Putative new biomarkers for renal transporter-mediated drug-drug interactions: Characterization as substrates of organic cation transporter 2, multidrug and toxin extrusion protein 1, and other important drug transporters

The inhibition of renally expressed transport proteins such as organic cation transporter (OCT) 2 or multidrug and toxin extrusion protein (MATE) 1 can cause clinically relevant drug-drug interactions (DDIs). Endogenous biomarkers have been proposed as tools to characterize the DDI risk of new molecules in drug development. Many previously proposed biomarkers for OCT2/MATE1-mediated DDIs lack specificity and/or sensitivity indicating a need for additional, well characterized biomarkers. Recently, we demonstrated that treatment with cimetidine, a classical OCT/MATE-inhibitor, decreased the renal excretion of serotonin, tyramine, 1-methylhistamine, 5-amino valeric acid betaine, and 4-guanidinobutanoic acid in humans. So far, these compounds are incompletely characterized as substrates of OCT2, MATE1, and other drug transporters. We therefore used established cell models overexpressing OCT2 and/or MATE1, and cell models for other clinically important drug transporters (organic anion transporters 1 and 3, organic anion transporting polypeptides 1B1 and 1B3, and P-glycoprotein) to investigate the cellular uptake and/or vectorial transport of these 5 putative biomarkers. The in vitro results show that serotonin, tyramine, 1-methylhistamine, 5-amino valeric acid betaine, and 4-guanidinobutanoic acid are substrates of OCT2 and/or MATE1, supporting that the in vivo effect of cimetidine is due to inhibition of these transporters. Based on their transport by OCT2 and/or MATE1 compared to the minimal transport by other drug transporters and the in vivo effects of classical transport protein inhibitors in healthy volunteers, serotonin and 1-methylhistamine appear to be the most promising candidates for further validation as endogenous biomarkers for the early detection of clinically relevant OCT2- and MATE1-mediated renal DDIs. SIGNIFICANCE STATEMENT: This study characterizes 5 endogenous metabolites as substrates of the renally expressed transport proteins organic cation transporter (OCT) 2, multidrug and toxin extrusion protein (MATE) 1, and other important drug transporters. These transport proteins are known as important contributors to clinically observed drug-drug interactions. Of the respective 5 compounds, serotonin and 1-methylhistamine are the most promising candidates to be further investigated as biomarkers for interactions via OCT2/MATE1, which could improve drug-drug interaction assessment during clinical drug development.