当前位置： SCI文献检索 > TOXICOLOGY AND APPLIED PHARMACOLOGY期刊下所有文献 > 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).

Abstract：

: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.

journal_name

Toxicol Appl Pharmacol

journal_title

Toxicology and applied pharmacology

authors

Li Q,Guo D,Dong Z,Zhang W,Zhang L,Huang SM,Polli JE,Shu Y

doi

10.1016/j.taap.2013.08.024

subject

Has Abstract

pub_date

2013-11-15 00:00:00

pages

100-9

issue

eissn

0041-008X

issn

1096-0333

pii

S0041-008X(13)00374-8

journal_volume

273

pub_type

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Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs).