Renal Tubular Secretion of Varenicline by Multidrug and Toxin Extrusion (MATE) Transporters
Renal Tubular Secretion of Varenicline by Multidrug and Toxin Extrusion (MATE) Transporters
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DOI：
10.2133/dmpk.dmpk-11-rg-156
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发表时间：
2012-12-25
影响因子：
2.1
通讯作者：
Inui, Ken-ichi
中科院分区：
文献类型：
--
作者：
Kajiwara, Moto;Masuda, Satohiro;Inui, Ken-ichi
MATE 1和MATE 2-K、H+/有机阳离子反向转运蛋白位于肾近端小管刷状缘膜。本研究旨在阐明MATE转运蛋白在伐尼克兰肾小管分泌中的作用。通过颈静脉向野生型和Mate 1基因敲除小鼠给予5 mg/kg剂量的伐尼克兰，并通过高效液相色谱法测定其摄取。Mate 1基因的破坏使伐尼克兰的肾分泌清除率显著降低（54.6%，p < 0.05），全身暴露量显著增加（116%，p < 0.05）。在瞬时表达人（h）MATE 1、hMATE 2-K、小鼠（m）MATE 1和hOCT 2基底外侧有机阳离子转运蛋白的HEK 293细胞中检查伐尼克兰和[C-14]四乙铵（TEA）的摄取。[C-14]在存在伐尼克兰的情况下，表达MATE转运蛋白和hOCT 2的HEK 293细胞中的TEA摄取减少。hMATE 1、hMATE 2-K、mMATE 1和hOCT 2的IC 50计算值分别为62.2 +/- 6.5、122.3 +/- 67.6、255.0 +/- 37.9和1，003.9 +/- 135.8（μ M;平均值+/- S.E.）。对于三个单独的实验）。与空载体转染细胞相比，在表达mMATE 1、hMATE 1或hMATE 2-K cDNA以及hOCT 2的HEK 293细胞中伐尼克兰摄取显著增加。总之，发现肾脏MATE转运蛋白负责肾小管分泌伐尼克兰。
Multidrug and toxin extrusion (MATE) 1 and MATE2-K, H+/organic cation antiporters, are located at the brush-border membrane of renal proximal tubules. The present study aimed to clarify the role of MATE transporters in tubular secretion of varenicline. Varenicline at a dose of 5 mg/kg was administered to wild-type and Mate1-knockout mice via the jugular vein, and its uptake was measured by high-performance liquid chromatography. The renal secretory clearance of and systemic exposure to varenicline were significantly decreased (54.6%, p < 0.05) and increased (116%, p < 0.05) respectively, by the genetic disruption of Mate1 in mice. Uptake of varenicline and [C-14]tetraethylammonium (TEA) was examined in HEK293 cells transiently expressing the human (h) MATE1, hMATE2-K, mouse (m) MATE1, and hOCT2 basolateral organic cation transporter. [C-14]TEA uptake in HEK293 cells expressing MATE transporters and hOCT2 was decreased in the presence of varenicline. The calculated IC50 values for hMATE1, hMATE2-K, mMATE1, and hOCT2 were 62.2 +/- 6.5, 122.3 +/- 67.6, 255.0 +/- 37.9, and 1,003.9 +/- 135.8 (mu M; mean +/- S.E. for three separate experiments), respectively. Varenicline uptake was significantly increased in HEK293 cells expressing mMATE1, hMATE1, or hMATE2-K cDNA as well as hOCT2 compared to empty vector-transfected cells. In conclusion, renal MATE transporters were found to be responsible for renal tubular secretion of varenicline.