Multiple organic cation transporters contribute to the renal transfer of sulpiride
Multiple organic cation transporters contribute to the renal transfer of sulpiride
复制标题
多种有机阳离子转运蛋白有助于舒必利的肾转运
DOI：
10.1002/bdd.2104
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Huidi Jiang
中科院分区：
文献类型：
--
作者：
Liping Li;Yayun Weng;Wei Wang;Mengru Bai;Hongmei Lei;Hui Zhou;Huidi Jiang
舒必利是一种选择性多巴胺D2受体阻滞剂，广泛用于治疗精神分裂症、抑郁症和胃/十二指肠溃疡。由于舒必利在生理pH 7.4时大部分带正电荷，且人体静脉注射舒必利后，尿液中回收的剂量约70%为原形，因此认为转运蛋白在舒必利的肾脏排泄中起重要作用。本研究的目的是探讨哪些转运蛋白有助于舒必利的肾脏处置。结果表明，舒必利是人肉毒碱/有机阳离子转运蛋白1（hOCTN 1）和2（hOCTN 2）、人有机阳离子转运蛋白2（hOCT 2）、人多药和毒素外排蛋白1（hMATE 1）和2-K（hMATE 2-K）的底物。MDCK-hOCT 2/pcDNA3.1细胞单层中舒必利从基底侧（BL）至顶侧（AP）的蓄积远大于MDCK-hOCT 2/hMATE 1细胞，西咪替丁显著降低了舒必利从BL至AP的细胞内蓄积。此外，Oct 2和Octns抑制剂可显著降低舒必利在小鼠原代肾小管细胞（mPRTCs）中的蓄积。结果表明，OCTN 1、OCTN 2、OCT 2、MATE 1和MATE 2-K可能促进舒必利的肾转移，其中OCT 2介导舒必利从血流中摄取至近端肾小管细胞，而MATE促进舒必利从近端肾小管细胞流出至肾腔，OCTN参与肾分泌和重吸收。
Sulpiride, a selective dopamine D2 receptor blocker, is used widely for the treatment of schizophrenia, depression and gastric/duodenal ulcers. Because the great majority of sulpiride is positively charged at physiological pH 7.4, and ~70% of the dose recovered in urine is in the unchanged form after human intravenous administration of sulpiride, it is believed that transporters play an important role in the renal excretion of sulpiride. The aim of the present study was to explore which transporters contribute to the renal disposition of sulpiride. The results demonstrated that sulpiride was a substrate of human carnitine/organic cation transporter 1 (hOCTN1) and 2 (hOCTN2), human organic cation transporter 2 (hOCT2), human multidrug and toxin efflux extrusion protein 1 (hMATE1) and 2‐K (hMATE2‐K). Sulpiride accumulation from the basolateral (BL) to the apical (AP) side in MDCK‐hOCT2/pcDNA3.1 cell monolayers was much greater than that in MDCK‐hOCT2/hMATE1 cells, and cimetidine dramatically reduced the intracellular accumulation of sulpiride from BL to AP. In addition, the accumulation of sulpiride in mouse primary renal tubular cells (mPRTCs) was markedly reduced by inhibitors of Oct2 and Octns. The results implied that OCTN1, OCTN2, OCT2, MATE1 and MATE2‐K probably contributed to the renal transfer of sulpiride, in which OCT2 mediated the uptake of sulpiride from the bloodstream to the proximal tubular cells, while MATEs contributed to the sulpiride efflux from the proximal tubular cells to the renal lumen, and OCTNs participated in both renal secretion and reabsorption.