Journal of Pharmacology and Experimental Therapeutics 1985-12-01

Pharmacokinetics of the toxic hydrazino metabolites formed from isoniazid in humans.

B H Lauterburg, C V Smith, E L Todd, J R Mitchell

Index: J. Pharmacol. Exp. Ther. 235(3) , 566-70, (1985)

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Abstract

The plasma concentrations of isoniazid and its hydrazino metabolites, acetylisoniazid, acetylhydrazine and diacetylhydrazine, were measured by gas chromatography-mass spectrometry in 12 healthy subjects after the ingestion of 300 mg of isoniazid. The area under the plasma concentration-time curve of acetylisoniazid and diacetylhydrazine increased with increasing rate of acetylation of isoniazid. In contrast, the area under the plasma concentration-time curve of acetylhydrazine, the postulated precursor of a toxic metabolite formed from isoniazid, was greater in slow acetylators. This occurred even though rapid acetylators generated more acetylisoniazid and thus more acetylhydrazine from isoniazid, because the rapid acetylators also acetylated acetylhydrazine faster to diacetylhydrazine than did the slow acetylators. Due to this complex relationship between area under the plasma concentration-time curve of acetylhydrazine and the rate of isoniazid acetylation (i.e., a faster rate of formation of acetylhydrazine is accompanied by a faster clearance to diacetylhydrazine), the rate of acetylation of isoniazid minimally influences the exposure of most patients to acetylhydrazine. This pharmacokinetic analysis, however, also shows that the apparent plasma half-life of acetylhydrazine is about five times longer than the plasma half-life of isoniazid, and thus repeated doses of isoniazid should lead to an accumulation of acetylhydrazine in the slowest acetylators in which the plasma half-life of acetylhydrazine is 20-plus hr.(ABSTRACT TRUNCATED AT 250 WORDS)