{"title":"Isoniazid-historical development, metabolism associated toxicity and a perspective on its pharmacological improvement.","authors":"Jishnu Sankar, Anjali Chauhan, Ramandeep Singh, Dinesh Mahajan","doi":"10.3389/fphar.2024.1441147","DOIUrl":null,"url":null,"abstract":"<p><p>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 <i>in vivo</i> metabolism involving biotransformation on its terminal -NH<sub>2</sub> group owing to its high nucleophilic nature. The human <i>N-acetyltransferase-2</i> enzyme (NAT-2) exploits the reactivity of INH's terminal -NH<sub>2</sub> functional group and inactivates it by transferring the acetyl group, which subsequently converts to toxic metabolites. This -NH<sub>2</sub> 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, and 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 -NH<sub>2</sub> 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.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4000,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447295/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3389/fphar.2024.1441147","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
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, and 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.
期刊介绍:
Frontiers in Pharmacology is a leading journal in its field, publishing rigorously peer-reviewed research across disciplines, including basic and clinical pharmacology, medicinal chemistry, pharmacy and toxicology. Field Chief Editor Heike Wulff at UC Davis is supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.