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.

Determination of p-methylthiobenzamide and p-methylthiobenzamide-S-oxide from rat plasma using solid-phase extraction and high-performance liquid chromatography.

p-Methylthiobenzamide (PMTB) is a thiocarbonyl compound exhibiting marked hepatotoxicity and nephrotoxicity. We describe a high-performance liquid chromatographic method for analyzing PMTB and a metabolite, p-methylthiobenzamide-S-oxide (PMTBSO), from rat plasma using a solid-phase extraction technique. In this way, PMTB and PMTBSO can be extracted from 0.5 ml of plasma and separation achieved by an ODS analytical column in as little as 9 min. The mobile phase used was methanol-water (55:45, v/v) and the wavelength for detection was 290 nm. The limits of detection in plasma were 15 ng/ml for PMTB and 33 ng/ml for PMTBSO; the absolute recovery from spiked plasma samples was greater than 84.4% for both compounds and the internal standard. The method was linear throughout the range used with correlation coefficients greater than 0.969. The intra-day accuracy ranged from 1.52 to 15.23% relative error for the PMTB concentration range 151-3025 ng/ml; accuracy of 4.97% or less was obtained for PMTBSO concentrations of 1672-20,068 ng/ml. The intra-day precision (coefficient of variation) of the procedure was found to be no greater than 5.28% for PMTB and 7.9% for PMTBSO. Inter-day accuracy and precision measurements were similar.