Assessment of substrate-dependent ligand interactions at the organic cation transporter OCT2 using six model substrates s

Philip J. Sandoval, Kimberley M. Zorn, Alex M. Clark, Sean Ekins, Stephen H. Wright

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


Organic cation transporter (OCT) 2 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 IC 50 values can be suspect because they can be influenced by choice of transported substrate; for example, IC 50 values for the inhibition of metformin versus MPP transport can vary by 5- to 10-fold. However, it is not clear whether the substrate dependence of a ligand interaction is common among OCT2 substrates. To address this question, we screened the inhibitory effectiveness of 20 mM concentrations of several hundred compounds against OCT2-mediated uptake of six structurally distinct substrates: MPP, metformin, N,N,N-trimethyl-2-[methyl(7-nitrobenzo[c][1,2,5]-oxadiazol-4-yl)amino]ethanaminium (NBD-MTMA), TEA, cimetidine, and 4-4-dimethylaminostyryl-N-methylpyridinium (ASP). Of these, MPP transport was least sensitive to inhibition. IC 50 values for 20 structurally diverse compounds confirmed this profile, with IC 50 values for MPP averaging 6-fold larger than those 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.

Original languageEnglish (US)
Pages (from-to)1057-1068
Number of pages12
JournalMolecular pharmacology
Issue number3
StatePublished - Sep 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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