Cellular Uptake of Levocetirizine by Organic Anion Transporter 4
Cellular Uptake of Levocetirizine by Organic Anion Transporter 4
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DOI：
10.1016/j.xphs.2017.03.026
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发表时间：
2017-09-01
影响因子：
3.8
通讯作者：
Tomi, Masatoshi
中科院分区：
文献类型：
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作者：
Noguchi, Saki;Nishimura, Tomohiro;Tomi, Masatoshi
西替利嗪是一种非镇静抗组胺药，其药代动力学深受转运体介导的肾脏膜转运的影响。本研究旨在探讨西替利嗪的药理活性对映体左西替利嗪通过表达于肾小管顶膜和胎盘合体滋养层细胞基底膜的人有机阴离子转运蛋白4(OAT4)转运机制。在四环素控制下表达人OAT4的细胞中，四环素处理可增加左西替利嗪的摄取。另一方面，无论细胞外有无氯离子，OAT4的表达都不会促进预先加载的左西替利嗪从细胞外排出。OAT4介导的左西替利嗪摄取是浓度依赖的，K-m值为38mM。OAT4对左西替利嗪的摄取速率约为外消旋西替利嗪的两倍，表明左西替利嗪具有立体选择性摄取。另一方面，右旋西替利嗪和左西替利嗪可抑制OAT4介导的[H-3]脱氢表雄酮硫酸酯摄取。总体而言，我们的发现表明，OAT4介导了左西替利嗪的摄取，但不太可能介导左西替利嗪的外排。(C)2017年美国药剂师协会(R)。爱思唯尔公司出版，版权所有。
The pharmacokinetics of cetirizine, a nonsedating antihistamine, is profoundly affected by transporter-mediated membrane transport in the kidney. In this study, we aimed to investigate the transport mechanism of levocetirizine, the pharmacologically active enantiomer of cetirizine, via human organic anion transporter 4 (OAT4) expressed in the apical membrane of renal proximal tubules and the basal plasma membrane of placental syncytiotrophoblasts. In cells expressing human OAT4 under the control of tetracycline, levocetirizine uptake was increased by tetracycline treatment. On the other hand, OAT4 expression did not facilitate efflux of preloaded levocetirizine from the cells, either in the presence or absence of extracellular Cl-. The OAT4-mediated levocetirizine uptake was concentration-dependent with a K-m of 38 mu M. The uptake rate of levocetirizine via OAT4 was approximately twice that of racemic cetirizine, indicating stereoselective uptake of levocetirizine. On the other hand, OAT4-mediated [H-3] dehydroepiandrosterone sulfate uptake was inhibited by dextrocetirizine and levocetirizine. Overall, our findings indicate that OAT4 mediates levocetirizine uptake but is unlikely to mediate the efflux. (C) 2017 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.