Acetylation of acetylhydrazine, the toxic metabolite of isoniazid, in humans. Inhibition by concomitant administration of isoniazid.

The effect of isoniazid and its metabolites on the disposition of acetylhydrazine, a toxic metabolite formed from isoniazid, was studied in humans. Acetylhydrazine was administered i.v. with and without prior ingestion of 300 mg of isoniazid. In the studies with isoniazid, 15N2-acetylhydrazine was administered in order to distinguish exogenous acetylhydrazine from the unlabeled acetylhydrazine formed from isoniazid. In each subject (two fast and three slow acetylators) the rate of elimination of acetylhydrazine was similar to the rate of elimination of isoniazid suggesting that the two compounds are subject to the same acetylation polymorphism. In the presence of isoniazid the rate of elimination of acetylhydrazine was consistently lower than in the absence of isoniazid, and the urinary excretion of diacetylhydrazine and the ratio of diacetyl/acetylhydrazine in urine decreased. The data indicate that therapeutic concentrations of isoniazid and its metabolites inhibit the acetylation of acetylhydrazine in humans. The inhibition of this detoxification pathway could contribute to the hepatotoxicity of isoniazid.