The hepatotoxicity of isoniazid in rats results from the metabolic activation of acetylhydrazine, a metabolite of isoniazid, by the cytochrome P450 monooxygenase system. Inhibition of the drugmetabolizing enzyme system with a compound suitable for clinical use such as cimetidine might therefore prevent liver injury in experimental animals and in patients on isoniazid without interfering with the antituberculous activity of the drug. To test this hypothesis, we studied the effect of cimetidine on acetylhydrazine-induced hepatocellular necrosis in rats and the formation of 14CO2 from [14C]acetylisoniazid, which provides an indirect assessment of the fraction of a dose of isoniazid metabolized via the toxifying pathway. Pretreatment of rats with 150 mg per kg of cimetidine significantly decreased the extent of hepatocellular necrosis produced by 100 mg per kg of aeetylhydrazine and the formation of 14CO2 from [14C]acetylisoniazid. In man, however, 300 mg of cimetidine administered every 6 hr did not decrease the formation of 14CO2 from [14C] acetylisoniazid administered concomitantly with 300 mg of isoniazid; similarly, cimetidine did not affect the urinary excretion of isoniazid, acetylisoniazid, acetylhydrazine and diacetylhydrazine. These data demonstrate that the mechanistic information obtained in animal models cannot be applied readily in clinical practice and that measurable inhibition of acetylhydrazine metabolism to prevent isoniazid liver injury does not occur after administration of therapeutic doses of cimetidine to patients.
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