Pregnancy Impacts Entecavir Pharmacokinetics but Does Not Alter Its Renal Excretion
Pregnancy Impacts Entecavir Pharmacokinetics but Does Not Alter Its Renal Excretion
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怀孕会影响恩替卡韦的药代动力学，但不会改变其肾脏排泄
DOI：
10.1016/j.xphs.2020.01.027
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Huidi Jiang
中科院分区：
文献类型：
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作者：
Shuanghui Lu;Xi Yang;Ting Jiang;Hui Zhou;Wei Wang;Nengming Lin;Su Zeng;Zhiyuan Ma;Huidi Jiang
恩替卡韦（ETV）是治疗乙型肝炎病毒的一线抗病毒药物。本研究旨在探讨ETV在妊娠期间是否会发生药代动力学变化及其机制。结果表明，妊娠大鼠血浆中ETV暴露量高于未妊娠大鼠，而分娩后暴露量恢复到未妊娠大鼠水平。由于口服ETV的70%被肾脏排出，我们研究了妊娠期两种重要激素雌二醇（E2）和黄体酮（P4）对ETV相关肾脏转运蛋白的影响。我们的研究结果显示，E2和P4明显抑制了ETV相关肾转运蛋白hOAT1、hOAT3、hMATE1和hMATE2-K的活性，导致转运蛋白转染的细胞模型中ETV的积累减少。尽管妊娠大鼠的内源性肌酐清除率是未妊娠大鼠的1.5倍，但妊娠大鼠尿中ETV的累积排泄量与未妊娠大鼠相比无显著差异。综上所述，妊娠期ETV血浆暴露量增加，但ETV肾排泄量无明显变化。这可能是因为，在怀孕期间，肾小球ETV滤过增加补偿了E2-和p4介导的相关转运蛋白抑制导致的肾小管ETV分泌减少。
Entecavir (ETV) is a first-line antiviral drug against the hepatitis B virus. This study was designed to investigate whether ETV pharmacokinetics changes during pregnancy and the underlying mechanism. The results showed that ETV exposure in plasma was higher in pregnant rats than in nonpregnant rats, whereas the exposure after delivery was recovered to that in nonpregnant rats. Because 70% of orally dosed ETV is eliminated by kidney, the effects of estradiol (E2) and progesterone (P4), 2 important hormones during pregnancy, on ETV-related renal transporters were investigated. Our results revealed that the activities of the ETV-related renal transporters hOAT1, hOAT3, hMATE1, and hMATE2-K were clearly inhibited by E2 and P4, resulting in reduced ETV accumulation in transporter-transfected cell models. However, the cumulative urinary excretion of ETV in pregnant rats exhibited no significant difference compared to nonpregnant rats, although the endogenous creatinine clearance in pregnant rats was 1.5-fold that of nonpregnant rats. In conclusion, ETV plasma exposure is increased during pregnancy, but ETV renal excretion displays no significant alteration. This may be because, during pregnancy, increased glomerular ETV filtration compensated for the decrease in renal tubular ETV secretion that occurs by E2- and P4-mediated inhibition of related transporters.