TY - JOUR T1 - Assessment of Substrate Dependent Ligand Interactions at the Organic Cation Transporter OCT2 Using Six Model Substrates JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.117.111443 SP - mol.117.111443 AU - Philip J Sandoval AU - Kimberely M Zorn AU - Alex M Clark AU - Sean Ekins AU - Stephen H Wright Y1 - 2018/01/01 UR - http://molpharm.aspetjournals.org/content/early/2018/06/08/mol.117.111443.abstract N2 - The organic cation transporter OCT2 mediates the entry step for organic cation secretion by renal proximal tubule cells and is a site of unwanted drug-drug interactions (DDIs). But reliance on decision tree-based predictions of DDIs at OCT2 that depend on IC50 values can be suspect because they can be influenced by choice of transported substrate; for example, IC50s for inhibition of metformin vs MPP transport can vary by 5 to 10-fold. However, it is not clear if substrate-dependence of ligand interaction is common among OCT2 substrates. To address this question we screened the inhibitory effectiveness of 20 μM concentrations of several hundred compounds against OCT2-mediated uptake of six structurally distinct substrates: MPP, metformin, NBD-MTMA, TEA, cimetidine, and ASP. Of these, MPP transport was least sensitive to inhibition. IC50 values for 20 structurally diverse compounds confirmed this profile, with IC50s for MPP averaging 6-fold larger than for the other substrates. Bayesian machine learning models of ligand-induced inhibition displayed generally good statistics after cross validation and external testing. Applying our ASP model to a previously published large scale screening study for inhibition of OCT2-mediated ASP transport resulted in comparable statistics, with approximately 75% of 'active' inhibitors predicted correctly. The differential sensitivity of MPP transport to inhibition suggests that multiple ligands can interact simultaneously with OCT2 and supports the recommendation that MPP not be used as a test substrate for OCT2 screening. Instead, metformin appears to be a comparatively representative OCT2 substrate for both in vitro and in vivo (clinical) use. ER -