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Renal Physiology
Open Access

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Sanjay K. Nigam, Wei Wu, Kevin T. Bush, Melanie P. Hoenig, Roland C. Blantz and Vibha Bhatnagar
CJASN November 2015, 10 (11) 2039-2049; DOI: https://doi.org/10.2215/CJN.02440314
Sanjay K. Nigam
*Department of Medicine,
†Department of Pediatrics,
‡Department of Cell & Molecular Medicine,
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Wei Wu
*Department of Medicine,
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Kevin T. Bush
†Department of Pediatrics,
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Melanie P. Hoenig
§Division of Nephrology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
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Roland C. Blantz
‖Division of Nephrology-Hypertension, and
¶Veterans Affairs San Diego Healthcare System, San Diego, California; and
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Vibha Bhatnagar
**Division of Family & Preventative Medicine, University of California–San Diego, La Jolla, California;
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Abstract

The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liver-derived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.

  • renal physiology
  • drug transporter
  • nephrotoxicity
  • ATP-Binding Cassette Transporters
  • Acute Kidney Injury
  • Anti-Bacterial Agents
  • Cations
  • Diuretics
  • Organic Anion Transporters
  • Renal Insufficiency
  • Chronic
  • Received March 7, 2014.
  • Accepted September 28, 2014.
  • Copyright © 2015 by the American Society of Nephrology

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Clinical Journal of the American Society of Nephrology: 10 (11)
Clinical Journal of the American Society of Nephrology
Vol. 10, Issue 11
November 06, 2015
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Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters
Sanjay K. Nigam, Wei Wu, Kevin T. Bush, Melanie P. Hoenig, Roland C. Blantz, Vibha Bhatnagar
CJASN Nov 2015, 10 (11) 2039-2049; DOI: 10.2215/CJN.02440314

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Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters
Sanjay K. Nigam, Wei Wu, Kevin T. Bush, Melanie P. Hoenig, Roland C. Blantz, Vibha Bhatnagar
CJASN Nov 2015, 10 (11) 2039-2049; DOI: 10.2215/CJN.02440314
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  • Article
    • Abstract
    • Classification of Organic Ion Transporters
    • Basic Organic Ion Transporter Physiology
    • Drugs and Toxins
    • Uremic Toxins
    • Gut Microbiome Products, Nutrients, and Natural Products
    • Metabolites and Signaling Molecules
    • DDIs and Drug-Metabolite Interactions
    • Pharmacogenomic and Toxicogenomic Considerations
    • Pediatric Developmental Pharmacology and Drug Elimination in the Aging Population
    • AKI and CKD
    • Remote Sensing and Signaling Hypothesis
    • Summary
    • Disclosures
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data Supps
  • Info & Metrics
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More in this TOC Section

  • Acid-Base Homeostasis
  • Physiology of the Renal Interstitium
Show more Renal Physiology

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  • Impaired Tubular Secretion of Organic Solutes in Acute Kidney Injury
  • Kidney Clearance of Secretory Solutes Is Associated with Progression of CKD: The CRIC Study
  • Diuretic Therapy for Patients With Heart Failure: JACC State-of-the-Art Review
  • A Randomized Trial of Distal Diuretics versus Dietary Sodium Restriction for Hypertension in Chronic Kidney Disease
  • Unique metabolite preferences of the drug transporters OAT1 and OAT3 analyzed by machine learning
  • Clinical Pharmacology in Diuretic Use
  • Dynamics of Organic Anion Transporter-Mediated Tubular Secretion during Postnatal Human Kidney Development and Maturation
  • Evidence for the Validity of Pyridoxic Acid (PDA) as a Plasma-Based Endogenous Probe for OAT1 and OAT3 Function in Healthy Subjects
  • Emerging Kidney Models to Investigate Metabolism, Transport, and Toxicity of Drugs and Xenobiotics
  • Uric acid stones, clinical manifestations and therapeutic considerations
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  • Expression of Organic Anion Transporter 1 or 3 in Human Kidney Proximal Tubule Cells Reduces Cisplatin Sensitivity
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  • 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
  • The drug transporter OAT3 (SLC22A8) and endogenous metabolite communication via the gut-liver-kidney axis
  • Disposition and clinical implications of protein-bound uremic toxins
  • Increased Plasma Exposures of Conjugated Metabolites of Morinidazole in Renal Failure Patients: A Critical Role of Uremic Toxins
  • Diurnal and Long-term Variation in Plasma Concentrations and Renal Clearances of Circulating Markers of Kidney Proximal Tubular Secretion
  • Protein-bound toxins: has the Cinderella of uraemic toxins turned into a princess?
  • Multiple Drug Transporters Are Involved in Renal Secretion of Entecavir
  • Molecular Properties of Drugs Interacting with SLC22 Transporters OAT1, OAT3, OCT1, and OCT2: A Machine-Learning Approach
  • An Organic Anion Transporter 1 (OAT1)-centered Metabolic Network
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Keywords

  • renal physiology
  • drug transporter
  • nephrotoxicity
  • ATP-Binding Cassette Transporters
  • acute kidney injury
  • Anti-Bacterial Agents
  • Cations
  • diuretics
  • Organic Anion Transporters
  • renal insufficiency
  • chronic

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