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Cisplatin is widely used for the treatment of multiple solid tumors. Cisplatin-induced nephrotoxicity is caused by renal accumulation of cisplatin via human organic cation transporter 2 (hOCT2). As lansoprazole (LPZ), a proton pump inhibitor (PPI), is known to inhibit hOCT2 activity, LPZ might ameliorate cisplatin-induced nephrotoxicity. Previous study showed that concomitant LPZ administration ameliorated nephrotoxicity in patients receiving cisplatin. However, the detailed mechanism remains to be clarified. In the present study, the drug-drug interaction between LPZ and cisplatin was examined using hOCT2-expressing cultured cells and rat renal slices. Moreover, we investigated the effect of LPZ on cisplatin-induced nephrotoxicity and pharmacokinetics of cisplatin in rats. In the uptake study, LPZ potently inhibited uptake of cisplatin in hOCT2-expressing cultured cells and rat renal slices. In vivo rat study showed that concomitant LPZ significantly ameliorated cisplatin-induced nephrotoxicity and reduced renal accumulation of platinum (Pt) up to approximately 60% of cisplatin alone at 72 h after cisplatin intraperitoneal administration. Furthermore, renal uptake of Pt at 3 min after intravenous cisplatin administration in rats with cisplatin and LPZ decreased to 78% of rats with cisplatin alone. In addition, there was no significant difference in plasma Pt concentration between rats treated with and without LPZ at 3 min after cisplatin intravenous administration. These findings suggested that concomitant LPZ ameliorated cisplatin-induced nephrotoxicity by inhibiting rOCT2-mediated cisplatin uptake in rats, thus decreasing cisplatin accumulation in the kidney. The present findings provided important information for the establishment of novel protective approaches to minimize cisplatin-induced nephrotoxicity.
本文/Department of Clinical Pharmacy and Biopharmaceutics, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
33p
Collection (particular)国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文
Date Accepted (W3CDTF)2021-05-16T23:51:55+09:00
Data Provider (Database)国立国会図書館 : 国立国会図書館デジタルコレクション