ArticleDrug metabolism and disposition: the biological fate of chemicals2016
Rapid Method To Determine Intracellular Drug Concentrations in Cellular Uptake Assays: Application to Metformin in Organic Cation Transporter 1-Transfected Human Embryonic Kidney 293 Cells.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
33 citing papers in PubMed, 66 citations in OpenAlex.
- Predicting OCT2/MATEs-Mediated Drug Interactions in Healthy Volunteers and Patients with Chronic Kidney Disease: Insights from Extended Clearance Concept, Endogenous Biomarkers, and In Vitro Inhibition Studies (Perspectives from the International Transporter Consortium).Clinical pharmacology and therapeutics · 2025Review
- Dual inhibition of IRAK1/TAK1 signaling in astrocytes reduces accelerated mortality in human APOE4 knock-in APPswe/PSEN1dE9/P301S-Tau triple transgenic mouse model.Journal of neuroinflammation · 2025Article
- Identification of potential SARS-CoV-2 inhibitors among well-tolerated drugs using drug repurposing and in vitro approaches.Scientific reports · 2025Article
- The direct targets of metformin in diabetes and beyond.Trends in endocrinology and metabolism: TEM · 2025Review
- Physiologically Based Pharmacokinetic Model of OATP1B Substrates with a Nonlinear Mixed Effect Approach: Estimating Empirical In Vitro-to-In Vivo Scaling Factors.Clinical pharmacokinetics · 2024Article
- Fluorometric Methods to Measure Bioavailable and Total Heme.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Depletion assisted hemin affinity (DAsHA) proteomics reveals an expanded landscape of heme-binding proteins in the human proteome.Metallomics : integrated biometal science · 2023Article
- Novel method for kinetic analysis applied to transport by the uniporter OCT2.American journal of physiology. Renal physiology · 2022Article
- Relationship between Plasma and Intracellular Concentrations of Bedaquiline and Its M2 Metabolite in South African Patients with Rifampin-Resistant Tuberculosis.Antimicrobial agents and chemotherapy · 2021Article
- A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan.Frontiers in endocrinology · 2021Review
- Consideration of the Unbound Drug Concentration in Enzyme Kinetics.Methods in molecular biology (Clifton, N.J.) · 2021Article
- A Novel Physiologically Based Model of Creatinine Renal Disposition to Integrate Current Knowledge of Systems Parameters and Clinical Observations.CPT: pharmacometrics & systems pharmacology · 2020Article
- Organic Cation Transporters (OCTs) in EpiAirway™, A Cellular Model of Normal Human Bronchial Epithelium.Biomedicines · 2020Article
- Mechanistic Models as Framework for Understanding Biomarker Disposition: Prediction of Creatinine-Drug Interactions.CPT: pharmacometrics & systems pharmacology · 2020Article
- Vulnerabilities of the SARS-CoV-2 Virus to Proteotoxicity-Opportunity for Repurposed Chemotherapy of COVID-19 Infection.Frontiers in pharmacology · 2020Article
- Drug Concentration Asymmetry in Tissues and Plasma for Small Molecule-Related Therapeutic Modalities.Drug metabolism and disposition: the biological fate of chemicals · 2019Review
- Validation of Cell-Based Assay for Quantification of Sesamol Uptake and Its Application for Measuring Target Exposure.Molecules (Basel, Switzerland) · 2019Article
- Physiologically-Based Pharmacokinetic Modeling Analysis for Quantitative Prediction of Renal Transporter-Mediated Interactions Between Metformin and Cimetidine.CPT: pharmacometrics & systems pharmacology · 2019Article
- Improved predictions of time-dependent drug-drug interactions by determination of cytosolic drug concentrations.Scientific reports · 2019Article
- Metformin Affects Heme Function as a Possible Mechanism of Action.G3 (Bethesda, Md.) · 2019Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Because of the importance of intracellular unbound drug concentrations in the prediction of in vivo concentrations that are determinants of drug efficacy and toxicity, a number of assays have been developed to assess in vitro unbound concentrations of drugs. Here we present a rapid method to determine the intracellular unbound drug concentrations in cultured cells, and we apply the method along with a mechanistic model to predict concentrations of metformin in subcellular compartments of stably transfected human embryonic kidney 293 (HEK293) cells. Intracellular space (ICS) was calculated by subtracting the [(3)H]-inulin distribution volume (extracellular space, ECS) from the [(14)C]-urea distribution volume (total water space, TWS). Values obtained for intracellular space (mean ± S.E.M.; μl/10(6) cells) of monolayers of HEK cells (HEK-empty vector [EV]) and cells overexpressing human organic cation transporter 1 (HEK-OCT1), 1.21± 0.07 and 1.25±0.06, respectively, were used to determine the intracellular metformin concentrations. After incubation of the cells with 5 µM metformin, the intracellular concentrations were 26.4 ± 7.8 μM and 268 ± 11.0 μM, respectively, in HEK-EV and HEK-OCT1. In addition, intracellular metformin concentrations were lower in high K(+) buffer (140 mM KCl) compared with normal K(+) buffer (5.4 mM KCl) in HEK-OCT1 cells (54.8 ± 3.8 μM and 198.1 ± 11.2 μM, respectively; P < 0.05). Our mechanistic model suggests that, depending on the credible range of assumed physiologic values, the positively charged metformin accumulates to particularly high levels in endoplasmic reticulum and/or mitochondria. This method together with the computational model can be used to determine intracellular unbound concentrations and to predict subcellular accumulation of drugs in other complex systems such as primary cells.
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