PT  - JOURNAL ARTICLE
AU  - Belzer, Mathew
AU  - Morales, Mark
AU  - Jagadish, Bhumasamudram
AU  - Mash, Eugene A.
AU  - Wright, Stephen H.
TI  - Substrate-Dependent Ligand Inhibition of the Human Organic Cation Transporter OCT2
AID  - 10.1124/jpet.113.203257
DP  - 2013 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 300--310
VI  - 346
IP  - 2
4099  - http://jpet.aspetjournals.org/content/346/2/300.short
4100  - http://jpet.aspetjournals.org/content/346/2/300.full
SO  - J Pharmacol Exp Ther2013 Aug 01; 346
AB  - Organic cation transporter 2 (OCT2) mediates the initial step in renal secretion of organic cations: uptake from the blood, across the basolateral membrane, and into the renal proximal tubule cells. Because of its potential as a target for unwanted drug-drug interactions (DDIs), considerable attention has been directed toward understanding the basis of OCT2 selectivity. These studies typically assess selectivity based on ligand inhibition profiles for OCT2-mediated transport of a probe substrate. However, little attention has been given to the potential influence of the substrate on the profile of ligand inhibition. Here we compared the IC50 values obtained for a set of structurally distinct inhibitors against OCT2-mediated transport of three structurally distinct substrates: 1-methyl-4-phenylpyridinium (MPP); metformin; and a novel fluorescent substrate, N,N,N-trimethyl-2-[methyl(7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino]ethanaminium iodide (NBD-MTMA). The median IC50 value for inhibition of MPP transport was 9-fold higher than that for inhibition of metformin transport. Similarly, the median IC50 value for inhibition of MPP transport was 5-fold higher than that for NBD-MTMA transport. However, this was not a systematic difference in inhibitory efficacy; the ratio of IC50 values, MPP versus NBD-MTMA, ranged from 88-fold (ipratropium) to 0.3-fold (metformin). These data show that 1) the choice of OCT2 substrate significantly influences both quantitative and qualitative inhibitory interactions with cationic drugs; and 2) ligand interactions with OCT2 are not restricted to competition for a common ligand binding site, consistent with a binding surface characterized by multiple, possibly overlapping interaction sites. Development of predictive models of DDIs with OCT2 must take into account the substrate dependence of ligand interaction with this protein.