Protective effect of concomitant administration of imatinib on cisplatin-induced nephrotoxicity focusing on renal organic cation transporter OCT2.
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.
Tanihara
Yuko
Y
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Masuda
Satohiro
S
Katsura
Toshiya
T
Inui
Ken-ichi
K
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001549:Benzamides; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000009:adverse effects* / Q000493:pharmacokinetics; D003404:Creatinine / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D027701:Organic Cation Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D001549:Benzamides; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D010879:Piperazines; D011743:Pyrimidines; C491013:SLC22A2 protein, human; D000068877:Imatinib Mesylate; D003404:Creatinine; D002945:Cisplatin