ArticleThe Journal of antimicrobial chemotherapy2016
Human oligopeptide transporter 2 (PEPT2) mediates cellular uptake of polymyxins.
Article in The Journal of antimicrobial chemotherapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 77 citations in OpenAlex.
- Influence of inflammation on drug transporter expression in human airway epithelia: Implications for inhaled drug pharmacokinetics.Drug metabolism and disposition: the biological fate of chemicals · 2026Article
- Preheating colistimethate sodium enhances its efficacy against multi/extensively drug-resistant Gram-negative bacilli in preservation fluid.Scientific reports · 2026Article
- A population pharmacokinetic model library for polymyxin B: clinical implementation of model-informed precision dosing.Frontiers in pharmacology · 2026Article
- Molecular mechanisms attributed to colistin renal proximal tubular epithelial cytotoxicity.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2025Review
- Functional and Physiological Implications of Oligopeptide Transporters: Potential Targets for Pharmacological Interventions.The Journal of membrane biology · 2025Review
- Population pharmacokinetics study on nebulized and intravenous administration of polymyxin B in patients with pneumonia caused by multidrug-resistant gram-negative bacteria.Antimicrobial agents and chemotherapy · 2025Article
- Artesunate, EDTA, and colistin work synergistically against MCR-negative and -positive colistin-resistanteLife · 2025Article
- A systematic evaluation of population pharmacokinetic models for polymyxin B in patients with liver and/or kidney dysfunction.Journal of pharmacokinetics and pharmacodynamics · 2024Article
- Evaluating nephrotoxicity reduction in a novel polymyxin B formulation: insights from a 3D kidney-on-a-chip model.Antimicrobial agents and chemotherapy · 2024Article
- L-carnitine co-administration prevents colistin-induced mitochondrial permeability transition and reduces the risk of acute kidney injury in mice.Scientific reports · 2024Article
- Mechanisms of gelofusine protection in an in vitro model of polymyxin B-associated renal injury.American journal of physiology. Renal physiology · 2024Article
- Colistin: Lights and Shadows of an Older Antibiotic.Molecules (Basel, Switzerland) · 2024Review
- Dextrin conjugation to colistin inhibits its toxicity, cellular uptake and acute kidney injuryRSC pharmaceutics · 2024Article
- Human ABC and SLC Transporters: The Culprit Responsible for Unspecific PSMA-617 Uptake?Pharmaceuticals (Basel, Switzerland) · 2024Article
- Recent Advances in the Development of Polymyxin Antibiotics: 2010-2023.ACS infectious diseases · 2024Review
- Genetic predisposition and high exposure to colistin in the early treatment period as independent risk factors for colistin-induced nephrotoxicity.Clinical and translational science · 2024Article
- Unravelling the Hepatic Elimination Mechanisms of Colistin.Pharmaceutical research · 2023Article
- Review
- Synchrotron-based X-ray fluorescence microscopy reveals accumulation of polymyxins in single human alveolar epithelial cells.Antimicrobial agents and chemotherapy · 2023Article
- Biology of Peptide Transporter 2 in Mammals: New Insights into Its Function, Structure and Regulation.Cells · 2022Review
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
objectivesPolymyxins are a last-line therapy to treat MDR Gram-negative bacterial infections. Nephrotoxicity is the dose-limiting factor for polymyxins and recent studies demonstrated significant accumulation of polymyxins in renal tubular cells. However, little is known about the mechanism of polymyxin uptake into these cells. Oligopeptide transporter 2 (PEPT2) is a solute carrier transporter (SLC) expressed at the apical membrane of renal proximal tubular cells and facilitates drug reabsorption in the kidney. In this study, we examined the role of PEPT2 in polymyxin uptake into renal tubular cells.
methodsWe investigated the inhibitory effects of colistin and polymyxin B on the substrate uptake mediated through 15 essential SLCs in overexpressing HEK293 cells. The inhibitory potency of both polymyxins on PEPT2-mediated substrate uptake was measured. Fluorescence imaging was employed to investigate PEPT2-mediated uptake of the polymyxin fluorescent probe MIPS-9541 and a transport assay was conducted with MIPS-9541 and [(3)H]polymyxin B1.
resultsColistin and polymyxin B potently inhibited PEPT2-mediated [(3)H]glycyl-sarcosine uptake (IC50 11.4 ± 3.1 and 18.3 ± 4.2 μM, respectively). In contrast, they had no or only mild inhibitory effects on the transport activity of the other 14 SLCs evaluated. MIPS-9541 potently inhibited PEPT2-mediated [(3)H]glycyl-sarcosine uptake (IC50 15.9 μM) and is also a substrate of PEPT2 (Km 74.9 μM). [(3)H]polymyxin B1 was also significantly taken up by PEPT2-expressing cells (Km 87.3 μM).
conclusionsOur study provides the first evidence of PEPT2-mediated uptake of polymyxins and contributes to a better understanding of the accumulation of polymyxins in renal tubular cells.
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