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)succinimide (DFPS). Male Fischer 344 rats were administered 0.2 or 0.6 mmol/kg [14C]NDPS or [14C]DFPS (i.p. in corn oil). Plasma concentrations were determined from blood samples obtained through the carotid artery. Urine samples were analyzed for metabolite content by HPLC. Rats were sacrificed at 3 h (DFPS) or 6 h (NDPS) and tissue radiolabel content and covalent binding were determined. [14C]NDPS-derived plasma radioactivity levels were 6- to 21-fold higher and peaked later than those from [14C]DFPS. Six hours after dosing, NDPS was 40% eliminated in the urine compared with approximately 90% for DFPS. By 48 h, only 67% of the NDPS dose was eliminated in urine. In contrast, DFPS excretion was virtually complete within 24 h. NDPS underwent oxidative metabolism to a slightly greater extent than DFPS. Distribution of [14C]NDPS-derived radioactivity into the kidneys was 3- to 6-fold higher than that into the liver or heart, and was more extensive than with [14C]DFPS. NDPS also covalently bound to plasma, renal, and hepatic proteins to a greater extent than DFPS. In summary, NDPS achieves higher tissue and plasma concentrations, covalently binds to a greater extent, and is eliminated more slowly than DFPS. Differences in the lipid solubility of NDPS metabolites 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.
Henesey
C M
CM
Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania 19104-4495, USA.
Kellner-Weibel
G L
GL
Tarloff
J B
JB
Harvison
P J
PJ
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D007408:Intestinal Absorption; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013386:Succinates / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013388:Succinimides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D014018:Tissue Distribution
C119990:N-(3,5-difluorophenyl)succinamic acid; D013386:Succinates; D013388:Succinimides; C007352:N-(3,5-dichlorophenyl)succinimide