acetylisoniazid

Acetylisoniazid, or N-acetylisoniazid, is a primary metabolite of the anti-tuberculosis drug isoniazid (INH). It is formed in the liver by the enzyme N-acetyltransferase 2 (NAT2) through acetylation of INH. Human NAT2 activity shows genetic polymorphism, producing different acetylation phenotypes, commonly described as rapid and slow acetylators, which influence the disposition of INH and its metabolites.

Metabolism and fate of acetylisoniazid involve further biotransformation. N-acetylisoniazid can be hydrolyzed to isonicotinic acid and acetylhydrazine; acetylhydrazine may be further processed, including additional acetylation or oxidation pathways. These downstream metabolites contribute to the overall pharmacokinetic profile of INH, and the balance of pathways varies with NAT2 genotype and potential drug interactions. The acetylated metabolite and its products are typically eliminated via urine.

Clinical and pharmacological relevance centers on the fact that acetylisoniazid itself is not considered the anti-tuberculosis active form. The therapeutic effect of INH derives mainly from the parent drug, while acetylation rate influences INH plasma levels and exposure. Slow acetylators tend to have higher INH concentrations, which can be associated with an increased risk of dose-related toxicity, partly linked to hydrazine- or acetylhydrazine-derived metabolites. Because acetylisoniazid levels reflect NAT2 activity, measuring this metabolite can be useful in pharmacokinetic studies and in understanding individual variability in INH metabolism.

In summary, acetylisoniazid is a NAT2-mediated metabolite of isoniazid with limited direct therapeutic relevance but significant implications for drug disposition and safety.