Changes in Disposition of Ezetimibe and Its Active Metabolites Induced by Impaired Hepatic Function: The Influence of Enzyme and Transporter Activities
文献类型：期刊论文
| 作者 | Xie, Ningjie1,2; Wang, Hong1,2; Qin, Hua3; Guo, Zitao2; Xue, Hao2; Hu, Jiafeng1,2; Chen, Xiaoyan1,2
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| 刊名 | PHARMACEUTICS
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| 出版日期 | 2022-12-01 |
| 卷号 | 14期号:12页码:22 |
| 关键词 | hepatic impairment ezetimibe active metabolites phase II enzymes transporters first-pass metabolism inhibitory bile acids |
| DOI | 10.3390/pharmaceutics14122743 |
| 通讯作者 | Chen, Xiaoyan(xychen@simm.ac.cn) |
| 英文摘要 | Ezetimibe (EZE) is a selective cholesterol absorption inhibitor. Hepatic impairment significantly increases the systemic exposure of EZE and its main active phenolic glucuronide, EZE-Ph. Although changes in efflux transporter activity partly explain the changes in EZE-Ph pharmacokinetics, the causes of the changes to EZE and the effects of the administration route on EZE-Ph remain unclear. A carbon tetrachloride (CCl4)-induced hepatic failure rat model was combined with in vitro experiments to explore altered EZE and EZE-Ph disposition caused by hepatic impairment. The plasma exposure of EZE and EZE-Ph increased by 11.1- and 4.4-fold in CCl4-induced rats following an oral administration of 10 mg/kg EZE, and by 2.1- and 16.4-fold after an intravenous injection. The conversion of EZE to EZE-Ph decreased concentration-dependently in CCl4-induced rat liver S9 fractions, but no change was observed in the intestinal metabolism. EZE-Ph was a substrate for multiple efflux and uptake transporters, unlike EZE. In contrast to efflux transporters, no difference was seen in the hepatic uptake of EZE-Ph between control and CCl4-induced rats. However, bile acids that accumulated due to liver injury inhibited the uptake of EZE-Ph by organic anion transporting polypeptides (OATPs) (glycochenodeoxycholic acid and taurochenodeoxycholic acid had IC50 values of 15.1 and 7.94 mu M in OATP1B3-overexpressed cells). In conclusion, the increased plasma exposure of the parent drug EZE during hepatic dysfunction was attributed to decreased hepatic glucuronide conjugation, whereas the increased exposure of the metabolite EZE-Ph was mainly related to transporter activity, particularly the inhibitory effects of bile acids on OATPs after oral administration. |
| WOS关键词 | CHOLESTEROL ABSORPTION INHIBITOR ; LIVER-DISEASE ; BILE-ACIDS ; PHARMACOKINETICS ; GLUCURONIDATION ; IDENTIFICATION ; EXPRESSION ; MODELS ; ABCC2 ; RATS |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | MDPI |
| WOS记录号 | WOS:000903318400001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/304168]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Chen, Xiaoyan |
| 作者单位 | 1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China 3.Beijing Tianheng Pharmaceut Res Inst Co Ltd, 93,Zone 6, Beijing 102433, Peoples R China |
| 推荐引用方式 GB/T 7714 | Xie, Ningjie,Wang, Hong,Qin, Hua,et al. Changes in Disposition of Ezetimibe and Its Active Metabolites Induced by Impaired Hepatic Function: The Influence of Enzyme and Transporter Activities[J]. PHARMACEUTICS,2022,14(12):22. |
| APA | Xie, Ningjie.,Wang, Hong.,Qin, Hua.,Guo, Zitao.,Xue, Hao.,...&Chen, Xiaoyan.(2022).Changes in Disposition of Ezetimibe and Its Active Metabolites Induced by Impaired Hepatic Function: The Influence of Enzyme and Transporter Activities.PHARMACEUTICS,14(12),22. |
| MLA | Xie, Ningjie,et al."Changes in Disposition of Ezetimibe and Its Active Metabolites Induced by Impaired Hepatic Function: The Influence of Enzyme and Transporter Activities".PHARMACEUTICS 14.12(2022):22. |
入库方式： OAI收割
来源：上海药物研究所
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