Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Journal of Pharmacology and Experimental Therapeutics
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Journal of Pharmacology and Experimental Therapeutics

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Transport of Lamivudine [(-)-β-l-2′,3′-Dideoxy-3′-thiacytidine] and High-Affinity Interaction of Nucleoside Reverse Transcriptase Inhibitors with Human Organic Cation Transporters 1, 2, and 3

Gerard Minuesa, Christopher Volk, Míriam Molina-Arcas, Valentin Gorboulev, Itziar Erkizia, Petra Arndt, Bonaventura Clotet, Marçal Pastor-Anglada, Hermann Koepsell and Javier Martinez-Picado
Journal of Pharmacology and Experimental Therapeutics April 2009, 329 (1) 252-261; DOI: https://doi.org/10.1124/jpet.108.146225
Gerard Minuesa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christopher Volk
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Míriam Molina-Arcas
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Valentin Gorboulev
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Itziar Erkizia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Petra Arndt
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bonaventura Clotet
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marçal Pastor-Anglada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hermann Koepsell
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Javier Martinez-Picado
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

This article has a correction. Please see:

  • Correction to “Transport of Lamivudine [(-)-β-l-2′,3′-Dideoxy-3′-thiacytidine] and High-Affinity Interaction of Nucleoside Reverse Transcriptase Inhibitors with Human Organic Cation Transporters 1, 2, and 3” - June 01, 2009

Abstract

Nucleoside reverse transcriptase inhibitors (NRTIs) need to enter cells to act against the HIV-1. Human organic cation transporters (hOCT1–3) are expressed and active in CD4+ T cells, the main target of HIV-1, and have been associated with antiviral uptake in different tissues. In this study, we examined whether NRTIs interact and are substrates of hOCT in cells stably expressing these transporters. Using [3H]N-methyl-4-phenylpyridinium, we found a high-affinity interaction among abacavir [[(1S,4R)-4-[2-amino-6-(cyclopropylamino)purin-9-yl]-cyclopent-2-enyl]methanol sulfate] (ABC); <0.08 nM], azidothymidine [3′-azido-3′-deoxythymidine (AZT); <0.4 nM], tenofovir disoproxil fumarate (<1.0 nM), and emtricitabine (<2.5 nM) and hOCTs. Using a wide range of concentrations of lamivudine [(-)-β-l-2′,3′-dideoxy-3′-thiacyitidine (3TC)], we determined two different binding sites for hOCTs: a high-affinity site (Kd1 = 12.3–15.4 pM) and a low-affinity site (Kd2 = 1.9–3.4 mM). Measuring direct uptake of [3H]3TC and inhibition with hOCT substrates, we identified 3TC as a novel substrate for hOCT1, 2, and 3, with hOCT1 as the most efficient transporter (Km = 1.25 ± 0.1 mM; Vmax = 10.40 ± 0.32 nmol/mg protein/min; Vmax/Km = 8.32 ± 0.40 μl/mg protein/min). In drug-drug interaction experiments, we analyzed cis-inhibition of [3H]3TC uptake by ABC and AZT and found that 40 to 50% was inhibited at low concentrations of the drugs (Ki = 22–500 pM). These data reveal that NRTIs experience a high-affinity interaction with hOCTs, suggesting a putative role for these drugs as modulators of hOCT activity. Finally, 3TC is a novel substrate for hOCTs and the inhibition of its uptake at low concentrations of ABC and AZT could have implications for the pharmacokinetics of 3TC.

Footnotes

  • This work was supported by Fundación para la Investigación y la Prevención del SIDA en España (FIPSE) [Grants FIPSE36372/03 and FIPSE36621/06] (to J.M.-P.). Additional support was provided by Plan Nacional de Salud from Ministerio de Ciencia e Innovación (MICINN) of Gobierno de España [Research Grants SAF2004-01259 and SAF2008-00577] (to M.P.-A.) and the Spanish AIDS network “Red Temática Cooperativa de Investigación en SIDA” (RIS) [Grants G03/173 and RD06/006]. G.M. was supported by Agència de Gestió d'Ajuts Universitaris i de Recerca from Generalitat de Catalunya [Grant 2005FI-00314].

  • The measurements were performed by G.M. during a visit to the laboratory of H.K. and were supported by the Agència de Gestió d'Ajuts Universitaris i de Recerca from Generalitat de Catalunya [Grant 2006BE-2 00228], the Spanish AIDS network “Red Temática Cooperativa de Investigación en SIDA” (RIS) and Deutsche Forschungsgesellschaft, Sonderforschungsbereich 487/A4.

  • H.K. and J.M.-P. contributed equally to this work.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.146225.

  • ABBREVIATIONS: NRTI, nucleoside reverse transcriptase inhibitor; 3TC, lamivudine, (-)-β-l-2′,3′-dideoxy-3′-thiacyitidine; ABC, abacavir, [[(1S,4R)-4-[2-amino-6-(cyclopropylamino)purin-9-yl]cyclopent-2-enyl]methanol sulfate]; AZT, azidothymidine, 3′-azido-3′-deoxythymidine; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate; SLC, solute carrier; h, human; OAT, organic anion transporter; OCT, organic cation transporter; CHO, Chinese hamster ovary; MPP+, N-methyl-4-phenylpyridinium; metformin, 1,1-[dimethyl]-biguanide hydrochloride; TEA, tetraethylammonium; TBuA, tetrabutylammonium; Rani, ranitidine; Atrop, atropine; D-22, 1,1′-diethyl-2,2′-cyanine iodide; HAART, highly active antiretroviral therapy; PI, protease inhibitor; r, rat.

  • ↵ Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

    • Received September 16, 2008.
    • Accepted January 12, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 329 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 329, Issue 1
1 Apr 2009
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Journal of Pharmacology and Experimental Therapeutics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Transport of Lamivudine [(-)-β-l-2′,3′-Dideoxy-3′-thiacytidine] and High-Affinity Interaction of Nucleoside Reverse Transcriptase Inhibitors with Human Organic Cation Transporters 1, 2, and 3
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Transport of Lamivudine [(-)-β-l-2′,3′-Dideoxy-3′-thiacytidine] and High-Affinity Interaction of Nucleoside Reverse Transcriptase Inhibitors with Human Organic Cation Transporters 1, 2, and 3

Gerard Minuesa, Christopher Volk, Míriam Molina-Arcas, Valentin Gorboulev, Itziar Erkizia, Petra Arndt, Bonaventura Clotet, Marçal Pastor-Anglada, Hermann Koepsell and Javier Martinez-Picado
Journal of Pharmacology and Experimental Therapeutics April 1, 2009, 329 (1) 252-261; DOI: https://doi.org/10.1124/jpet.108.146225

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Transport of Lamivudine [(-)-β-l-2′,3′-Dideoxy-3′-thiacytidine] and High-Affinity Interaction of Nucleoside Reverse Transcriptase Inhibitors with Human Organic Cation Transporters 1, 2, and 3

Gerard Minuesa, Christopher Volk, Míriam Molina-Arcas, Valentin Gorboulev, Itziar Erkizia, Petra Arndt, Bonaventura Clotet, Marçal Pastor-Anglada, Hermann Koepsell and Javier Martinez-Picado
Journal of Pharmacology and Experimental Therapeutics April 1, 2009, 329 (1) 252-261; DOI: https://doi.org/10.1124/jpet.108.146225
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • HDL Mimetic 4F Modulates Aβ Distribution in Brain and Plasma
  • AOX1 Inhibition by Gefitinib, Erlotinib, and Metabolites
  • Catalytic Activity of CYP2C9 Variants
Show more Metabolism, Transport, and Pharmacogenomics

Similar Articles

  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About JPET
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2021 by the American Society for Pharmacology and Experimental Therapeutics