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Concomitant lansoprazole ameliorates cisplatin-induced nephrotoxicity by inhibiting renal organic cation transporter 2 in rats.
- Source :
-
Biopharmaceutics & drug disposition [Biopharm Drug Dispos] 2020 Jun; Vol. 41 (6), pp. 239-247. Date of Electronic Publication: 2020 Jun 25. - Publication Year :
- 2020
-
Abstract
- Cisplatin is used widely 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, a proton pump inhibitor, is known to inhibit hOCT2 activity, lansoprazole might ameliorate cisplatin-induced nephrotoxicity. A previous study showed that concomitant lansoprazole administration ameliorated nephrotoxicity in patients receiving cisplatin. However, the detailed mechanism remains to be clarified. In the present study, the drug-drug interaction between lansoprazole and cisplatin was examined using hOCT2-expressing cultured cells and rat renal slices. Moreover, the effect of lansoprazole on cisplatin-induced nephrotoxicity and the pharmacokinetics of cisplatin in rats was investigated. In the uptake study, lansoprazole potently inhibited the uptake of cisplatin in hOCT2-expressing cultured cells and rat renal slices. The in vivo rat study showed that concomitant lansoprazole significantly ameliorated cisplatin-induced nephrotoxicity and reduced the renal accumulation of platinum up to approximately 60% of cisplatin alone at 72 h after cisplatin intraperitoneal administration. Furthermore, the renal uptake of platinum at 3 min after intravenous cisplatin administration in rats with cisplatin and lansoprazole decreased to 78% of rats with cisplatin alone. In addition, there was no significant difference in the plasma platinum concentration between rats treated with and without lansoprazole at 3 min after cisplatin intravenous administration. These findings suggested that concomitant lansoprazole 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.<br /> (© 2020 John Wiley & Sons, Ltd.)
- Subjects :
- Animals
Antineoplastic Agents pharmacokinetics
Cisplatin pharmacokinetics
HEK293 Cells
Humans
Kidney drug effects
Kidney metabolism
Kidney Diseases chemically induced
Kidney Diseases metabolism
Lansoprazole pharmacology
Male
Organic Cation Transporter 2 metabolism
Protective Agents pharmacology
Rats, Wistar
Antineoplastic Agents adverse effects
Cisplatin adverse effects
Kidney Diseases drug therapy
Lansoprazole therapeutic use
Organic Cation Transporter 2 antagonists & inhibitors
Protective Agents therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1099-081X
- Volume :
- 41
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Biopharmaceutics & drug disposition
- Publication Type :
- Academic Journal
- Accession number :
- 32473602
- Full Text :
- https://doi.org/10.1002/bdd.2242