Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • 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
  • Submit
  • 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
    • Special Sections
    • 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
  • Submit
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Potent and Specific Inhibition of mMate1-Mediated Efflux of Type I Organic Cations in the Liver and Kidney by Pyrimethamine

Sumito Ito, Hiroyuki Kusuhara, Yushun Kuroiwa, Chunyong Wu, Yoshinori Moriyama, Katsuhisa Inoue, Tsunenori Kondo, Hiroaki Yuasa, Hideki Nakayama, Shigeru Horita and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics April 2010, 333 (1) 341-350; DOI: https://doi.org/10.1124/jpet.109.163642
Sumito Ito
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (S.I., H.K., Y.K., C.W., Y.S.); Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan (Y.M.); Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (K.I., H.Y.); and Department of Urology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan (T.K., H.N., S.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hiroyuki Kusuhara
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (S.I., H.K., Y.K., C.W., Y.S.); Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan (Y.M.); Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (K.I., H.Y.); and Department of Urology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan (T.K., H.N., S.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yushun Kuroiwa
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (S.I., H.K., Y.K., C.W., Y.S.); Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan (Y.M.); Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (K.I., H.Y.); and Department of Urology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan (T.K., H.N., S.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chunyong Wu
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (S.I., H.K., Y.K., C.W., Y.S.); Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan (Y.M.); Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (K.I., H.Y.); and Department of Urology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan (T.K., H.N., S.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yoshinori Moriyama
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (S.I., H.K., Y.K., C.W., Y.S.); Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan (Y.M.); Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (K.I., H.Y.); and Department of Urology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan (T.K., H.N., S.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Katsuhisa Inoue
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (S.I., H.K., Y.K., C.W., Y.S.); Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan (Y.M.); Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (K.I., H.Y.); and Department of Urology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan (T.K., H.N., S.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tsunenori Kondo
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (S.I., H.K., Y.K., C.W., Y.S.); Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan (Y.M.); Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (K.I., H.Y.); and Department of Urology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan (T.K., H.N., S.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hiroaki Yuasa
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (S.I., H.K., Y.K., C.W., Y.S.); Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan (Y.M.); Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (K.I., H.Y.); and Department of Urology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan (T.K., H.N., S.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hideki Nakayama
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (S.I., H.K., Y.K., C.W., Y.S.); Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan (Y.M.); Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (K.I., H.Y.); and Department of Urology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan (T.K., H.N., S.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shigeru Horita
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (S.I., H.K., Y.K., C.W., Y.S.); Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan (Y.M.); Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (K.I., H.Y.); and Department of Urology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan (T.K., H.N., S.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yuichi Sugiyama
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (S.I., H.K., Y.K., C.W., Y.S.); Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan (Y.M.); Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan (K.I., H.Y.); and Department of Urology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan (T.K., H.N., S.H.)
  • 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
Loading

Abstract

This report describes a potent and selective inhibitor of multidrug and toxin extrusion (MATE) protein, pyrimethamine (PYR), and examines its effect on the urinary and biliary excretion of typical Mate1 substrates in mice. In vitro inhibition studies demonstrated that PYR is a potent inhibitor of mouse (m)Mate1 (Ki = 145 nM) among renal organic cation transporters mOctn1 and mOctn2 (Ki > 30 μM), mOct1 (Ki = 3.6 μM), and mOct2 (Ki = 6.0 μM). PYR inhibited the uptake of metformin by kidney brush-border membrane vesicles (BBMVs) (Ki = 41 nM) and canalicular membrane vesicles in the presence of outward gradient of H+. PYR treatment significantly increased the kidney-to-plasma ratio of tetraethylammonium, and both the liver- and kidney-to-plasma ratios of metformin in mice, whereas it did not affect their plasma concentrations and urinary excretion rates. Furthermore, the plasma lactate concentration, a biomarker for inhibition of gluconeogenesis by metformin, was significantly higher in the PYR-treated group than in the control group. These results not only suggest the importance of mMate1 in the efflux of organic cations into the urine and bile in mice but also the importance of canalicular efflux mediated by MATE proteins for the therapeutic efficacy of metformin. PYR is a potent inhibitor of human (h)MATE1 and hMATE2-K (Ki = 77 and 46 nM, respectively) and H+ and organic cation exchanger in human kidney BBMVs (Ki = 31 nM) in the presence of outward gradient of H+. Taken together, PYR can be used as a potent probe inhibitor of human MATE transporters.

Footnotes

    • Received November 11, 2009.
    • Accepted January 6, 2010.
  • This study was supported by the Translational Research Promotion Project, New Energy and Industrial Technology Development Organization of Japan (in 2008 to Y.S.); the Ministry of Education, Culture, Sports, Science and Technology, Jpan [Grant-in-Aid for Scientific Research on Priority Areas KAKENHI 20056005] (to H.K.); Japan Research Foundation for Clinical Pharmacology (to H.K.); and The Smoking Research Foundation (to Y.M.).

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

    doi:10.1124/jpet.109.163642.

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

  • ABBREVIATIONS:

    OCT
    organic cation transporter
    TEA
    tetraethylammonium
    h
    human
    BBMV
    brush-border membrane vesicle
    OCTN
    organic cation/carnitine transporter
    MATE
    multidrug and toxin extrusion
    SNP
    single-nucleotide polymorphism
    PYR
    pyrimethamine
    HEK
    human embryonic kidney
    m
    mouse
    MES
    2-(N-morpholino)ethanesulfonic acid
    CMV
    canalicular membrane vesicle
    GFR
    glomerular filtration rate
    LC/MS
    liquid chromatography/mass spectrometry.

  • Copyright © 2010 by 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.
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 385 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 1
1 Apr 2023
  • Table of Contents
  • About the Cover
  • Index by author
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.
Potent and Specific Inhibition of mMate1-Mediated Efflux of Type I Organic Cations in the Liver and Kidney by Pyrimethamine
(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 ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Potent and Specific Inhibition of mMate1-Mediated Efflux of Type I Organic Cations in the Liver and Kidney by Pyrimethamine

Sumito Ito, Hiroyuki Kusuhara, Yushun Kuroiwa, Chunyong Wu, Yoshinori Moriyama, Katsuhisa Inoue, Tsunenori Kondo, Hiroaki Yuasa, Hideki Nakayama, Shigeru Horita and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics April 1, 2010, 333 (1) 341-350; DOI: https://doi.org/10.1124/jpet.109.163642

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Potent and Specific Inhibition of mMate1-Mediated Efflux of Type I Organic Cations in the Liver and Kidney by Pyrimethamine

Sumito Ito, Hiroyuki Kusuhara, Yushun Kuroiwa, Chunyong Wu, Yoshinori Moriyama, Katsuhisa Inoue, Tsunenori Kondo, Hiroaki Yuasa, Hideki Nakayama, Shigeru Horita and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics April 1, 2010, 333 (1) 341-350; DOI: https://doi.org/10.1124/jpet.109.163642
Reddit logo Twitter logo Facebook 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

Related Articles

Cited By...

More in this TOC Section

  • MIP3α in Progressive Renal Injury Associated with Obesity
  • A Novel Long-Acting GLP-2, HM15912, for Short Bowel Syndrome
  • H2S Overproduction and Colonic Hypomotility in DM
Show more Gastrointestinal, Hepatic, Pulmonary, and Renal

Similar Articles

Advertisement
  • 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 © 2023 by the American Society for Pharmacology and Experimental Therapeutics