Roles of organic anion transporter 2 and equilibrative nucleoside transporter 1 in hepatic disposition and antiviral activity of entecavir during non-pregnancy and pregnancy.
Roles of organic anion transporter 2 and equilibrative nucleoside transporter 1 in hepatic disposition and antiviral activity of entecavir during non-pregnancy and pregnancy.
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有机阴离子转运蛋白2和平衡核苷转运蛋白1在非妊娠和妊娠期间恩替卡韦的肝脏处置和抗病毒活性中的作用
DOI：
10.1111/bph.14756
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发表时间：
2019
影响因子：
7.3
通讯作者：
Huidi Jiang
中科院分区：
文献类型：
--
作者：
Zhiyuan Ma;Shuanghui Lu;Dongli Sun;Mengru Bai;Ting Jiang;Nengming Lin;Hui Zhou;Su Zeng;Huidi Jiang
背景和目的恩替卡韦(Entecavir，ETV)是一种抗乙肝病毒的一线药物，有可能用于预防母婴传播。本研究旨在阐明ETV进入肝细胞的机制，评价ETV在妊娠期间肝脏分布的变化。分别在人ENT1或OAT2过表达细胞模型和HepG2.2.15细胞中研究平衡核苷酸转运体(ENT)1和有机阴离子转运体(OAT)2在ETV蓄积和抗HBV活性中的作用；同时测定未孕和妊娠小鼠的肝/血浆ETV浓度比，以评价妊娠对ETV肝分布的影响。ENT1抑制剂显著降低了ETV在HepG2.2.15细胞中的作用，而OAT2的过表达则增加了乙肝病毒对ETV的易感性。妊娠小鼠肝脏与血浆中ETV的浓度比显著降低，而肝脏中ETV的绝对浓度在妊娠期间无明显变化。尽管雌二醇和孕酮对ETV在肝细胞系和原代肝细胞中的积聚均表现出浓度依赖性的抑制作用，但生理浓度的雌二醇和孕酮并不影响ETV的抗病毒活性。结论OAT2和ENT1是参与ETV的肝脏摄取和抗HBV活性的主要转运体。ETV在孕期肝脏中的浓度无明显变化，提示孕期不需要调整剂量。
Background and PurposeEntecavir (ETV), a first‐line antiviral drug against hepatitis B virus (HBV), has the possibility to be used to prevent mother‐to‐child transmission. The aim of present study was to clarify the mechanism of ETV uptake into hepatocytes and evaluate the alteration of ETV's hepatic distribution during pregnancy.Experimental ApproachThe roles of equilibrative nucleotide transporter (ENT) 1 and organic anion transporter (OAT) 2 in ETV accumulation and anti‐HBV efficacy were studied in human ENT1 or OAT2 overexpressed cell models and HepG2.2.15 cells, respectively; meanwhile, the liver‐to‐plasma ETV concentration ratios in non‐pregnant and pregnant mice were measured to evaluate the effect of pregnancy on ETV hepatic distribution.Key ResultsETV was shown to be a substrate of ENT1 and OAT2. An ENT1 inhibitor significantly decreased the efficacy of ETV in HepG2.2.15 cells, while overexpression of OAT2 increased susceptibility of HBV to ETV. The liver‐to‐plasma ETV concentration ratios in pregnant mice were sharply reduced; whereas, the absolute concentration of ETV in the liver did not obviously alter in pregnancy. Although oestradiol and progesterone showed a concentration‐dependent inhibition on ETV accumulation both in hepatic cell lines and in primary human hepatocytes, a physiologically relevant concentration of oestradiol and progesterone did not affect antiviral activity of ETV.Conclusions and ImplicationsOAT2 and ENT1 are the main transporters involved in the hepatic uptake and anti‐HBV efficacy of ETV. The concentration of ETV in the liver was not obviously altered during pregnancy, which indicates that dosage adjustment in pregnancy is not necessary.