Role of OCT2 and MATE1 in renal disposition and toxicity of nitidine chloride

被引：39

作者：

Li, L. P. ^{[1
]}

Song, F. F. ^{[1
]}

Weng, Y. Y. ^{[1
]}

Yang, X. ^{[1
]}

Wang, K. ^{[1
]}

Lei, H. M. ^{[1
]}

Ma, J. ^{[2
]}

Zhou, H. ^{[1
]}

Jiang, H. D. ^{[1
]}

机构：

[1] Zhejiang Univ, Coll Pharmaceut Sci, Lab Pharmaceut Anal & Drug Metab, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou, Zhejiang, Peoples R China

[2] Zhejiang Univ, Ctr Drug Safety Evaluat & Res, Hangzhou, Zhejiang, Peoples R China

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 2016年 / 173卷 / 16期

基金：

对外科技合作项目（国际科技项目）; 中国国家自然科学基金;

关键词：

ORGANIC CATION TRANSPORTERS; IN-VIVO; BENZOPHENANTHRIDINE ALKALOIDS; TOPOISOMERASE-I; CONCISE GUIDE; CELL MODELS; PHARMACOLOGY; NEPHROTOXICITY; CAMPTOTHECIN; PUBLICATION;

D O I：

10.1111/bph.13537

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Background and PurposeNitidine chloride (NC), a alkaloid, has various biological properties including anticancer and analgesic activities. The aim of the present study was to evaluate the role of organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1) in the renal disposition and nephrotoxicity of NC. Experimental ApproachMDCK cells stably expressing human OCT2 and/or hMATE1 were used to investigate the OCT2- and MATE1-mediated transport of NC. In addition, the accumulation of NC and its potential toxicity were studied in rat primary-cultured proximal tubular (rPCPT) cells and in rats in vivo. Key ResultsNC was found to be a high-affinity substrate of both OCT2 and MATE1 with high cytotoxicity in MDCK-hOCT2/hMATE1 and MDCK-hOCT2 compared to mock cells. The OCT2 inhibitors, cimetidine and (+)-tetrahydropalmatine ((+)-THP), significantly reduced NC accumulation and cytotoxicity in MDCK-hOCT2, MDCK-hOCT2/hMATE1 and rPCPT cells. Severe kidney damage with high levels of blood urea nitrogen and lactate dehydrogenase (LDH), reduced levels of alkaline phosphatase (ALP) and pathological changes were found in rats after 20days of successive i.v. doses of NC (5mgkg(-1)day(-1)). Concomitantly, the concentration of NC in the kidney reached similar high levels at 2h after the last dose of the 20 day treatment as those observed at 0.5 h after a single i.v. dose of 5mgkg(-1). Conclusions and ImplicationsOur data indicate that NC-induced nephrotoxicity might be mainly attributed to OCT2-mediated extensive renal uptake and weak tubular secretion by MATE1.

引用

页码：2543 / 2554

页数：12

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