RT Journal Article
SR Electronic
T1 Assessment of Substrate Dependent Ligand Interactions at the Organic Cation Transporter OCT2 Using Six Model Substrates
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.117.111443
DO 10.1124/mol.117.111443
A1 Philip J Sandoval
A1 Kimberely M Zorn
A1 Alex M Clark
A1 Sean Ekins
A1 Stephen H Wright
YR 2018
UL http://molpharm.aspetjournals.org/content/early/2018/06/08/mol.117.111443.abstract
AB 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.