorophenyl)succinimide in Fischer 344 rats: comparison with N-(3,4,5-trichlorophenyl)succinimide

Numerous structure-nephrotoxicity relationship studies from our laboratory have demonstrated that N-(3,5-dichlorophenyl)succinimide (NDPS) is one of t he most potent nephrotoxicants among the N-arylsuccinimides. The purpose of this study was to extend our previous structure-nephrotoxicity relationshi p studies by examining the effect of addition of a fluoro verses a chloro g roup at the 4-phenyl position in NDPS. Male Fischer 344 rats (four rats/gro up) received a single intraperitoneal (i.p.) injection of N-(3,5-dichloro-4 -fluorophenyl)succinimide (NDCFPS) or N-(3,4,5-trichlorophenyl)succinimide (NTCPS)(0.4 or 0.8 mmol/kg) or vehicle, and renal function monitored at 24 and 48 h. NDCFPS did not induce significant nephrotoxicity at either dose t ested. In contrast, NTCPS (0.4 or 0.8 mmol/kg) induced marked nephrotoxicit y characterized by diuresis, increased proteinuria, glucosuria, elevated ki dney weight and increased blood urea nitrogen (BUN) concentration. NTCPS al so induced marked proximal tubular necrosis at both doses tested. Neither N DCFPS nor NTCPS induced hepatotoxicity at either dose tested. The results o f these experiments indicate that addition of a fluoro group at the 4-posit ion on the phenyl ring of NDPS produces a nonnephrotoxicant NDPS derivative (NDCFPS), while addition of a chloro group at this site produces an NDPS d erivative with similar nephrotoxic potential to NDPS. The mechanism for thi s differential effect between 4-halophenyl substitution is unclear, but may result from increased hydrolysis of the succinimide ring and/or increased clearance of N-arylsuccinimide metabolites when a fluoro group is added to the 4-position of the phenyl ring. (C) 1999 Elsevier Science Ireland Ltd. A ll rights reserved.