Isoniazid: metabolic aspects and toxicological correlates

Area of Science:

• Pharmacology and Toxicology
• Medicinal Chemistry
• Drug Metabolism

Background:

• Isoniazid (isonicotinyl hydrazide; INH) is a primary anti-tuberculosis drug.
• INH metabolism produces various metabolites, some associated with toxicity.
• Key metabolites include hydrazine (HZ), isonicotinic acid (INA), and acetylated derivatives.

Purpose of the Study:

• To review the metabolism of INH and its toxicological implications.
• To examine the roles of INH metabolites, particularly HZ, in neurotoxicity and hepatotoxicity.
• To discuss the impact of genetic factors (e.g., acetylation status) and drug interactions on INH toxicity.

Main Methods:

• Review of existing literature on INH metabolism and toxicity.
• Analysis of identified INH metabolites and their formation pathways (hydrolysis, CYP oxidation, NAT activity).
• Examination of pharmacogenetic evidence related to INH metabolism and toxicity.

Main Results:

• INH metabolism involves hydrolysis, CYP-dependent oxidation, and N-acetyltransferase (NAT) activity.
• Major metabolites include N(1)-acetyl-N(2)-isonicotinylhydrazide (AcINH), hydrazine (HZ), and ammonia.
• Slow acetylation, an autosomal recessive trait, is linked to increased peripheral neurotoxicity and hepatotoxicity.
• INH hepatotoxicity is primarily associated with HZ and its free radical-generating metabolites.
• The exact mechanism of INH neurotoxicity is unclear but likely involves HZ and ammonia.
• CYP interactions with INH can lead to clinically significant drug-drug interactions.

Conclusions:

• INH metabolism is complex, with several metabolites contributing to its toxicity.
• Genetic variations in acetylation significantly influence INH-induced hepato- and neurotoxicity.
• Further research is needed to fully elucidate the mechanisms of INH neurotoxicity and its interactions.