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

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

doi:10.3390/ijms22126439

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.

Highlights

Renal secretion is achieved by the coordinated uptake and efflux of drugs across the tubule epithelium
Initial studies characterized the uptake of ASP+ into cells overexpressing an empty vector (EV), organic cation transporter 2 (OCT2), or multidrug and toxin extrusion protein 1 (MATE1) (Figure 2)
Most notoarbdloyl,asoentrdoann. setron has been shown to reduce the transport of cisplatin and metformin by3

Summary

Introduction

Renal secretion is achieved by the coordinated uptake and efflux of drugs across the tubule epithelium. Prior to discovering the OCT2/SLC22A1 and MATE1/SLC47A1 genes, it was well understood that the secretion of organic cations could be inhibited pharmacologically [1]. Using a variety of experimental approaches across different preclinical species, it was demonstrated that organic cations undergo active transport and renal secretion [2,3,4]. Since these early observations, the research has advanced to understand the molecular mechanisms of organic cation secretion and the potential for clinically-relevant drug interactions following the disruption of OCT2 and MATE1 (reviewed in [5]).

Results

Cell Lines and Cell Culture

Uptake and Efflux Inhibition Assays in HEK293 Cells

Statistical Analysis