Evaluation of the inhibitory effects of antigout drugs on human carboxylesterases in vitro

IF 2.6 3区医学 Q3 TOXICOLOGY Toxicology in Vitro Pub Date : 2024-04-24 DOI:10.1016/j.tiv.2024.105833

Jia-hong Liang , Xiao-lei Yi , Jia-min Gong , Zuo Du

{"title":"Evaluation of the inhibitory effects of antigout drugs on human carboxylesterases in vitro","authors":"Jia-hong Liang , Xiao-lei Yi , Jia-min Gong , Zuo Du","doi":"10.1016/j.tiv.2024.105833","DOIUrl":null,"url":null,"abstract":"<div>Gout is an immune-metabolic disease that frequently coexists with multiple comorbidities such as chronic kidney disease, cardiovascular disease and metabolic syndrome, therefore, it is often treated in combination with these complications. The present study aimed to evaluate the inhibitory effect of antigout drugs (allopurinol, febuxostat, topiroxostat, benzbromarone, lesinurad and probenecid) on the activity of the crucial phase I drug-metabolizing enzymes, carboxylesterases (CESs). 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) and fluorescein diacetate (FD) were utilized as the probe reactions to determine the activity of CES1 and CES2, respectively, through in vitro culturing with human liver microsomes. Benzbromarone and lesinurad exhibited strong inhibition towards CESs with Ki values of 2.16 and 5.15 μM for benzbromarone towards CES1 and CES2, respectively, and 2.94 μM for lesinurad towards CES2. In vitro-in vivo extrapolation (IVIVE) indicated that benzbromarone and lesinurad might disturb the metabolic hydrolysis of clinical drugs in vivo by inhibiting CESs. In silico docking showed that hydrogen bonds and hydrophobic interactions contributed to the intermolecular interactions of antigout drugs on CESs. Therefore, vigilant monitoring of potential drug-drug interactions (DDIs) is imperative when co-administering antigout drugs in clinical practice.</div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":null,"pages":null},"PeriodicalIF":2.6000,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxicology in Vitro","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0887233324000638","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"TOXICOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Gout is an immune-metabolic disease that frequently coexists with multiple comorbidities such as chronic kidney disease, cardiovascular disease and metabolic syndrome, therefore, it is often treated in combination with these complications. The present study aimed to evaluate the inhibitory effect of antigout drugs (allopurinol, febuxostat, topiroxostat, benzbromarone, lesinurad and probenecid) on the activity of the crucial phase I drug-metabolizing enzymes, carboxylesterases (CESs). 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) and fluorescein diacetate (FD) were utilized as the probe reactions to determine the activity of CES1 and CES2, respectively, through in vitro culturing with human liver microsomes. Benzbromarone and lesinurad exhibited strong inhibition towards CESs with Ki values of 2.16 and 5.15 μM for benzbromarone towards CES1 and CES2, respectively, and 2.94 μM for lesinurad towards CES2. In vitro-in vivo extrapolation (IVIVE) indicated that benzbromarone and lesinurad might disturb the metabolic hydrolysis of clinical drugs in vivo by inhibiting CESs. In silico docking showed that hydrogen bonds and hydrophobic interactions contributed to the intermolecular interactions of antigout drugs on CESs. Therefore, vigilant monitoring of potential drug-drug interactions (DDIs) is imperative when co-administering antigout drugs in clinical practice.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

评估抗痛风药物对体外人体羧基酯酶的抑制作用

痛风是一种免疫代谢性疾病，经常与多种并发症（如慢性肾脏病、心血管疾病和代谢综合征）同时存在，因此经常与这些并发症合并治疗。本研究旨在评估抗痛风药物（别嘌醇、非布索坦、托吡索坦、苯溴马隆、来西诺德和丙磺舒）对关键的 I 期药物代谢酶--羧基酯酶（CESs）活性的抑制作用。利用 2-（2-苯甲酰基-3-甲氧基苯基）苯并噻唑（BMBT）和二乙酸荧光素（FD）作为探针反应，通过体外培养人肝微粒体来分别测定 CES1 和 CES2 的活性。苯溴马隆和雷西努拉对 CES 具有很强的抑制作用，苯溴马隆对 CES1 和 CES2 的 Ki 值分别为 2.16 和 5.15 μM，雷西努拉对 CES2 的 Ki 值为 2.94 μM。体外-体内外推法（IVIVE）表明，苯溴马隆和lesinurad可能通过抑制CES而干扰临床药物在体内的代谢水解。硅学对接表明，氢键和疏水相互作用是抗痛风药物在 CESs 上产生分子间相互作用的原因。因此，在临床实践中联合使用抗痛风药物时，必须警惕潜在的药物间相互作用（DDI）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Toxicology in Vitro 医学-毒理学

CiteScore

6.50

自引率

3.10%

发文量

181

审稿时长

65 days

期刊介绍： Toxicology in Vitro publishes original research papers and reviews on the application and use of in vitro systems for assessing or predicting the toxic effects of chemicals and elucidating their mechanisms of action. These in vitro techniques include utilizing cell or tissue cultures, isolated cells, tissue slices, subcellular fractions, transgenic cell cultures, and cells from transgenic organisms, as well as in silico modelling. The Journal will focus on investigations that involve the development and validation of new in vitro methods, e.g. for prediction of toxic effects based on traditional and in silico modelling; on the use of methods in high-throughput toxicology and pharmacology; elucidation of mechanisms of toxic action; the application of genomics, transcriptomics and proteomics in toxicology, as well as on comparative studies that characterise the relationship between in vitro and in vivo findings. The Journal strongly encourages the submission of manuscripts that focus on the development of in vitro methods, their practical applications and regulatory use (e.g. in the areas of food components cosmetics, pharmaceuticals, pesticides, and industrial chemicals). Toxicology in Vitro discourages papers that record reporting on toxicological effects from materials, such as plant extracts or herbal medicines, that have not been chemically characterized.