The roles of CYP2C19 and CYP3A4 in the in vitro metabolism of β-eudesmol in human liver: Reaction phenotyping and enzyme kinetics.

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Nadda Muhamad, Kesara Na-Bangchang
{"title":"The roles of CYP2C19 and CYP3A4 in the in vitro metabolism of β-eudesmol in human liver: Reaction phenotyping and enzyme kinetics.","authors":"Nadda Muhamad, Kesara Na-Bangchang","doi":"10.1002/prp2.1149","DOIUrl":null,"url":null,"abstract":"<p><p>β-eudesmol is a major bioactive component of Atractylodes lancea (AL). AL has been developed as the capsule formulation of standardized AL extract for treating cholangiocarcinoma (CCA). However, the complex constituents of herbal products increase the risk of adverse drug interactions. β-eudesmol has demonstrated inhibitory effects on rCYP2C19 and rCYP3A4 in the previous research. This study aimed to identify the cytochrome P450 (CYP) isoforms responsible for the metabolism of β-eudesmol and determine the enzyme kinetic parameters and the metabolic stability of β-eudesmol metabolism in the microsomal system. Reaction phenotyping using human recombinant CYPs (rCYPs) and selective chemical inhibitors of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 was performed, and enzyme kinetics and metabolic stability were investigated using human liver microsome (HLM). The results suggest that CYP2C19 and CYP3A4 play significant roles in β-eudesmol metabolism. The disappearance half-life (t<sub>1/2</sub> ) and intrinsic clearance (CL<sub>int</sub> ) of β-eudesmol were 17.09 min and 0.20 mL/min·mg protein, respectively. Enzyme kinetic analysis revealed the Michaelis-Menten constant (K<sub>m</sub> ) and maximum velocity (V<sub>max</sub> ) of 16.76 μM and 3.35 nmol/min·mg protein, respectively. As a component of AL, β-eudesmol, as a substrate and inhibitor of CYP2C19 and CYP3A4, has a high potential for drug-drug interactions when AL is co-administered with other herbs or conventional medicines.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 6","pages":"e01149"},"PeriodicalIF":2.9000,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614204/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmacology Research & Perspectives","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/prp2.1149","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

Abstract

β-eudesmol is a major bioactive component of Atractylodes lancea (AL). AL has been developed as the capsule formulation of standardized AL extract for treating cholangiocarcinoma (CCA). However, the complex constituents of herbal products increase the risk of adverse drug interactions. β-eudesmol has demonstrated inhibitory effects on rCYP2C19 and rCYP3A4 in the previous research. This study aimed to identify the cytochrome P450 (CYP) isoforms responsible for the metabolism of β-eudesmol and determine the enzyme kinetic parameters and the metabolic stability of β-eudesmol metabolism in the microsomal system. Reaction phenotyping using human recombinant CYPs (rCYPs) and selective chemical inhibitors of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 was performed, and enzyme kinetics and metabolic stability were investigated using human liver microsome (HLM). The results suggest that CYP2C19 and CYP3A4 play significant roles in β-eudesmol metabolism. The disappearance half-life (t1/2 ) and intrinsic clearance (CLint ) of β-eudesmol were 17.09 min and 0.20 mL/min·mg protein, respectively. Enzyme kinetic analysis revealed the Michaelis-Menten constant (Km ) and maximum velocity (Vmax ) of 16.76 μM and 3.35 nmol/min·mg protein, respectively. As a component of AL, β-eudesmol, as a substrate and inhibitor of CYP2C19 and CYP3A4, has a high potential for drug-drug interactions when AL is co-administered with other herbs or conventional medicines.

Abstract Image

CYP2C19和CYP3A4在人肝脏中β-去氨醇体外代谢中的作用:反应表型和酶动力学。
β-结氨醇是苍术的主要生物活性成分。AL已被开发为标准化AL提取物的胶囊制剂,用于治疗胆管癌(CCA)。然而,草药产品的复杂成分增加了药物不良相互作用的风险。在先前的研究中,β-结氨醇已经显示出对rCYP2C19和rCYP3A4的抑制作用。本研究旨在鉴定负责β-去结蛋白代谢的细胞色素P450(CYP)异构体,并确定微粒体系统中β-去连蛋白代谢的酶动力学参数和代谢稳定性。使用人重组CYP(rCYPs)和CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4的选择性化学抑制剂进行反应表型分析,并使用人肝微粒体(HLM)研究酶动力学和代谢稳定性。结果表明,CYP2C19和CYP3A4在β-结氨醇代谢中起重要作用。β-结氨醇的消失半衰期(t1/2)和固有清除率(CLint)为17.09 最小值和0.20 mL/min·mg蛋白质。酶动力学分析显示米氏常数(Km)和最大速度(Vmax)为16.76 μM和3.35 nmol/min·mg蛋白。作为AL的一种成分,β-去氨醇作为CYP2C19和CYP3A4的底物和抑制剂,当AL与其他草药或常规药物联合给药时,具有很高的药物相互作用潜力。
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 求助全文
来源期刊
Pharmacology Research & Perspectives
Pharmacology Research & Perspectives Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
5.30
自引率
3.80%
发文量
120
审稿时长
20 weeks
期刊介绍: PR&P is jointly published by the American Society for Pharmacology and Experimental Therapeutics (ASPET), the British Pharmacological Society (BPS), and Wiley. PR&P is a bi-monthly open access journal that publishes a range of article types, including: target validation (preclinical papers that show a hypothesis is incorrect or papers on drugs that have failed in early clinical development); drug discovery reviews (strategy, hypotheses, and data resulting in a successful therapeutic drug); frontiers in translational medicine (drug and target validation for an unmet therapeutic need); pharmacological hypotheses (reviews that are oriented to inform a novel hypothesis); and replication studies (work that refutes key findings [failed replication] and work that validates key findings). PR&P publishes papers submitted directly to the journal and those referred from the journals of ASPET and the BPS
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信