Important role of OATP in the liver disposition of ezetimibe and its consequent glucuronidation metabolite

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics Pub Date : 2025-12-01 Epub Date: 2025-09-18 DOI:10.1016/j.dmpk.2025.101503

Ying Su , Xinyi Zhang , Yiguo Jiang , Cheng Wang , Jianqing Ruan

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引用次数: 0

Abstract

Ezetimibe is a widely used antilipemic agent that lowers LDL-C and raises HDL-C by inhibiting intestinal cholesterol absorption. However, the mechanisms governing the hepatic transport of ezetimibe and its glucuronide metabolite remain unclear. In this study, we demonstrated that ezetimibe is rapidly metabolized to its glucuronide in mouse, rat, and human liver microsomes, with UGT1A1 showing the highest catalytic activity, followed by UGT1A3. In vitro transport assays revealed that human OATP1B1 and OATP1B3 selectively mediate the uptake of ezetimibe-glucuronide, but not parent ezetimibe. Using Slco1b2 knockout mice, an in vivo model for hepatic OATP deficiency, we found that knockout significantly increased the plasma AUC and decreased the liver-to-plasma ratio of ezetimibe-glucuronide, without affecting parent ezetimibe. These results indicate that OATP-mediated hepatic uptake is key to the disposition of ezetimibe-glucuronide, which may influence the pharmacokinetics and clinical efficacy of ezetimibe.

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OATP在依泽可米及其后续糖醛酸化代谢产物的肝脏处理中的重要作用。

依折替米贝是一种广泛使用的降脂剂，通过抑制肠道胆固醇吸收来降低LDL-C和升高HDL-C。然而，依折麦布及其葡萄糖醛酸代谢产物的肝脏转运机制尚不清楚。在本研究中，我们证明依折麦比在小鼠、大鼠和人的肝微粒体中被快速代谢为葡萄糖醛酸盐，其中UGT1A1的催化活性最高，其次是UGT1A3。体外转运实验显示，人OATP1B1和OATP1B3选择性地介导依zetimibe-glucuronide的摄取，而不是亲本依zetimibe。使用肝脏OATP缺乏的体内模型Slco1b2敲除小鼠，我们发现敲除显著增加血浆AUC，降低依zetimibe-glucuronide的肝-血浆比值，而不影响亲本依zetimibe。这些结果表明ooatp介导的肝脏摄取是依zetimibe-glucuronide处置的关键，可能影响依zetimibe的药代动力学和临床疗效。

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

Drug Metabolism and Pharmacokinetics 医学-药学

CiteScore

4.80

自引率

9.50%

发文量

审稿时长

69 days

期刊介绍： DMPK publishes original and innovative scientific papers that address topics broadly related to xenobiotics. The term xenobiotic includes medicinal as well as environmental and agricultural chemicals and macromolecules. The journal is organized into sections as follows: - Drug metabolism / Biotransformation - Pharmacokinetics and pharmacodynamics - Toxicokinetics and toxicodynamics - Drug-drug interaction / Drug-food interaction - Mechanism of drug absorption and disposition (including transporter) - Drug delivery system - Clinical pharmacy and pharmacology - Analytical method - Factors affecting drug metabolism and transport - Expression of genes for drug-metabolizing enzymes and transporters - Pharmacogenetics and pharmacogenomics - Pharmacoepidemiology.