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 language | English |
|---|---|
| Pages (from-to) | 1263-1271 |
| Number of pages | 9 |
| Journal | Biochemical Pharmacology |
| Volume | 78 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - Nov 1 2009 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Pharmacology
Cite this
Protective effect of concomitant administration of imatinib on cisplatin-induced nephrotoxicity focusing on renal organic cation transporter OCT2. / Tanihara, Yuko; Masuda, Satohiro; Katsura, Toshiya; Inui, Ken ichi.
In: Biochemical Pharmacology, Vol. 78, No. 9, 01.11.2009, p. 1263-1271.Research output: Contribution to journal › Article
}
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
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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UR - http://www.scopus.com/inward/citedby.url?scp=70249087629&partnerID=8YFLogxK
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 -