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 ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Characterization of Methotrexate Transport and Its Drug Interactions with Human Organic Anion Transporters

Michio Takeda, Suparat Khamdang, Shinichi Narikawa, Hiroaki Kimura, Makoto Hosoyamada, Seok Ho Cha, Takashi Sekine and Hitoshi Endou
Journal of Pharmacology and Experimental Therapeutics August 2002, 302 (2) 666-671; DOI: https://doi.org/10.1124/jpet.102.034330
Michio Takeda
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Suparat Khamdang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shinichi Narikawa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hiroaki Kimura
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Makoto Hosoyamada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Seok Ho Cha
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Takashi Sekine
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hitoshi Endou
  • 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

Life-threatening drug interactions are known to occur between methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs), probenecid, and penicillin G. The purpose of this study was to characterize methotrexate transport, as well as to determine the site and the mechanism of drug interactions in the proximal tubule. Mouse proximal tubule cells stably expressing basolateral human organic anion transporters (hOAT1 and hOAT3) and apical hOAT (hOAT4) were established. The Km values for hOAT1-, hOAT3-, and hOAT4-mediated methotrexate uptake were 553.8 μM, 21.1 μM, and 17.8 μM, respectively. NSAIDs (salicylate, ibuprofen, ketoprofen, phenylbutazone, piroxicam, and indomethacin), probenecid, and penicillin G dose dependently inhibited methotrexate uptake mediated by hOAT1, hOAT3, and hOAT4. Kinetic analysis of inhibitory effects of these drugs on hOAT3-mediated methotrexate uptake revealed that these inhibitions were competitive. TheKi values for the effects of salicylate, phenylbutazone, indomethacin, and probenecid on hOAT3-mediated methotrexate uptake were comparable with therapeutically relevant plasma concentrations of unbound drugs. In addition, in the presence of human serum albumin, the Ki values were comparable with therapeutically relevant total plasma concentrations of drugs. In conclusion, these results suggest that methotrexate is taken up via hOAT3 and hOAT1 at the basolateral side of the proximal tubule and effluxed or taken up at the apical side via hOAT4. In addition, hOAT1, hOAT3, and hOAT4 are the sites of drug interactions between methotrexate and NSAIDs, probenecid, and penicillin G. Furthermore, it was predicted that hOAT3 is the site of drug interactions between methotrexate and salicylate, phenylbutazone, indomethacin, and probenecid in vivo.

Footnotes

  • This study was supported in part by grants-in-aid from the Ministry of Education, Sports, Science and Technology (11671048, 11694310, and 13671128), the Science Research Promotion Fund of the Japan Private School Promotion Foundation, and Research on Health Sciences focusing on Drug Innovation from Japan Health Sciences Foundation.

  • DOI: 10.1124/jpet.102.034330

  • Abbreviations:
    NSAID
    nonsteroidal anti-inflammatory drug
    OAT
    organic anion transporter
    hOAT
    human organic anion transporter
    OAT-K1
    OAT-K2, renal organic anion transporter 1 and 2
    oatp1
    oatp2, organic anion-transporting polypeptide 1 and 2
    MRP2
    multidrug resistance protein 2
    NPT1
    human type I sodium-dependent inorganic phosphate transporter
    S1
    S2, S3, the first, second, and third segment of proximal tubule
    D-PBS
    Dulbecco's modified phosphate-buffered saline
    hPAHT
    human kidneyp-aminohippurate transporter
    • Received February 20, 2002.
    • Accepted April 8, 2002.
  • 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: 302 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 302, Issue 2
1 Aug 2002
  • Table of Contents
  • 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.
Characterization of Methotrexate Transport and Its Drug Interactions with Human Organic Anion Transporters
(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 ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Characterization of Methotrexate Transport and Its Drug Interactions with Human Organic Anion Transporters

Michio Takeda, Suparat Khamdang, Shinichi Narikawa, Hiroaki Kimura, Makoto Hosoyamada, Seok Ho Cha, Takashi Sekine and Hitoshi Endou
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 666-671; DOI: https://doi.org/10.1124/jpet.102.034330

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Characterization of Methotrexate Transport and Its Drug Interactions with Human Organic Anion Transporters

Michio Takeda, Suparat Khamdang, Shinichi Narikawa, Hiroaki Kimura, Makoto Hosoyamada, Seok Ho Cha, Takashi Sekine and Hitoshi Endou
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 666-671; DOI: https://doi.org/10.1124/jpet.102.034330
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
    • Experimental Procedures
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Transport Is Not Rate-Limiting in Morphine Glucuronidation in the Single-Pass Perfused Rat Liver Preparation
  • Enhanced Hepatic Uptake and Bioactivity of Type α1(I) Collagen Gene Promoter-Specific Triplex-Forming Oligonucleotides after Conjugation with Cholesterol
  • Characterization of P-glycoprotein Inhibition by Major Cannabinoids from Marijuana
Show more ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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