title: Impact of Substrate-Dependent Inhibition on Renal Organic Cation Transporters hOCT2 and hMATE1/2-K-Mediated Drug Transport and Intracellular Accumulation.
abstract: Renal transporter-mediated drug-drug interactions (DDIs) are of significant clinical concern, as they can adversely impact drug disposition, efficacy, and toxicity. Emerging evidence suggests that human renal organic cation transporter 2 (hOCT2) and multidrug and toxin extrusion proteins 1 and 2-K (hMATE1/2-K) exhibit substrate-dependent inhibition, but their impact on renal drug secretion and intracellular accumulation is unknown. Using metformin and atenolol as the probe substrates, we found that the classic inhibitors (e.g., cimetidine) of renal organic cation secretion were approximately 10-fold more potent for hOCT2 when atenolol was used, suggesting that atenolol is a more sensitive in vitro substrate for hOCT2 than metformin. In contrast, inhibition of hMATE1/2-K was influenced much less by the choice of substrate. Cimetidine is a much more potent inhibitor for hMATE1/2-K when metformin is the substrate but acts as an equally potent inhibitor of hOCT2 and hMATE1/2-K when atenolol is the substrate. Using hOCT2/hMATE1 double-transfected Madin-Darby canine kidney cells, we evaluated the impact of substrate-dependent inhibition on hOCT2/hMATE1-mediated transepithelial flux and intracellular drug accumulation. At clinically relevant concentrations, cimetidine dose dependently inhibited basal-to-apical flux of atenolol and metformin but impacted their intracellular accumulation differently, indicating that substrate-dependent inhibition may shift the major substrate-inhibitor interaction site between apical and basolateral transporters. Cimetidine is effective only when applied to the basal compartment. Our findings revealed the complex and dynamic nature of substrate-dependent inhibition of renal organic cation drug transporters and highlighted the importance of considering substrate-dependent inhibition in predicting transporter-mediated renal drug interaction, accumulation, and toxicity.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington.
authors.forename: Jia
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington.
authors.forename: Haichuan
authors.initials: H
authors.lastname: Duan
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington jowang@uw.edu.
authors.forename: Joanne
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001262:Atenolol / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002927:Cimetidine / Q000378:metabolism / Q000494:pharmacology; D004285:Dogs; D004347:Drug Interactions; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects* / Q000378:metabolism*; D007668:Kidney / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008687:Metformin / Q000378:metabolism / Q000494:pharmacology; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*
chemical_list: D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D004364:Pharmaceutical Preparations; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; D001262:Atenolol; D002927:Cimetidine; D008687:Metformin