Macitentan:概述其降解产物,工艺相关杂质和硅毒性

IF 3.1 Q2 TOXICOLOGY
Eduardo Costa Pinto, Luana Gonçalves de Souza, Carolina Trajano Velozo, Gil Mendes Viana, Lucio Mendes Cabral, Valeria Pereira de Sousa
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引用次数: 2

摘要

马西坦是一种双重内皮素受体拮抗剂,用于治疗肺动脉高压这一慢性复杂疾病。在不同的应激条件下,如pH和温度的变化,药物可以产生大量的降解产物,而在四种主要合成路线中会产生许多与工艺相关的杂质。对这些杂质的潜在毒性进行评估是药品质量和安全的基本监管要求。本研究的目的是鉴定马西坦的所有代谢物和潜在杂质,并评估其硅毒性。文献中发现了35种与macitentan相关的化合物,其中两种同时被描述为代谢物、降解产物和工艺相关杂质。在本研究中,讨论了主要的降解产物及其形成的条件,以及合成路线中主要的杂质。与工艺相关的杂质的类型和数量取决于合成路线和工艺控制,而macitentan被发现更容易在酸性介质中降解,从而产生最不同类型的降解产物。生成了每种化合物的结构,并使用三种不同的硅平台确定了潜在的致突变性和致癌性风险,此外还评估了每种化合物的代谢底物/抑制谱。总的来说,五种化合物被认为是关键的,因为它们在致突变性、致瘤性、刺激性和生殖效应方面可能具有毒性风险。这些数据支持目前关于含有马西坦的原料和医药产品的立法,以防止这种药物的任何不良影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Macitentan: An overview of its degradation products, process-related impurities, and in silico toxicity.

Macitentan is a dual endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension, a chronic and complex disease. Under different stress conditions, such as changes in pH and temperature, the drug can generate a large number of degradation products, while many process-related impurities can occur during the four main synthetic routes. The assessment of the potential toxicity of these impurities is an essential regulatory requirement for the quality and safety of drugs. The goal of this study was to identify all metabolites and potential impurities for macitentan and evaluate their in silico toxicity. Thirty-five compounds related to macitentan were found reported in the literature, two of which were described simultaneously as metabolites, degradation products, and process-related impurities. In the present study, the main degradation products and the conditions under which they could be formed, and the major impurities according to the synthetic route, are discussed. The types and amounts of process-related impurities were dependent on the synthesis route and process controls, while macitentan was found to be more susceptible to degradation in acidic media resulting in the most different types of degradation products. The structure of each compound was generated and the potential risk for mutagenicity and carcinogenicity were determined using three different in silico platforms, in addition the metabolic substrate/inhibition profile for each compound was assessed. Overall, five compounds were considered critical as they had a possible toxicity risk in terms of mutagenicity, tumorigenicity, irritation, and reproductive effects. These data support the current legislation for raw materials and pharmaceutical products containing macitentan as to prevent any adverse effects from this drug.

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来源期刊
Computational Toxicology
Computational Toxicology Computer Science-Computer Science Applications
CiteScore
5.50
自引率
0.00%
发文量
53
审稿时长
56 days
期刊介绍: Computational Toxicology is an international journal publishing computational approaches that assist in the toxicological evaluation of new and existing chemical substances assisting in their safety assessment. -All effects relating to human health and environmental toxicity and fate -Prediction of toxicity, metabolism, fate and physico-chemical properties -The development of models from read-across, (Q)SARs, PBPK, QIVIVE, Multi-Scale Models -Big Data in toxicology: integration, management, analysis -Implementation of models through AOPs, IATA, TTC -Regulatory acceptance of models: evaluation, verification and validation -From metals, to small organic molecules to nanoparticles -Pharmaceuticals, pesticides, foods, cosmetics, fine chemicals -Bringing together the views of industry, regulators, academia, NGOs
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