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 ArticleArticle

Modulation of the Permeability of H2 Receptor Antagonists Cimetidine and Ranitidine by P-Glycoprotein in Rat Intestine and the Human Colonic Cell Line Caco-2

A. Collett, N. B. Higgs, E. Sims, M. Rowland and G. Warhurst
Journal of Pharmacology and Experimental Therapeutics January 1999, 288 (1) 171-178;
A. Collett
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
N. B. Higgs
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
E. Sims
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
M. Rowland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
G. Warhurst
  • 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

The influence of secretory transporters on intestinal permeability characteristics of the H2 receptor antagonists ranitidine and cimetidine was studied in Caco-2 monolayers and rat intestinal mucosa mounted in Ussing chambers. Both drugs exhibited vectorial transport across rat ileum with significantly greater (2–4-fold) permeability in the serosal-to-mucosal than the mucosal-to-serosal direction, indicative of net mucosal secretion. Mucosal ranitidine secretion was also observed in rat distal colon, although to a lesser degree. Ileal ranitidine secretion was concentration dependent and significantly reduced by the P-glycoprotein (P-gp) substrates verapamil and cyclosporin. In contrast, probenicid, an inhibitor of the multidrug-related protein, had no effect on ranitidine permeability. The paracellular marker mannitol showed no evidence of asymmetric permeability or sensitivity to P-gp inhibitors. Significant expression of P-gp protein in rat intestinal epithelial cells was confirmed by immunoblotting. Caco-2 monolayers, which overexpress P-gp, also showed asymmetric permeability of ranitidine and cimetidine. In this model, ranitidine permeability in the mucosal-to-serosal direction decreased by ≈95% as monolayer resistance increased from 150 to 500 Ω/cm2, indicating a primarily paracellular route of transport. However, serosal-to-mucosal permeability was insensitive to resistance changes, consistent with a primarily transcellular route in this direction. These data indicate that ranitidine and cimetidine can act as substrates for intestinal P-gp and suggest that the balance between absorptive and secretory mechanisms as a factor in determining intestinal absorption needs to be a routine consideration even for compounds expected to have a predominantly paracellular route of absorption.

Footnotes

  • Send reprint requests to: Dr. Geoffrey Warhurst, Department of Medicine, Clinical Sciences Building, Hope Hospital, Salford M6 8HD, UK.

  • ↵1 This work was supported by GlaxoWellcome Research and Development.

  • Abbreviations:
    P-gp
    P-glycoprotein
    MDR
    multidrug resistance
    MRP
    multidrug-related protein
    Rt
    transepithelial electrical resistance, PD, potential difference
    TEA
    tetraethylammonium
    • Received February 17, 1998.
    • Accepted July 10, 1998.
  • 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: 288 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 1
1 Jan 1999
  • 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.
Modulation of the Permeability of H2 Receptor Antagonists Cimetidine and Ranitidine by P-Glycoprotein in Rat Intestine and the Human Colonic Cell Line Caco-2
(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 ArticleArticle

Modulation of the Permeability of H2 Receptor Antagonists Cimetidine and Ranitidine by P-Glycoprotein in Rat Intestine and the Human Colonic Cell Line Caco-2

A. Collett, N. B. Higgs, E. Sims, M. Rowland and G. Warhurst
Journal of Pharmacology and Experimental Therapeutics January 1, 1999, 288 (1) 171-178;

Citation Manager Formats

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

Modulation of the Permeability of H2 Receptor Antagonists Cimetidine and Ranitidine by P-Glycoprotein in Rat Intestine and the Human Colonic Cell Line Caco-2

A. Collett, N. B. Higgs, E. Sims, M. Rowland and G. Warhurst
Journal of Pharmacology and Experimental Therapeutics January 1, 1999, 288 (1) 171-178;
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

  • CRV431 Decreases Liver Fibrosis and Tumor Development
  • Effects of Antidepressants and Benzodiazepine-Type Anxiolytic Agents on Hepatic Porphyrin Accumulation in Primary Cultures of Chick Embryo Liver Cells
  • Interaction of Diclofenac and Quinidine in Monkeys: Stimulation of Diclofenac Metabolism
Show more Article

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