A Human Renal Proximal Tubule Cell Line with Stable Organic Anion Transporter 1 and 3 Expression Predictive for Antiviral-Induced Toxicity

Drug-induced nephrotoxicity still hampers drug development, because current translation from in vitro or animal studies to human lacks high predictivity. Often, renal adverse effects are recognized only during clinical stages of drug development. The current study aimed to establish a robust and a more complete human cell model suitable for screening of drug-related interactions and nephrotoxicity. In addition to endogenously expressed renal organic cation transporters and efflux transporters, conditionally immortalized proximal tubule epithelial cells (ciPTEC) were completed by transduction of cells with the organic anion transporter (OAT) 1 or OAT3. Fluorescence-activated cell sorting upon exposure to the OAT substrate fluorescein successfully enriched transduced cells. A panel of organic anions was screened for drug-interactions in ciPTEC-OAT1 and ciPTEC-OAT3. The cytotoxic response to the drug-interactions with antivirals was further examined by cell viability assays. Upon subcloning, concentration-dependent fluorescein uptake was found with a higher affinity for ciPTEC-OAT1 (Km = 0.8 ± 0.1 μM) than ciPTEC-OAT3 (Km = 3.7 ± 0.5 μM). Co-exposure to known OAT1 and/or OAT3 substrates (viz. para-aminohippurate, estrone sulfate, probenecid, furosemide, diclofenac, and cimetidine) in cultures spanning 29 passage numbers revealed relevant inhibitory potencies, confirming the robustness of our model for drug-drug interactions studies. Functional OAT1 was directly responsible for cytotoxicity of adefovir, cidofovir, and tenofovir, while a drug interaction with zidovudine was not associated with decreased cell viability. Our data demonstrate that human-derived ciPTEC-OAT1 and ciPTEC-OAT3 are promising platforms for highly predictive drug screening during early phases of drug development.

• Publication year

  2016

• Venue

  AAPS Journal

• Publication date

  2016-01-28

• Fields of study

  Medicine

• Identifiers
  DOI 10.1208/s12248-016-9871-8PMID 26821801PMCID 4779111
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Intracellular concentrations determine the cytotoxicity of adefovir, cidofovir and tenofovir.

  2015influential reference
• Expression of xenobiotic transporters in the human renal proximal tubule cell line RPTEC/TERT1.

  2015cited by this paper
• Drug-induced nephrotoxicity: clinical impact and preclinical in vitro models.

  2014cited by this paper
• What do drug transporters really do?

  2014cited by this paper
• Microfluidic organs-on-chips

  2014cited by this paper
• Extrahepatic metabolism at the body's internal–external interfaces

  2014cited by this paper
• Emerging clinical issues related to management of multiorgan comorbidities and polypharmacy.

  2014cited by this paper
• A morphological and functional comparison of proximal tubule cell lines established from human urine and kidney tissue.

  2014influential reference
• Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

  2013cited by this paper
• Mesenchymal stem cell-conditioned medium accelerates regeneration of human renal proximal tubule epithelial cells after gentamicin toxicity.

  2013cited by this paper
• Species differences in drug transporters and implications for translating preclinical findings to humans

  2013cited by this paper
• Interactions with selected drug renal transporters and transporter-mediated cytotoxicity in antiviral agents from the group of acyclic nucleoside phosphonates.

  2013cited by this paper
• Uremic toxins inhibit renal metabolic capacity through interference with glucuronidation and mitochondrial respiration.

  2013cited by this paper
• Tenofovir effect on the kidneys of HIV-infected patients: a double-edged sword?

  2013cited by this paper
• Renal transporters in drug development.

  2013cited by this paper
• Organic Cation Transporter OCTs (SLC22) and MATEs (SLC47) in the Human Kidney

  2013cited by this paper
• Cationic uremic toxins affect human renal proximal tubule cell functioning through interaction with the organic cation transporter

  2013influential reference
• Potential for food-drug interactions by dietary phenolic acids on human organic anion transporters 1 (SLC22A6), 3 (SLC22A8), and 4 (SLC22A11).

  2012cited by this paper
• Renal Organic Anion Transporters (SLC22 Family): Expression, Regulation, Roles in Toxicity, and Impact on Injury and Disease

  2012cited by this paper
• The EMA has published an updated guideline on the investigation of drug interactions.

  2012cited by this paper
• Pharmacokinetics and Safety of Single-Dose Tenofovir Disoproxil Fumarate and Emtricitabine in HIV-1-Infected Pregnant Women and Their Infants

  2011cited by this paper
• Tenofovir Renal Proximal Tubular Toxicity Is Regulated By OAT1 and MRP4 Transporters

  2011cited by this paper
• Mechanisms of drug toxicity and relevance to pharmaceutical development.

  2011cited by this paper
• In vitro and in vivo evidence of the importance of organic anion transporters (OATs) in drug therapy.

  2011cited by this paper
• Guideline on the Investigation of Drug Interactions

  2010cited by this paper
• Therapeutic implications of renal anionic drug transporters.

  2010cited by this paper
• Membrane transporters in drug development

  2010cited by this paper
• Impact and prevalence of safety pharmacology-related toxicities throughout the pharmaceutical life cycle

  2010cited by this paper
• The nephrotoxic effects of HAART

  2009cited by this paper
• Novel conditionally immortalized human proximal tubule cell line expressing functional influx and efflux transporters

  2009influential reference
• Physicochemical determinants of human renal clearance.

  2009cited by this paper
• hTERT alone immortalizes epithelial cells of renal proximal tubules without changing their functional characteristics.

  2008cited by this paper
• Characterisation of human tubular cell monolayers as a model of proximal tubular xenobiotic handling.

  2008cited by this paper
• Novel Nucleotide Human Immunodeficiency Virus Reverse Transcriptase Inhibitor GS-9148 with a Low Nephrotoxic Potential: Characterization of Renal Transport and Accumulation

  2008influential reference
• Functional Involvement of Multidrug Resistance-Associated Protein 4 (MRP4/ABCC4) in the Renal Elimination of the Antiviral Drugs Adefovir and Tenofovir

  2007cited by this paper
• Drug Interaction Studies: Study Design, Data Analysis, and Implications for Dosing and Labeling

  2007cited by this paper
• Transport of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin by Human Organic Anion Transporter 3, Organic Anion Transporting Polypeptide 4C1, and Multidrug Resistance P-glycoprotein

  2007cited by this paper
• Membrane transport function in primary cultures of human proximal tubular cells.

  2006cited by this paper
• Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1.

  2005cited by this paper
• Interactions of Stevioside and Steviol with Renal Organic Anion Transporters in S2 Cells and Mouse Renal Cortical Slices

  2005cited by this paper
• Systemic and Renal Pharmacokinetics of Adefovir and Tenofovir Upon Coadministration

  2005cited by this paper
• Antiviral drugs in current clinical use.

  2004cited by this paper
• Antiviral drugs in current clinical use.

  2004cited by this paper
• Tenofovir Disoproxil Fumarate

  2004cited by this paper
• Characterization of uremic toxin transport by organic anion transporters in the kidney.

  2004cited by this paper
• Different transport properties between famotidine and cimetidine by human renal organic ion transporters (SLC22A).

  2004cited by this paper
• Interactions of human- and rat-organic anion transporters with pravastatin and cimetidine.

  2004cited by this paper
• Interactions of Human Organic Anion Transporters with Diuretics

  2004cited by this paper
• Mitochondrial toxicity of nrti antiviral drugs: an integrated cellular perspective

  2003cited by this paper
• Toxicity of nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase.

  2003cited by this paper
• Interactions of Human Organic Anion Transporters and Human Organic Cation Transporters with Nonsteroidal Anti-Inflammatory Drugs

  2002cited by this paper
• A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression.

  2002cited by this paper
• Human organic anion transporters and human organic cation transporters mediate renal antiviral transport.

  2002cited by this paper
• Characterization of ochratoxin A transport by human organic anion transporters.

  2001cited by this paper
• Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney.

  2001cited by this paper
• Fluorescence-based assay for the interaction of small molecules with the human renal organic anion transporter 1.

  2000cited by this paper
• Nonsteroidal anti-inflammatory drugs efficiently reduce the transport and cytotoxicity of adefovir mediated by the human renal organic anion transporter 1.

  2000cited by this paper
• The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1.

  1999cited by this paper
• Effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous cidofovir in cynomolgus monkeys.

  1998cited by this paper
• Anti-human immunodeficiency virus (HIV) activity, safety, and pharmacokinetics of adefovir dipivoxil (9-[2-(bis-pivaloyloxymethyl)-phosphonylmethoxyethyl]adenine) in HIV-infected patients.

  1997cited by this paper
• Pharmacokinetics, safety and bioavailability of HPMPC (cidofovir) in human immunodeficiency virus-infected subjects.

  1996cited by this paper
• Pharmacokinetics and bioavailability of zidovudine and its glucuronidated metabolite in patients with human immunodeficiency virus infection and hepatic disease (AIDS Clinical Trials Group protocol 062)

  1995cited by this paper
• Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients

  1995cited by this paper
• Clinical pharmacokinetics of adefovir in human immunodeficiency virus type 1-infected patients

  1995cited by this paper
• Pharmacokinetics and bioavailability of zidovudine in humans.

  1988cited by this paper
• Reversibility by dipyridamole of thallium-201 myocardial scan defects in patients with sarcoidosis.

  1988cited by this paper
• Guidance for Industry Drug Interaction Studies — Study Design , Data Analysis , Implications for Dosing , and Labeling Recommendations

  year unknowncited by this paper

• Rat and human primary proximal tubule epithelial cells allow for cross-species comparisons of drug-induced nephrotoxicity in vitro.

  2026cites this paper
• Fluorescent dyes as functional probes for studying drug-transporting solute carriers

  2026cites this paper
• Applications of in vitro transporter assays for mechanistic characterization and prediction of clinical drug-drug interactions.

  2026cites this paper
• Lack of Modulation of In Vivo Activity of Organic Anion Transporters 1 and 3 in Pregnancy Using Furosemide as a Probe

  2026cites this paper
• Microphysiological Systems for Comorbidity Studies: Chronic Kidney Disease and Osteoarthritis

  2025cites this paper
• A High‐Throughput AngioPlate Platform with Integrated AngioTEER for Modeling and Monitoring Renal Proximal Tubule Injury

  2025cites this paper
• Enhancing therapeutic strategies and drug development for patients with kidney disease

  2025cites this paper
• Indoxyl sulfate as a potential tubular function marker across kidney disease models.

  2025cites this paper
• hTERT and SV40LgT Renal Cell Lines Adjust Their Transcriptional Responses After Copy Number Changes from the Parent Proximal Tubule Cells

  2025cites this paper
• Human and rat renal proximal tubule in vitro models for ADME applications

  2025influential citation
• A perfused iPSC-derived proximal tubule model for predicting drug-induced kidney injury.

  2025cites this paper
• Three-dimensional-cultured renal tubular model reveals FXR-HNF4α-OAT1/3 axis as a target for preventing nucleotide analog-induced kidney injury.

  2025cites this paper
• The Chorioallantoic Membrane as a Platform for Developing Vascularized Cell Macroencapsulation Devices

  2025influential citation
• Advances and continuing challenges in differentiation of stem cells to human kidney tissue

  2025cites this paper
• Comparative Analysis of Proximal Tubule Cell Sources for In Vitro Studies of Renal Proximal Tubule Toxicity

  2025cites this paper
• Advanced in vitro evaluation of drug-induced kidney injury using microphysiological systems in drug discovery and development.

  2025cites this paper
• Albumin-Mediated Drug Uptake by Organic Anion Transporter 1/3 Is Real: Implications for the Prediction of Active Renal Secretion Clearance

  2024cites this paper
• Three-dimensional culture of human proximal tubular epithelial cells for an in vitro evaluation of drug-induced kidney injury.

  2024cites this paper
• Characterization of Organic Anion and Cation Transport in Three Human Renal Proximal Tubular Epithelial Models

  2024cites this paper
• The Future for End-Stage Kidney Disease Treatment: Implantable Bioartificial Kidney Challenge

  2024cites this paper
• Gut microbial-derived short chain fatty acids enhance kidney proximal tubule cell secretory function

  2024cites this paper
• Efficient proximal tubule-on-chip model from hiPSC-derived kidney organoids for functional analysis of renal transporters

  2024cites this paper
• Metabolic impact of genetic and chemical ADP/ATP carrier inhibition in renal proximal tubule epithelial cells

  2023cites this paper
• The Uremic Toxin Indoxyl Sulfate Accelerates Senescence in Kidney Proximal Tubule Cells

  2023cites this paper
• Substrate binding and lipid-mediated allostery in the human organic anion transporter 1 at the atomic-scale

  2023cites this paper
• Cell and gene therapy for kidney disease

  2023cites this paper
• Delivery and Transcriptome Assessment of an In Vitro Three-Dimensional Proximal Tubule Model Established by Human Kidney 2 Cells in Clinical Gelatin Sponges

  2023cites this paper
• Bioengineered Kidney Tubules Efficiently Clear Uremic Toxins in Experimental Dialysis Conditions

  2023influential citation
• Improvement of Protein Expression Profile in Three-Dimensional Renal Proximal Tubular Epithelial Cell Spheroids Selected Based on OAT1 Gene Expression: A Potential In Vitro Tool for Evaluating Human Renal Proximal Tubular Toxicity and Drug Disposition

  2023cites this paper
• Portable, wearable and implantable artificial kidney systems: needs, opportunities and challenges

  2023cites this paper
• Differentiated kidney tubular cell-derived extracellular vesicles enhance maturation of tubuloids

  2022cites this paper
• Identification of 5-Carboxyfluorescein as a Probe Substrate of SLC46A3 and Its Application in a Fluorescence-Based In Vitro Assay Evaluating the Interaction with SLC46A3.

  2022cites this paper
• Examination of the emerging role of transporters in the assessment of nephrotoxicity

  2022cites this paper
• Synthesis and Evaluation of Polymyxins Bearing Reductively Labile Disulfide-Linked Lipids

  2022cites this paper
• Inhibition of Transforming Growth Factor-β Improves Primary Renal Tubule Cell Differentiation in Long-Term Culture

  2022cites this paper
• Pathophysiological and Genetic Basis of Tenofovir-Induced Acute Renal Dysfunction: Strategies and Recent Developments for Better Clinical Outcomes

  2022cites this paper
• Mapping Adverse Outcome Pathways for Kidney Injury as a Basis for the Development of Mechanism-Based Animal-Sparing Approaches to Assessment of Nephrotoxicity

  2022cites this paper
• A Human Conditionally Immortalized Proximal Tubule Epithelial Cell Line as a Novel Model for Studying Senescence and Response to Senolytics

  2022cites this paper
• Dissecting Drug-Induced Cytotoxicity and Metabolic Dysfunction in Conditionally Immortalized Human Proximal Tubule Cells

  2022cites this paper
• A robust, accurate, sensitive LC–MS/MS method to measure indoxyl sulfate, validated for plasma and kidney cells

  2022cites this paper
• In vitro models for accurate prediction of renal tubular xenobiotic transport in vivo

  2021cites this paper
• Implementation of a Human Renal Proximal Tubule on a Chip for Nephrotoxicity and Drug Interaction Studies.

  2021cites this paper
• Microphysiological systems in early stage drug development: Perspectives on current applications and future impact.

  2021cites this paper
• Follow-Up of Adefovir Dipivoxil Induced Osteomalacia: Clinical Characteristics and Genetic Predictors

  2021cites this paper
• Nephroscreen: A robust and versatile renal tubule-on-a-chip platform for nephrotoxicity assessment

  2021cites this paper
• Dissecting drug-induced in vitro cytotoxicity and metabolic dysfunction in conditionally immortalized human proximal tubule cells

  2021cites this paper
• Urine-Derived Epithelial Cells as Models for Genetic Kidney Diseases

  2021cites this paper
• Bioengineered Kidney Models: Methods and Functional Assessments

  2021cites this paper
• Vancomyxins: Vancomycin-Polymyxin Nonapeptide Conjugates That Retain Anti-Gram-Positive Activity with Enhanced Potency against Gram-Negative Strains

  2021cites this paper
• Para‐aminosalicylic acid significantly reduced tenofovir exposure in human subjects: Mismatched findings from in vitro to in vivo translational research

  2021cites this paper
• In Vitro Nephrotoxicity Studies of Established and Experimental Platinum-Based Compounds

  2021cites this paper
• Regulation of Solute Carriers OCT2 and OAT1/3 in the Kidney: A Phylogenetic, Ontogenetic and Cell Dynamic Perspective.

  2021cites this paper
• Protein-Bound Uremic Toxins Induce Reactive Oxygen Species-Dependent and Inflammasome-Mediated IL-1β Production in Kidney Proximal Tubule Cells

  2021cites this paper
• The Influence of OAT1 Density and Functionality on Indoxyl Sulfate Transport in the Human Proximal Tubule: An Integrated Computational and In Vitro Study

  2021cites this paper
• Experimental Cell Line Models for Nephrotoxicity Screening

  2021cites this paper
• Drug-Induced Nephrotoxicity Assessment in 3D Cellular Models

  2021cites this paper
• Research and development of drug delivery systems based on drug transporter and nano-formulation

  2020cites this paper
• Protective effect of cilastatin against diclofenac‐induced nephrotoxicity through interaction with diclofenac acyl glucuronide via organic anion transporters

  2020cites this paper
• Predictive and translational models for renal drug safety evaluation

  2020cites this paper
• A pharmaceutical industry perspective on microphysiological kidney systems for evaluation of safety for new therapies.

  2020cites this paper
• Renal proximal tubular epithelial cells: review of isolation, characterization, and culturing techniques

  2020cites this paper
• A simple method for the isolation and detailed characterization of primary human proximal tubule cells for renal replacement therapy

  2020cites this paper
• Freshly isolated primary human proximal tubule cells as an in vitro model for the detection of renal tubular toxicity.

  2020cites this paper
• Extrahepatic metabolism of ibrutinib

  2020cites this paper
• Drugs Commonly Applied to Kidney Patients May Compromise Renal Tubular Uremic Toxins Excretion

  2020cites this paper
• Quantitative translation of microfluidic transporter in vitro data to in vivo reveals impaired albumin-facilitated indoxyl sulfate secretion in chronic kidney disease.

  2019cites this paper
• Safety evaluation of conditionally immortalized cells for renal replacement therapy

  2019cites this paper
• Safety considerations with current and emerging antiviral therapies for cytomegalovirus infection in transplantation

  2019influential citation
• Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion

  2019cites this paper
• Relationship of MATE1 Inhibition and Cytotoxicity in Nephrotoxicity: Application for Safety Evaluation in Early Drug Discovery.

  2019cites this paper
• Therapy with 2′-O-Me Phosphorothioate Antisense Oligonucleotides Causes Reversible Proteinuria by Inhibiting Renal Protein Reabsorption

  2019cites this paper
• ABC Family Transporters.

  2019cites this paper
• Organic anion transporters 1 and 3 influence cellular energy metabolism in renal proximal tubule cells

  2019cites this paper
• Organic anion transporter 3 (OAT3)‐mediated transport of dicaffeoylquinic acids and prediction of potential drug‐drug interaction

  2019cites this paper
• Emerging In Vitro Systems to Screen and Predict Drug-Induced Kidney Toxicity.

  2019cites this paper
• Clinically-relevant OATP2B1 inhibitors in marketed drug space.

  2019cites this paper
• Kidney-based in vitro models for drug-induced toxicity testing

  2019cites this paper
• In vitro nephrotoxicity and anticancer potency of newly synthesized cadmium complexes

  2019cites this paper
• SLC Family Transporters.

  2019cites this paper
• Predictive in vitro toxicology screening to guide chemical design in drug discovery

  2019cites this paper
• Hnf4a deletion in the mouse kidney phenocopies Fanconi renotubular syndrome.

  2018cites this paper
• A bioartificial kidney device with polarized secretion of immune modulators

  2018cites this paper
• Transporter-dependent cytotoxicity of antiviral drugs in primary cultures of human proximal tubular cells.

  2018cites this paper
• Advances in predictive in vitro models of drug-induced nephrotoxicity

  2018cites this paper
• Fabrication of Kidney Proximal Tubule Grafts Using Biofunctionalized Electrospun Polymer Scaffolds

  2018cites this paper
• Renal Epithelial Monolayer Formation on Monomeric and Polymeric Catechol Functionalized Supramolecular Biomaterials.

  2018cites this paper
• A Fluorescent Benzo[g]isoquinoline‐Based HIF Prolyl Hydroxylase Inhibitor for Cellular Imaging

  2018cites this paper
• Bioengineering Organs for Blood Detoxification

  2018cites this paper
• Emerging Kidney Models to Investigate Metabolism, Transport, and Toxicity of Drugs and Xenobiotics

  2018cites this paper
• A novel multi-parametric high content screening assay in ciPTEC-OAT1 to predict drug-induced nephrotoxicity during drug discovery

  2018cites this paper
• Carbon Nanotube Reinforced Supramolecular Hydrogels for Bioapplications.

  2018cites this paper
• Special Section – New Models in Drug Metabolism and Transport — Minireview Emerging Kidney Models to Investigate Metabolism , Transport , and Toxicity of Drugs and Xenobiotics

  2018cites this paper
• Screening of Drug-Transporter Interactions in a 3D Microfluidic Renal Proximal Tubule on a Chip

  2018influential citation
• Discovery and Validation of Pyridoxic Acid and Homovanillic Acid as Novel Endogenous Plasma Biomarkers of Organic Anion Transporter (OAT) 1 and OAT3 in Cynomolgus Monkeys

  2018cites this paper
• Combining Extracellular miRNA Determination with Microfluidic 3D Cell Cultures for the Assessment of Nephrotoxicity: a Proof of Concept Study

  2018cites this paper
• Recellularized Native Kidney Scaffolds as a Novel Tool in Nephrotoxicity Screening

  2018cites this paper
• Expression of Organic Anion Transporter 1 or 3 in Human Kidney Proximal Tubule Cells Reduces Cisplatin Sensitivity

  2018influential citation
• Development and Application of Human Renal Proximal Tubule Epithelial Cells for Assessment of Compound Toxicity

  2017cites this paper
• Disposition and clinical implications of protein-bound uremic toxins.

  2017cites this paper
• Recapitulating Development to Generate Kidney Organoid Cultures

  2017cites this paper