Abstract
Disposition of the nephrotoxicantN-(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.
Footnotes
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Send reprint requests to: Peter J. Harvison, Ph.D., University of the Sciences in Philadelphia, 600 South Forty-third Street, Philadelphia, PA 19104-4495. E-mail: p.harvis{at}usip.edu
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This work was supported by National Institute for Environmental Health Sciences, National Institutes of Health Grant ES05189. Presented in part at the 36th Annual Meeting of the Society of Toxicology, Anaheim, CA, March 1996 (abstract 1564).
- Abbreviations used are::
- NDPS
- N-(3,5-dichlorophenyl)succinimide
- DFPS
- N-(3,5-difluorophenyl)succinimide
- NDPSA
- N-(3,5-dichlorophenyl)succinamic acid
- DFPSA
- N-(3,5-difluorophenyl)succinamic acid
- 2-NDHSA
- N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid
- 2-DFHSA
- N-(3,5-difluorophenyl)-2-hydroxysuccinamic acid
- 3-NDHSA
- N-(3,5-dichlorophenyl)-3-hydroxysuccinamic acid
- 3-DFHSA
- N-(3,5-difluorophenyl)-3-hydroxysuccinamic acid
- NDHS
- N-(3,5-dichlorophenyl)-2-hydroxysuccinimide
- DFHS
- N-(3,5-difluorophenyl)-2-hydroxysuccinimide
- NDHPSA
- N-(3,5-dichloro-4-hydroxyphenyl)succinamic acid
- DFHPSA
- N-(3,5-difluoro-4-hydroxyphenyl)succinamic acid
- Received October 30, 1998.
- Accepted March 11, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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