Abstract
Multidrug and toxin extrusion 1 (MATE1/SLC47A1) is expressed in the brush-border membrane of renal proximal tubules and mediates the efflux of cationic drugs. In the present study, the role of MATE1 in the nephrotoxicity of cisplatin was investigated in vivo and in vitro. Cisplatin (15 mg/kg) was administered intraperitoneally to wild-type (Mate1(+/+)) and Mate1 knockout (Mate1(−/−)) mice. Lifespan was significantly shorter in Mate1(−/−) mice than Mate1(+/+) mice. Three days after the administration of cisplatin, plasma creatinine and blood urea nitrogen (BUN) levels were increased in both Mate1(+/+) and Mate1(−/−) mice compared with vehicle-treated controls, and creatinine clearance was decreased. Moreover, a significant rise in creatinine and BUN levels was observed in cisplatin-treated Mate1(−/−) mice in comparison to Mate1(+/+) mice. A pharmacokinetic analysis revealed the plasma concentration and renal accumulation of cisplatin to be higher in Mate1(−/−) mice than Mate1(+/+) mice 1 h after a single intravenous administration of cisplatin (0.5 mg/kg). Furthermore, the combination of a selective MATE inhibitor, pyrimethamine, with cisplatin also elevated creatinine and BUN levels compared to cisplatin alone. In experiments in vitro, the cellular uptake of cisplatin was stimulated by the expression of mouse MATE1 as well as organic cation transporters OCT1 and OCT2. In conclusion, MATE1 mediates the efflux of cisplatin and is involved in cisplatin-induced nephrotoxicity.
Submitted Version (
Free)
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
