Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, Germany.
Biochem Pharmacol. 2013 Sep 15;86(6):808-15. doi: 10.1016/j.bcp.2013.07.008. Epub 2013 Jul 20.
The antiviral lamivudine is cleared predominantly by the kidney with a relevant contribution of renal tubular secretion. It is not clear which drug transporters mediate lamivudine renal secretion. Our aim was to investigate lamivudine as substrate of the renal drug transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins MATE1 and MATE2-K. Uptake experiments were performed in OCT2, MATE1, or MATE2-K single-transfected human embryonic kidney 293 (HEK) cells. Transcellular transport experiments were performed in OCT2 and/or MATE1 single- or double-transfected Madin-Darby canine kidney II (MDCK) cells grown on transwell filters. Lamivudine uptake was significantly increased in HEK-OCT2, HEK-MATE1, and HEK-MATE2-K cells compared to control cells. In transcellular experiments, OCT2 located in the basolateral membrane had no effect on transcellular lamivudine transport. MATE1 located in the apical membrane decreased intracellular concentrations and increased transcellular transport of lamivudine from the basal to the apical compartment. MATE1- or MATE2-K-mediated transport was increased by an oppositely directed pH gradient. Several simultaneously administered drugs inhibited OCT2- or MATE2-K-mediated lamivudine uptake. The strongest inhibitors were carvedilol for OCT2 and trimethoprim for MATE2-K (inhibition by 96.3 and 83.7% at 15 μM, respectively, p<0.001). Trimethoprim inhibited OCT2- and MATE2-K-mediated lamivudine uptake with IC₅₀ values of 13.2 and 0.66 μM, respectively. Transcellular lamivudine transport in OCT2-MATE1 double-transfected cells was inhibited by trimethoprim with an IC₅₀ value of 6.9 μM. Lamivudine is a substrate of renal drug transporters OCT2, MATE1, and MATE2-K. Concomitant administration of drugs that inhibit these transporters could decrease renal clearance of lamivudine.
抗病毒药物拉米夫定主要通过肾脏清除，其中肾小管分泌起重要作用。目前尚不清楚哪种药物转运体介导拉米夫定的肾脏分泌。我们的目的是研究拉米夫定是否为肾脏药物转运体有机阳离子转运体 2（OCT2）和多药和毒素外排蛋白 MATE1 和 MATE2-K 的底物。在 OCT2、MATE1 或 MATE2-K 单转染的人胚肾 293（HEK）细胞中进行摄取实验。在 OCT2 和/或 MATE1 单转或双转染的犬肾传代细胞系（MDCK）细胞中进行跨细胞转运实验。与对照细胞相比，拉米夫定在 HEK-OCT2、HEK-MATE1 和 HEK-MATE2-K 细胞中的摄取显著增加。在跨细胞实验中，位于基底外侧膜的 OCT2 对拉米夫定的跨细胞转运没有影响。位于顶膜的 MATE1 降低细胞内浓度并增加拉米夫定从基底侧向顶侧腔室的跨细胞转运。由相反方向的 pH 梯度增加 MATE1-或 MATE2-K 介导的转运。几种同时给予的药物抑制了 OCT2 或 MATE2-K 介导的拉米夫定摄取。最强的抑制剂是卡维地洛对 OCT2 和甲氧苄啶对 MATE2-K（分别在 15 μM 时抑制 96.3%和 83.7%，p<0.001）。甲氧苄啶对 OCT2 和 MATE2-K 介导的拉米夫定摄取的抑制作用的 IC₅₀值分别为 13.2 和 0.66 μM。OCT2-MATE1 双转染细胞中的跨细胞拉米夫定转运被甲氧苄啶抑制，IC₅₀值为 6.9 μM。拉米夫定是肾脏药物转运体 OCT2、MATE1 和 MATE2-K 的底物。同时给予抑制这些转运体的药物可能会降低拉米夫定的肾脏清除率。
