Relationship between N-acetylator phenotype and susceptibility toward hydrazine-induced lethal central nervous system toxicity in the rabbit.

Toxicity experiments carried out with rapid and slow acetylator rabbits showed that the slow acetylators exhibited greater susceptibility to lethal central nervous system actions of isoniazid and its metabolite, monoacetylhydrazine. Slow acetylator rabbits receiving a daily 30-mg/kg dose of isoniazid survived an average of 3.4 weeks, whereas rapid acetylators presented no signs of toxicity for the duration of the experiment (12 weeks). Concomitant administration of vitamin B6 (pyridoxine hydrochloride) raised the dose necessary for lethal convulsions by these agents in both rapid and slow acetylators. Inasmuch as isoniazid and other hydrazine drugs and foreign chemicals may produce a vitamin B6 deficiency in humans that can elicit seizures and lethal convulsions at high dose levels, these results suggest that the central nervous system toxicity produced by these agents might be more frequent and more severe in human slow acetylators.