Thioacetamide-induced hepatic necrosis. II. Pharmacokinetics of thioacetamide and thioacetamide-S-oxide in the rat
Porter, W.R.; Gudzinowicz, M.J.; Neal, R.A.
Journal of Pharmacology and Experimental Therapeutics 208(3): 386-391
1979
ISSN/ISBN: 0022-3565 PMID: 430359 Document Number: 144195
The distribution of radioactivity from 3H-, 14C- or 35S-labeled thioacetamide and thioacetamide-S-oxide was studied as a function of time in liver, kidney, plasma and muscle. Liver and plasma concentrations of thioacetamide, thioacetamide-S-oxide, acetamide, sulfate, polar products and products bound to tissue macromolecules were also determined. The development of centrilobular hepatic necrosis was first observed 6 h after peak plasma levels of thioacetamide-S-oxide were obtained (6 h after administration of the S-oxide or 9 h after administration of thioacetamide). Maximum hepatic necrosis occurred at 24 h and was correlated with the peak concentrations of polar products in the liver and with radioactivity bound to hepatic macromolecules. Maximum concentrations of polar products in the liver and radioactivity bound to hepatic macromolecules were obtained 3-6 h after peak plasma levels of thioacetamide-S-oxide were reached. Equimolar doses of thioacetamide-S-oxide produced a more rapid onset and a greater severity of centrilobular hepatic necrosis than did corresponding doses of thioacetamide. Thioacetamide-induced necrosis can be explained by a scheme which requires the metabolic conversion of thioacetamide to its S-oxide followed by the further metabolism of thioacetamide-S-oxide to a reactive intermediate which can either bind to liver macromolecules or be degraded to acetamide and polar products. The methyl group and thiocarbonyl carbon atom, but not the S atom, of thioacetamide or its S-oxide appear bound to tissue macromolecules after reaction with the reactive intermediate. Under the conditions of these experiments acetamide, formed metabolically from thioacetamide or thioacetamide-S-oxide, does not appear further degraded. The administration of [14C]acetamide does not lead to incorporation of a measurable amount of radioactivity into the macromolecules of liver.