Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S Nagar, 160062, Punjab, India.
Aurigene Discovery Technologies Ltd., Electronics City Phase II, Bengaluru, 560100, Karnataka, India.
J Pharm Biomed Anal. 2021 Sep 5;203:114223. doi: 10.1016/j.jpba.2021.114223. Epub 2021 Jun 24.
Isoniazid (INH) is the first-line anti-tubercular drug that is used both for the prophylaxis as well as the treatment of tuberculosis (TB). The patients with TB are more vulnerable to secondary infections and other health complications, hence, they are usually administered a cocktail of drugs. This increases the likelihood of drug-drug interactions (DDIs). INH is clinically proven to interact with drugs like phenytoin, carbamazepine, diazepam, triazolam, acetaminophen, etc. Most of such clinical observations have been supported by in vitro inhibition studies involving INH and cytochrome P450 (CYP) enzymes. A few published in vitro studies have explored the CYP2E1 inhibition potential of INH to explain its interactions with acetaminophen and other CY2E1 substrates, such as chlorzoxazone, but none of them were able to demonstrate any significant inhibition of the enzyme by the drug. It was reported that metabolites of INH, such as acetylhydrazine and hydrazine, were bioactivated by CYP2E1, highlighting that perhaps the drug metabolites were responsible for the mechanism based inhibition (MBI) of the enzyme. Therefore, the purpose of this investigation was to explore CYP2E1 enzyme inhibition potential of INH and its four major metabolites, viz., acetylisoniazid, isonicotinic acid, acetylhydrazine and hydrazine, using human liver microsomes (HLM). Additionally, we determined the fraction unbound in microsomal incubation (fu) for all the five compounds using equilibrium dialysis assay. We observed that INH and its metabolites had lower propensity for microsomal binding, and the metabolites also lacked the potential to inhibit CYP2E1 enzyme, either by direct inhibition or through MBI. This suggests involvement of some other mechanism to explain interactions of INH with CY2E1 substrates, signifying need of further exploration.
异烟肼（INH）是一线抗结核药物，既用于结核病（TB）的预防，也用于治疗。TB 患者更容易发生二次感染和其他健康并发症，因此，他们通常会服用药物鸡尾酒。这增加了药物-药物相互作用（DDI）的可能性。临床已经证实 INH 与苯妥英、卡马西平、地西泮、三唑仑、对乙酰氨基酚等药物相互作用。大多数此类临床观察结果都得到了涉及 INH 和细胞色素 P450（CYP）酶的体外抑制研究的支持。一些已发表的体外研究探讨了 INH 对 CYP2E1 的抑制潜力，以解释其与对乙酰氨基酚和其他 CYP2E1 底物（如氯唑沙宗）的相互作用，但没有一项研究能够证明药物对该酶有任何显著的抑制作用。据报道，INH 的代谢物，如乙酰肼和肼，被 CYP2E1 生物激活，这表明可能是药物代谢物导致了酶的基于机制的抑制（MBI）。因此，本研究旨在使用人肝微粒体（HLM）探索 INH 及其四种主要代谢物，即乙酰异烟肼、烟酸、乙酰肼和肼对 CYP2E1 酶的抑制潜力。此外，我们使用平衡透析测定法确定了所有五种化合物在微粒体孵育中的未结合分数（fu）。我们观察到 INH 及其代谢物对微粒体结合的倾向较低，而且代谢物也缺乏通过直接抑制或 MBI 抑制 CYP2E1 酶的潜力。这表明需要进一步探索其他机制来解释 INH 与 CYP2E1 底物的相互作用。
