ArticleThe Journal of pharmacology and experimental therapeutics2016
Impact of Substrate-Dependent Inhibition on Renal Organic Cation Transporters hOCT2 and hMATE1/2-K-Mediated Drug Transport and Intracellular Accumulation.
Article in The Journal of pharmacology and experimental therapeutics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 46 citations in OpenAlex.
- Exploring Experimental and Statistical Approaches to Control Oversensitivity of In Vitro Permeability to Excipient Effects.Pharmaceutics · 2025Article
- Use of a Double-Transfected System to Predict hOCT2/hMATE1-Mediated Renal Drug-Drug Interactions.Drug metabolism and disposition: the biological fate of chemicals · 2024Article
- Interaction and Transport of Benzalkonium Chlorides by the Organic Cation and Multidrug and Toxin Extrusion Transporters.Drug metabolism and disposition: the biological fate of chemicals · 2024Article
- Dysregulation of the mRNA Expression of Human Renal Drug Transporters by Proinflammatory Cytokines in Primary Human Proximal Tubular Epithelial Cells.Pharmaceutics · 2024Article
- Effect of Cimetidine on Metformin Pharmacokinetics and Endogenous Metabolite Levels in Rats.Drug metabolism and disposition: the biological fate of chemicals · 2024Article
- Interaction of ALK Inhibitors with Polyspecific Organic Cation Transporters and the Impact of Substrate-Dependent Inhibition on the Prediction of Drug-Drug Interactions.Pharmaceutics · 2023Article
- Advances in Pharmacokinetic Mechanisms of Transporter-Mediated Herb-Drug Interactions.Pharmaceuticals (Basel, Switzerland) · 2022Review
- In vitro evaluation suggests fenfluramine and norfenfluramine are unlikely to act as perpetrators of drug interactions.Pharmacology research & perspectives · 2022Review
- Transport Turnover Rates for Human OCT2 and MATE1 Expressed in Chinese Hamster Ovary Cells.International journal of molecular sciences · 2022Article
- Identification of Drug Transporter Genomic Variants and Inhibitors That Protect Against Doxorubicin-Induced Cardiotoxicity.Circulation · 2022Article
- Repositioning of Lansoprazole as a Protective Agent Against Cisplatin-Induced Ototoxicity.Frontiers in pharmacology · 2022Article
- Article
- Cationic Compounds with SARS-CoV-2 Antiviral Activity and Their Interaction with Organic Cation Transporter/Multidrug and Toxin Extruder Secretory Transporters.The Journal of pharmacology and experimental therapeutics · 2021Article
- Characterization ofMolecular pharmacology · 2020Article
- Molecular and cellular physiology of organic cation transporter 2.American journal of physiology. Renal physiology · 2019Review
- Kinetic basis of metformin-MPP interactions with organic cation transporter OCT2.American journal of physiology. Renal physiology · 2019Article
- Physiologically-Based Pharmacokinetic Modeling Analysis for Quantitative Prediction of Renal Transporter-Mediated Interactions Between Metformin and Cimetidine.CPT: pharmacometrics & systems pharmacology · 2019Article
- The Importance of Incorporating OCT2 Plasma Membrane Expression and Membrane Potential in IVIVE of Metformin Renal Secretory Clearance.Drug metabolism and disposition: the biological fate of chemicals · 2018Article
- Assessment of Substrate-Dependent Ligand Interactions at the Organic Cation Transporter OCT2 Using Six Model Substrates.Molecular pharmacology · 2018Article
- Fampridine is a Substrate and Inhibitor of Human OCT2, but not of Human MATE1, or MATE2K.Pharmaceutical research · 2018Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
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.
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