Comparative disposition of the nephrotoxicant N-(3,5-dichlorophenyl)succinimide and the non-nephrotoxicant N-(3,5-difluorophenyl)succinimide in Fischer 344 rats

Disposition of the nephrotoxicant N-(3,5-dichlorophenyl)succinimide (NDPS) was compared with that of a nontoxic analog, N-(3,5-difluorophenyl)succinim ide (DFPS). Male Fischer 344 rats were administered 0.2 or 0.6 mmol/kg [C-1 4]NDPS or [C-14]DFPS (i.p. in corn oil). Plasma concentrations were determi ned from blood samples obtained through the carotid artery. Urine samples w ere analyzed for metabolite content by HPLC. Rats were sacrificed at 3 h (D FPS) or 6 h (NDPS) and tissue radiolabel content and covalent binding were determined. [C-14]NDPS-derived plasma radioactivity levels were 6- to 21-fo ld higher and peaked later than those from [C-14]DFPS. Six hours after dosi ng, NDPS was 40% eliminated in the urine compared with approximately 90% fo r DFPS. By 48 h, only 67% of the NDPS dose was eliminated in urine. In cont rast, DFPS excretion was virtually complete within 24 h. NDPS underwent oxi dative metabolism to a slightly greater extent than DFPS. Distribution of [ C-14]NDPS-derived radioactivity into the kidneys was 3- to 6-fold higher th an that into the liver or heart, and was more extensive than with [C-14]DFP S. NDPS also covalently bound to plasma, renal, and hepatic proteins to a g reater extent than DFPS. In summary, NDPS achieves higher tissue and plasma concentrations, covalently binds to a greater extent, and is eliminated mo re slowly than DFPS. Differences in the lipid solubility of NDPS metabolite s and DFPS metabolites may help explain these results. The overall greater tissue exposure of NDPS and its metabolites may contribute to differential toxicity of these analogs.