Substrate Specificity of the Organic Cation Transporters MATE1 and MATE2K and Functional Overlap with OCT1 and OCT2

The multidrug and toxin extrusion proteins MATE1 and MATE2K may determine the pharmacokinetics and drug-drug interactions of many drugs. However, their substrate spectrum and synergy with organic cation transporters OCT1 and OCT2 remain incompletely understood. Therefore, we screened 590 predominantly positively charged, low molecular weight compounds for transport via these four transporters in HEK293 cells using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). MATE1 and MATE2K transported 164 and 114 compounds, respectively, with significant overlap. High-affinity substrates included berberine, pentamidine, and amisulpride, while epinephrine and atenolol had the highest V_max. Despite less than 16% sequence homology, there was high overlap among MATE1/-2K and OCT1/-2 substrates. Neither isolated physicochemical properties nor their linear combinations predicted the substrates of these organic cation transporters. However, machine learning classifiers using 15 parameters allowed 69 to 87% correct prediction. The large number of substrates indicates a possibly broad role of multidrug and toxin extrusion (MATE) transporters in pharmacokinetics and drug interactions.