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National Institute of Environmental Health Sciences

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Publication Detail

Title: In Vitro Inhibition of Renal OCT2 and MATE1 Secretion by Antiemetic Drugs.

Authors: George, Blessy; Wen, Xia; Jaimes, Edgar A; Joy, Melanie S; Aleksunes, Lauren M

Published In Int J Mol Sci, (2021 Jun 16)

Abstract: The organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the renal secretion of drugs. Recent studies suggest that ondansetron, a 5-HT3 antagonist drug used to prevent nausea and vomiting, can inhibit OCT2- and MATE1-mediated transport. The purpose of this study was to test the ability of five 5-HT3 antagonist drugs to inhibit the OCT2 and MATE1 transporters. The transport of the OCT2/MATE1 probe substrate ASP+ was assessed using two models: (1) HEK293 kidney cells overexpressing human OCT2 or MATE1, and (2) MDCK cells transfected with human OCT2 and MATE1. In HEK293 cells, the inhibition of ASP+ uptake by OCT2 listed in order of potency was palonosetron (IC50: 2.6 μM) > ondansetron > granisetron > tropisetron > dolasetron (IC50: 85.4 μM) and the inhibition of ASP+ uptake by MATE1 in order of potency was ondansetron (IC50: 0.1 μM) > palonosetron = tropisetron > granisetron > dolasetron (IC50: 27.4 μM). Ondansetron (0.5-20 μM) inhibited the basolateral-to-apical transcellular transport of ASP+ up to 64%. Higher concentrations (10 and 20 μM) of palonosetron, tropisetron, and dolasetron similarly reduced the transcellular transport of ASP+. In double-transfected OCT2-MATE1 MDCK cells, ondansetron at concentrations of 0.5 and 2.5 μM caused significant intracellular accumulation of ASP+. Taken together, these data suggest that 5-HT3 antagonist drugs may inhibit the renal secretion of cationic drugs by interfering with OCT2 and/or MATE1 function.

PubMed ID: 34208557 Exiting the NIEHS site

MeSH Terms: Animals; Antiemetics/chemistry; Antiemetics/pharmacology*; Biological Transport/drug effects; Cell Line; Cells, Cultured; Dogs; Gene Expression; HEK293 Cells; Humans; Kidney/drug effects*; Kidney/metabolism*; Madin Darby Canine Kidney Cells; Molecular Structure; Organic Cation Transport Proteins/biosynthesis*; Organic Cation Transport Proteins/genetics; Organic Cation Transport Proteins/metabolism; Organic Cation Transporter 2/biosynthesis*; Organic Cation Transporter 2/genetics; Serotonin 5-HT3 Receptor Antagonists/pharmacology

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