Involvement of Human Multidrug and Toxin Extrusion 1 in the Drug Interaction between Cimetidine and Metformin in Renal Epithelial Cells
Involvement of Human Multidrug and Toxin Extrusion 1 in the Drug Interaction between Cimetidine and Metformin in Renal Epithelial Cells
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DOI：
10.1124/jpet.108.147918
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发表时间：
2009-04-01
影响因子：
3.5
通讯作者：
Inui, Ken-ichi
中科院分区：
文献类型：
--
作者：
Tsuda, Masahiro;Terada, Tomohiro;Inui, Ken-ichi
在人近端小管中，有机阳离子通过人有机阳离子转运蛋白2 [hOCT 2/溶质载体（SLC）22 A2]从血液中摄取到细胞中，然后通过顶端H+/有机阳离子反向转运蛋白、人多药和毒素排出蛋白1（hMATE 1/SLC 47 A1）和hMATE 2-K（SLC 47 A2）消除到管腔中。为了评价阳离子药物在分泌过程中的药物相互作用，需要经工程改造以表达hOCT 2和hMATE转运蛋白的上皮细胞同时评价药物与肾基底外侧和顶端有机阳离子转运蛋白的相互作用。因此，在本研究中，我们评估了西咪替丁和二甲双胍之间的药物相互作用，使用稳定表达hOCT 2和hMATE 1的双转染Madin-Darby犬肾细胞作为近端肾小管上皮细胞的体外模型。双转染子引起的[C-14]二甲双胍的基底外侧至顶端转运和细胞内蓄积在基底外侧受到1 mM西咪替丁的显著抑制。另一方面，基底侧1 μ M西咪替丁中度降低[C-14]二甲双胍的基底侧至顶端转运，并显著增加基底侧[C-14]二甲双胍的细胞内蓄积，表明低浓度西咪替丁抑制顶端hMATE 1，而非基底侧hOCT 2。实际上，在单一转运蛋白表达系统（如稳定表达hMATE 1、hMATE 2-K或hOCT 2的人胚肾293）的浓度依赖性抑制研究中，西咪替丁对hMATE的亲和力高于对hOCT 2的亲和力。这些结果表明，顶端hMATE 1参与了近端肾小管上皮细胞中西咪替丁和阳离子化合物之间的药物相互作用。
In human proximal tubules, organic cations are taken up from blood into cells by human organic cation transporter 2 [hOCT2/solute carrier (SLC) 22A2] and then eliminated into the lumen by apical H+/organic cation antiporters, human multidrug and toxin extrusion 1 (hMATE1/SLC47A1) and hMATE2-K (SLC47A2). To evaluate drug interactions of cationic drugs in the secretion process, epithelial cells engineered to express both hOCT2 and hMATE transporters are required to simultaneously evaluate drug interactions with renal basolateral and apical organic cation transporters. In the present study, therefore, we assessed the drug interaction between cimetidine and metformin with double-transfected Madin-Darby canine kidney cells stably expressing both hOCT2 and hMATE1 as an in vitro model of the proximal tubular epithelial cells. The basolateral-to-apical transport and intracellular accumulation of [C-14] metformin by a double transfectant were markedly inhibited by 1 mM cimetidine at the basolateral side. On the other hand, 1 mu M cimetidine at the basolateral side moderately decreased the basolateral-to-apical transport of [C-14] metformin and significantly increased the intracellular accumulation of [C-14] metformin from the basolateral side, suggesting that cimetidine at a low concentration inhibits apical hMATE1, rather than basolateral hOCT2. Actually, in concentration-dependent inhibition studies by a single transporter expression system, such as human embryonic kidney 293 stably expressing hMATE1, hMATE2-K, or hOCT2, cimetidine showed higher affinity for hMATEs than for hOCT2. These results suggest that apical hMATE1 is involved in drug interactions between cimetidine and cationic compounds in the proximal tubular epithelial cells.