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 Vmax. 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.