Indinavir Alters the Pharmacokinetics of Lamivudine Partially via Inhibition of Multidrug and Toxin Extrusion Protein 1 (MATE1)
Indinavir Alters the Pharmacokinetics of Lamivudine Partially via Inhibition of Multidrug and Toxin Extrusion Protein 1 (MATE1)
复制标题
茚地那韦部分通过抑制多药和毒素挤出蛋白 1 (MATE1) 改变拉米夫定的药代动力学
DOI：
10.1007/s11095-017-2290-4
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发表时间：
2018-01-01
影响因子：
3.7
通讯作者：
Shu, Yan
中科院分区：
文献类型：
--
作者：
Li, Qing;Ye, Zhi;Shu, Yan
拉米夫定是体外人类多药和毒素排泄蛋白1(HMATE1)的特征底物，常与吲哚那韦一起用于治疗人类免疫缺陷病毒(HIV)。我们的目的是研究小鼠MATE1是否参与拉米夫定在体内的处置，以及吲哚那韦和拉米夫定之间是否存在转运体介导的相互作用。利用Mate1野生型(+/+)和基因敲除(−/−)小鼠，确定MATE1在拉米夫定处置中的作用。在稳定表达OCT2和MATE1转运蛋白的人胚胎肾293(HEK 293)细胞中，检测了吲地那韦对OCT2和MATE1介导的拉米夫定摄取的抑制作用。用Mate1(+/+)和Mate1(−/−)小鼠研究MATE_1在体内吲哚那韦和拉米夫定相互作用中的作用。与Mate1(+/+)小鼠相比，Mate1(−/−)小鼠的拉米夫定血药浓度和组织蓄积显著增加。依地那韦显著增加了拉米夫定在小鼠体内的药代动力学暴露；然而，与Mate1(+/+)小鼠相比，在Mate1(−/−)小鼠中，Indinavir的影响要小得多。在拉米夫定的药代动力学过程中，MATE1起着重要作用。在体内，吲哚那韦可能通过抑制MATE1和其他机制而与拉米夫定发生药物相互作用。
Lamivudine, a characterized substrate for human multidrug and toxin extrusion protein 1 (hMATE1) in vitro, was commonly used with indinavir as a therapy against human immunodeficiency virus (HIV). We aimed to investigate whether mouse MATE1 is involved in the disposition of lamivudine in vivo, and whether there is any transporter-mediated interaction between indinavir and lamivudine. The role of MATE1 in the disposition of lamivudine was determined using Mate1 wild type (+/+) and knockout (−/−) mice. The inhibitory potencies of indinavir on lamivudine uptake mediated by OCT2 and MATE1 were determined in human embryonic kidney 293 (HEK 293) cells stably expressing these transporters. The role of MATE1 in the interaction between indinavir and lamivudine in vivo was determined using Mate1 (+/+) and Mate1 (−/−) mice. The plasma concentrations and tissue accumulation of lamivudine were markedly elevated in Mate1 (−/−) mice as compared to those in Mate1 (+/+) mice. Indinavir significantly increased the pharmacokinetic exposure of lamivudine in mice; however, the effect by indinavir was significantly less pronounced in Mate1 (−/−) mice as compared to Mate1(+/+) mice. MATE1 played an important role in lamivudine pharmacokinetics. Indinavir could cause drug-drug interaction with lamivudine in vivo via inhibition of MATE1 and additional mechanism.