Protective effect of concomitant administration of imatinib on cisplatin-induced nephrotoxicity focusing on renal organic cation transporter OCT2

Yuko Tanihara, Satohiro Masuda, Toshiya Katsura, Ken ichi Inui

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Although the organic cation transporter 2 (OCT2/SLC22A2) mediate renal tubular uptake of cisplatin from the circulation, neither apical multidrug and extrusion (MATE) 1 or MATE2-K mediate tubular secretion of the agent. Therefore, the highly concentrated tubular cisplatin potentiates nephrotoxicity, and these are considered to be a critical mechanism for cisplatin-induced nephrotoxicity. In the present study, we examined the protective effect of imatinib, a cationic anticancer agent, on that nephrotoxicity. Imatinib markedly reduced cisplatin-induced cytotoxicity and platinum accumulation in OCT2-expressing HEK293 cells, but almost no change was found in the cells expressing human MATE1, MATE2-K and rat MATE1. In rats, the renal accumulation of platinum and subsequent nephrotoxicity, based on the blood urea nitrogen, plasma creatinine and creatinine clearance, were significantly decreased with the oral administration of imatinib. The orally administered imatinib significantly increased the area under the plasma concentration-time curve of intravenously administered cisplatin for 3 min by an average of 120%. In additional, the concomitant administration of imatinib clearly avoided the severe renal impairment by the histological examination. In conclusion, the concomitant administration of imatinib with cisplatin prevents cisplatin-induced nephrotoxicity inhibiting the OCT2-mediated renal accumulation of cisplatin.

Original languageEnglish
Pages (from-to)1263-1271
Number of pages9
JournalBiochemical Pharmacology
Volume78
Issue number9
DOIs
Publication statusPublished - Nov 1 2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

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