Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs).
Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs).
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Ondansetron 可通过抑制多种毒素和挤压蛋白 (MATE) 来增强顺铂诱导的肾毒性。
DOI：
10.1016/j.taap.2013.08.024
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发表时间：
2013-11-15
影响因子：
3.8
通讯作者：
Shu, Yan
中科院分区：
文献类型：
--
作者：
Li, Qing;Guo, Dong;Dong, Zhongqi;Zhang, Wei;Zhang, Lei;Huang, Shiew-Mei;Polli, James E.;Shu, Yan
关键词：
顺铂的肾毒性限制了其临床应用。人有机阳离子转运蛋白2（OCT 2）和多药和毒素排出蛋白（MATE）在从肾脏消除阳离子药物（如顺铂）中协同工作。我们假设联合使用昂丹司琼会通过改变顺铂转运蛋白的功能对顺铂肾毒性产生影响。在表达这些转运蛋白的稳定HEK-293细胞中测定了昂丹司琼对OCT 2和MATE介导的二甲双胍蓄积的抑制效力。通过在野生型和Mate 1 −/−小鼠中进行二甲双胍（OCT和MATE的经典底物）的药代动力学研究，检查了昂丹司琼对体内药物分布的影响。在野生型和Mate 1 −/−小鼠中评估了肾毒性，这些小鼠接受了顺铂联合和不联合昂丹司琼。两种MATE（包括人MATE 1、人MATE 2-K和小鼠MATE 1）和OCT 2（人和小鼠）均受到昂丹司琼抑制，昂丹司琼对MATE的效力更高。昂丹司琼显著增加了野生型小鼠二甲双胍的组织蓄积和药代动力学暴露，但在Mate 1 −/−小鼠中没有。此外，昂丹司琼治疗显着增强顺铂的肾蓄积和顺铂诱导的肾毒性，这表明在小鼠中的生化和分子生物标志物的水平增加和更严重的病理组织学变化。小鼠中MATE功能的遗传缺陷导致肾毒性的类似增加。因此，昂丹司琼对MATE的强效抑制增强了小鼠中与顺铂治疗相关的肾毒性。联合化疗顺铂和止吐药5-羟色胺-3（5-HT 3）受体拮抗剂（如昂丹司琼）的潜在肾毒性作用应在患者中进行研究。
The nephrotoxicity limits the clinical application of cisplatin. Human organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins (MATEs) work in concert in the elimination of cationic drugs such as cisplatin from the kidney. We hypothesized that co-administration of ondansetron would have an effect on cisplatin nephrotoxicity by altering the function of cisplatin transporters. The inhibitory potencies of ondansetron on metformin accumulation mediated by OCT2 and MATEs were determined in the stable HEK-293 cells expressing these transporters. The effects of ondansetron on drug disposition in vivo were examined by conducting the pharmacokinetics of metformin, a classical substrate for OCTs and MATEs, in wild-type and Mate1−/− mice. The nephrotoxicity was assessed in the wild-type and Mate1−/− mice received cisplatin with and without ondansetron. Both MATEs, including human MATE1, human MATE2-K, and mouse Mate1, and OCT2 (human and mouse) were subject to ondansetron inhibition, with much greater potencies by ondansetron on MATEs. Ondansetron significantly increased tissue accumulation and pharmacokinetic exposure of metformin in wild-type but not in Mate1−/− mice. Moreover, ondansetron treatment significantly enhanced renal accumulation of cisplatin and cisplatin-induced nephrotoxicity which were indicated by increased levels of biochemical and molecular biomarkers and more severe pathohistological changes in mice. Similar increases in nephrotoxicity were caused by genetic deficiency of MATE function in mice. Therefore, the potent inhibition of MATEs by ondansetron enhances the nephrotoxicity associated with cisplatin treatment in mice. Potential nephrotoxic effects of combining the chemotherapeutic cisplatin and the antiemetic 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, such as ondansetron, should be investigated in patients.
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影响因子：
6.7
作者：
通讯作者：
--
DOI：
10.1196/annals.1304.008
发表时间：
2003-01-01
期刊：
AGMATINE AND IMIDAZOLINES: THEIR NOVEL RECEPTORS AND ENZYMES
影响因子：
--
作者：
Molderings, GJ;Brüss, M;Göthert, M
通讯作者：
Göthert, M
影响因子：
3.9
作者：
Kalayda, Ganna V.;Wagner, Christina H.;Jaehde, Ulrich
通讯作者：
Jaehde, Ulrich
影响因子：
5.8
作者：
Nakamura, Takanori;Yonezawa, Atsushi;Inui, Ken-ichi
通讯作者：
Inui, Ken-ichi
DOI：
10.1158/1078-0432.ccr-10-0949
发表时间：
2010-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Franke RM;Kosloske AM;Lancaster CS;Filipski KK;Hu C;Zolk O;Mathijssen RH;Sparreboom A
通讯作者：
Sparreboom A