Vol. 26, Issue 9, 907-913, September 1998

In Vivo Metabolism and Disposition of the Nephrotoxicant N-(3,5-Dichlorophenyl)succinimide in Fischer 344 Rats

Robert J. Griffin and Peter J. Harvison

Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy and Science

N-(3,5-Dichlorophenyl)succinimide (NDPS) was originally developed as an agricultural fungicide. Previous work indicated that NDPS-induced renal damage in rats is metabolism-dependent and that hydroxylated metabolites might be involved in the nephrotoxic response. In this study, the disposition and nephrotoxicity of [¹⁴C]NDPS at two time points (3 and 24 hr) and three doses (0.2, 0.4, and 0.6 mmol/kg) were examined in male Fischer 344 rats. At 3 hr, only approximately 6.0% of the administered dose (0.6 mmol/kg) had been excreted. Elimination was nearly complete by 24 hr, except at the highest dose. Urinary elimination far exceeded fecal elimination at all doses. The urinary metabolites were identified as N-(3,5-dichlorophenyl)succinamic acid, N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid, N-(3,5-dichlorophenyl)-3-hydroxysuccinamic acid, and N-(3,5-dichlorophenyl)malonamic acid. N-(3,5Dichlorophenyl)-3-hydroxysuccinamic acid had not been previously detected in vivo. The same metabolites were also detected in the feces, blood, liver, and kidneys of rats. In addition, two novel in vivo NDPS metabolites were detected in liver and kidney homogenates. These metabolites were tentatively identified as N-(3,5-dichlorophenyl)-2-hydroxysuccinimide and N-(3,5-dichloro-4-hydroxyphenyl)succinamic acid. Dose-dependent increases in blood urea nitrogen levels, diuresis, proteinuria, glucosuria, and covalent protein adducts correlated with increases in oxidative metabolism. Rapid NDPS metabolism could help explain the early onset of nephrotoxicity. These studies provide additional evidence for the importance of oxidative metabolism in NDPS-induced kidney damage.