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

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-HT 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-HT 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 (IC: 2.6 μM) > ondansetron > granisetron > tropisetron > dolasetron (IC: 85.4 μM) and the inhibition of ASP uptake by MATE1 in order of potency was ondansetron (IC: 0.1 μM) > palonosetron = tropisetron > granisetron > dolasetron (IC: 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-HT antagonist drugs may inhibit the renal secretion of cationic drugs by interfering with OCT2 and/or MATE1 function.