The effect of partial hepatectomy on the metabolism, distribution, and nephrotoxicity of para-methylthiobenzamide in the rat.
Para-Methylthiobenzamide (PMTB) produces injury to the liver and kidney. Toxicity is mediated via its biotransformation to a reactive S,S-dioxide metabolite. The objective of this study was to examine the role of hepatic metabolism in the production of PMTB-induced renal toxicity. Renal injury was assessed in partially hepatectomized and sham-operated rats and the effect of this procedure on the distribution and metabolism of PMTB was examined. The in vitro oxidation of PMTB and [14C]thiobenzamide by rat kidney microsomes was also examined. Plasma urea levels and renal cortical slice uptake of organic ions were used to monitor renal function. Partial hepatectomy alone did not alter renal function nor raise blood urea nitrogen levels. Nephrotoxicity resulted when a nonnephrotoxic dose of PMTB (1.2 mmol/kg) was given to partially hepatectomized rats. An HPLC method was used for measurement of PMTB and its metabolites para-methylthiobenzamide S-oxide (PMTBSO) and para-methylbenzamide (PMBA) in plasma and kidney. Hepatectomy delayed the removal of this dose of PMTB from plasma and allowed greater concentrations of PMTB and PMTBSO to accumulate in plasma and kidney at 6 and 15 hr. The level of PMBA was similar in both groups at 6 hr, but was increased in plasma and kidney of the hepatectomized group at 15 hr. Kidney microsomes rapidly converted PMTB to PMTBSO and small amounts of PMBA. [14C]TB was oxidized by microsomes to thiobenzamide S-oxide, benzamide, and covalently bound metabolites. The results indicate that partial hepatectomy lowered the threshold for the expression of nephrotoxicity by PMTB. This procedure is associated with an increased renal accumulation of PMTB and PMTBSO, which are both sequentially transformed to the toxic metabolite.
Cox
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DN
Department of Pharmacology and Toxicology, University of Kansas, Lawrence 66045-2505.
Davidson
V P
VP
Judd
C E
CE
Stodgell
C
C
Traiger
G J
GJ
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D006498:Hepatectomy; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D008297:Male; D008861:Microsomes / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013854:Thioamides / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D014018:Tissue Distribution
D013854:Thioamides; C071096:4-methylthiobenzamide; C071098:4-methylthiobenzamide-S-oxide