Icaritin exhibits potential drug–drug interactions through the inhibition of human UDP-glucuronosyltransferase in vitro

IF 16.4 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Accounts of Chemical Research Pub Date : 2024-06-17 DOI:10.1002/bdd.2397

Yi Rong, Nanxi Li, Xuan Qiao, Lei Yang, Peng Han, Zhiyun Meng, Hui Gan, Zhuona Wu, Xiaoxia Zhu, Yunbo Sun, Shuchen Liu, Guifang Dou, Ruolan Gu

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Abstract

Icaritin is a prenylflavonoid derivative of the genus Epimedium (Berberidaceae) and has a variety of pharmacological actions. Icaritin is approved by the National Medical Products Administration as an anticancer drug that exhibits efficacy and safety advantages in patients with hepatocellular carcinoma cells. This study aimed to evaluate the inhibitory effects of icaritin on UDP-glucuronosyltransferase (UGT) isoforms. 4-Methylumbelliferone (4-MU) was employed as a probe drug for all the tested UGT isoforms using in vitro human liver microsomes (HLM). The inhibition potentials of UGT1A1 and 1A9 in HLM were further tested by employing 17β-estradiol (E2) and propofol (PRO) as probe substrates, respectively. The results showed that icaritin inhibits UGT1A1, 1A3, 1A4, 1A7, 1A8, 1A10, 2B7, and 2B15. Furthermore, icaritin exhibited a mixed inhibition of UGT1A1, 1A3, and 1A9, and the inhibition kinetic parameters (K_i) were calculated to be 3.538, 2.117, and 0.306 (μM), respectively. The inhibition of human liver microsomal UGT1A1 and 1A9 both followed mixed mechanism, with K_i values of 2.694 and 1.431 (μM). This study provides supporting information for understanding the drug–drug interaction (DDI) potential of the flavonoid icaritin and other UGT-metabolized drugs in clinical settings. In addition, the findings provide safety evidence for DDI when liver cancer patients receive a combination therapy including icaritin.

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淫羊藿苷通过在体外抑制人类 UDP-葡萄糖醛酸转移酶，表现出潜在的药物间相互作用。

淫羊藿苷是小檗科淫羊藿属植物的一种前黄酮类衍生物，具有多种药理作用。淫羊藿苷被国家医药产品管理局批准为抗癌药物，对肝癌细胞患者具有疗效和安全性优势。本研究旨在评估伊卡立汀对 UDP-葡萄糖醛酸转移酶（UGT）同工酶的抑制作用。采用体外人肝微粒体（HLM），以 4-甲基伞形酮（4-MU）为探针药物，对所有受测 UGT 同工酶进行检测。以 17β-estradiol (E2) 和异丙酚 (PRO) 分别作为探针底物，进一步测试了 UGT1A1 和 1A9 在 HLM 中的抑制潜能。结果表明，西卡利汀可抑制 UGT1A1、1A3、1A4、1A7、1A8、1A10、2B7 和 2B15。此外，西卡利丁还对 UGT1A1、1A3 和 1A9 具有混合抑制作用，其抑制动力学参数（Ki）分别为 3.538、2.117 和 0.306（μM）。对人肝脏微粒体 UGT1A1 和 1A9 的抑制均遵循混合机制，Ki 值分别为 2.694 和 1.431（μM）。这项研究为了解黄酮类化合物冰醋酸和其他 UGT 代谢药物在临床中的药物相互作用（DDI）潜力提供了支持性信息。此外，研究结果还提供了肝癌患者接受包括伊卡立汀在内的联合疗法时发生 DDI 的安全性证据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.