TY - JOUR
T1 - Protective effect of concomitant administration of imatinib on cisplatin-induced nephrotoxicity focusing on renal organic cation transporter OCT2
AU - Tanihara, Yuko
AU - Masuda, Satohiro
AU - Katsura, Toshiya
AU - Inui, Ken ichi
N1 - Funding Information:
This work was supported in part by a grant-in-aid for Research on Biological Markers for New Drug Development, Health and Labour Sciences Research Grants from the Ministry of Health, Labor and Welfare of Japan, and by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Culture, and Sports of Japan. Y.T. was supported as a Research Assistant by Establishment of International Center of Excellence (COE) Formation for Genomic Analysis of Disease Model Animals with Multiple Genetic Alterations (COE program), Ministry of Education, Culture, Sports, Science and Technology, Japan.
PY - 2009/11/1
Y1 - 2009/11/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.bcp.2009.06.014
DO - 10.1016/j.bcp.2009.06.014
M3 - Article
C2 - 19540211
AN - SCOPUS:70249087629
VL - 78
SP - 1263
EP - 1271
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 9
ER -