Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic Cation Transporter 1 (OCT1) and 2 (OCT2).
Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic Cation Transporter 1 (OCT1) and 2 (OCT2).
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伊立替康通过抑制有机阳离子转运蛋白 1 (OCT1) 和 2 (OCT2) 改变吗啡的处置
DOI：
10.1007/s11095-018-2526-y
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发表时间：
2018-10-25
影响因子：
3.7
通讯作者：
Shu Y
中科院分区：
文献类型：
--
作者：
Zhu P;Ye Z;Guo D;Xiong Z;Huang S;Guo J;Zhang W;Polli JE;Zhou H;Li Q;Shu Y
有机阳离子转运蛋白（OCT）和多药物和毒素挤出物（MATE）一起被认为是对许多有机阳离子药物的处置和反应至关重要的有机阳离子转运系统。患者对镇痛吗啡（人类 OCT1 的一种特征底物）的反应存在很大差异。本研究旨在检查吗啡与常用联合用药之间是否存在有机阳离子转运蛋白介导的药物和药物相互作用（DDI）。在稳定表达 OCT1、OCT2 和 MATE1 的人胚肾 293 (HEK293) 细胞中评估吗啡的摄取及其对临床上常见与吗啡合用的六种药物的抑制作用。通过比较小鼠中不存在与存在伊立替康治疗时吗啡的分布，确定吗啡和选定的伊立替康之间的体内相互作用。表达人OCT1和OCT2的稳定HEK293细胞中吗啡的摄取分别比对照细胞显着增加3.56和3.04倍，而表达人MATE1的细胞中的摄取没有显着增加。所有检查的六种药物，包括阿米替林、氟西汀、丙咪嗪、伊立替康、昂丹司琼和维拉帕米，都是 OCT1/2 介导的吗啡摄取的抑制剂。选择的伊立替康显着增加小鼠吗啡的血浆浓度并减少吗啡的肝脏和肾脏蓄积。吗啡是 OCT1 和 OCT2 的底物。
The organic cation transporters (OCTs) and multidrug and toxin extrusions (MATEs) together are regarded as an organic cation transport system critical to the disposition and response of many organic cationic drugs. Patient response to the analgesic morphine, a characterized substrate for human OCT1, is highly variable. This study was aimed to examine whether there is any organic cation transporter-mediated drug and drug interaction (DDI) between morphine and commonly co-administrated drugs. The uptake of morphine and its inhibition by six drugs which are commonly co-administered with morphine in the clinic were assessed in human embryonic kidney 293 (HEK293) cells stably expressing OCT1, OCT2 and MATE1. The in vivo interaction between morphine and the select irinotecan was determined by comparing the disposition of morphine in the absence versus presence of irinotecan treatment in mice. The uptake of morphine in the stable HEK293 cells expressing human OCT1 and OCT2 was significantly increased by 3.56 and 3.04 fold, respectively, than that in the control cells, with no significant uptake increase in the cells expressing human MATE1. All of the six drugs examined, including amitriptyline, fluoxetine, imipramine, irinotecan, ondansetron, and verapamil, were inhibitors of OCT1/2-mediated morphine uptake. The select irinotecan significantly increased the plasma concentrations and decreased hepatic and renal accumulation of morphine in mice. Morphine is a substrate of OCT1 and OCT2.
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影响因子：
6.7
作者：
通讯作者：
--
影响因子：
2.1
作者：
Fukuda T;Chidambaran V;Mizuno T;Venkatasubramanian R;Ngamprasertwong P;Olbrecht V;Esslinger HR;Vinks AA;Sadhasivam S
通讯作者：
Sadhasivam S
影响因子：
12.3
作者：
Lazar, Andreas;Zimmermann, Tim;Schoemig, Edgar
通讯作者：
Schoemig, Edgar
影响因子：
2.6
作者：
Chen Y;Li S;Brown C;Cheatham S;Castro RA;Leabman MK;Urban TJ;Chen L;Yee SW;Choi JH;Huang Y;Brett CM;Burchard EG;Giacomini KM
通讯作者：
Giacomini KM
影响因子：
6.7
作者：
Campa, D.;Gioia, A.;Barale, R.
通讯作者：
Barale, R.