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REVIEW article
Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 15 - 2024 |
doi: 10.3389/fphar.2024.1441147
Isoniazid-historical development, metabolism associated toxicity and a perspective on its pharmacological improvement
Provisionally accepted- Translational Health Science and Technology Institute (THSTI), Faridabad, India
Despite the extraordinary anti-tubercular activity of isoniazid (INH), the drug-induced hepatotoxicity and peripheral neuropathy pose a significant challenge to its wider clinical use.The primary cause of INH-induced hepatotoxicity is in vivo metabolism involving biotransformation on its terminal -NH2 group owing to its high nucleophilic nature. The human N-acetyltransferase-2 enzyme (NAT-2) exploits the reactivity of INH's terminal -NH2 functional group and inactivates it by transferring the acetyl group, which subsequently converts to toxic metabolites. This -NH2 group also tends to react with vital endogenous molecules such as pyridoxine, leading to their deficiency, a major cause of peripheral neuropathy. The elevation of liver functional markers is observed in 10-20% of subjects on INH treatment. INH-induced risk of fatal hepatitis is about 0.05-1%. The incidence of peripheral neuropathy is 2-6.5%. In this review, we discuss the genesis and historical development of INH, highlighting different reported mechanisms of action of INH. This is followed by a brief review of various clinical trials in chronological order, highlighting treatment-associated adverse events and their occurrence rates, including details such as geographical location, number of subjects, dosing concentration, and regimen used in these clinical studies. Further, we elaborated on various known metabolic transformations highlighting the involvement of the terminal -NH2 group of INH and corresponding host enzymes, the structure of different metabolites/conjugates, and their association with hepatotoxicity or neuritis. Post this deliberation, we propose a hydrolysable chemical derivatives-based approach as a way forward to restrict this metabolism.
Keywords: Isoniazid, Metabolism, Hepatotoxicity, peripheral neuropathy, N-acetyltransferase, prodrug
Received: 30 May 2024; Accepted: 30 Aug 2024.
Copyright: © 2024 Sankar, Chauhan, Singh and Mahajan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Dinesh Mahajan, Translational Health Science and Technology Institute (THSTI), Faridabad, India
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