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
Drug Metabolism & Disposition
  • 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
Drug Metabolism & Disposition

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 dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

Kinetic Characterization of Rat Hepatic Uptake of 16 Actively Transported Drugs

Yoshiyuki Yabe, Aleksandra Galetin and J. Brian Houston
Drug Metabolism and Disposition October 2011, 39 (10) 1808-1814; DOI: https://doi.org/10.1124/dmd.111.040477
Yoshiyuki Yabe
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Aleksandra Galetin
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
J. Brian Houston
  • 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

To explore the determinants of hepatic uptake, 16 compounds were investigated with different physicochemical and disposition characteristics, including five statins, three sartans, saquinavir, ritonavir, erythromycin, clarithromycin, nateglinide, repaglinide, fexofenadine, and bosentan. Freshly isolated rat hepatocytes in suspension were used with the oil-spin method to generate kinetic parameters. Clearances, via passive diffusion (Pdiff) and active uptake (CLactive, characterized by maximal uptake rate and Km), were estimated from the initial uptake rate data over a 0.01 to 100 μM concentration range. The Km values had a range of 15-fold, with 10 of the 16 drugs with Km < 10 μM (median 6 μM). Both CLactive and Pdiff ranged over 100-fold (median 188 and 14 μl/min/106 cells). Assessment of the relative contribution of Pdiff and CLactive indicated that, at low concentrations (approximately 0.1 μM), the active process contributes >80% to the overall uptake for 13 drugs. Although high Pdiff values were obtained for ritonavir and repaglinide, active process contributed predominantly to uptake; in contrast, high passive permeability dominates over transporter-mediated uptake for saquinavir over the full concentration range. For bosentan and erythromycin, active and passive processes were equally important. Hepatocyte-to-medium unbound concentration ratio was >10 for 9 of the 16 drugs, ranging from 2 to 494 for bosentan and atorvastatin, respectively. Some drugs showed extensive intracellular binding (fraction unbound range 0.01–0.6), which was not correlated with active uptake. LogD7.4 correlated significantly with Pdiff and the extent of intracellular binding but not with active uptake. This study provides systematic assessment of the role of active uptake relative to the passive process; implications of the findings are discussed.

Footnotes

  • This work was partially funded by a consortium of pharmaceutical companies (GlaxoSmithKline, Lilly, Novartis, Pfizer, and Servier) within the Centre for Applied Pharmacokinetic Research at the University of Manchester and Daiichi-Sankyo Ltd.

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

    doi:10.1124/dmd.111.040477.

  • ABBREVIATIONS:

    ABT
    1-aminobenzotriazole
    OATP
    organic anion transporter polypeptide
    LC-MS/MS
    liquid chromatography-mass spectrometry/mass spectrometry
    CLactive
    clearance by active uptake
    CLint
    intrinsic clearance
    CLuptake
    total clearance by active and passive uptake
    fucell
    intracellular fraction of unbound drug
    Kptotal
    hepatocyte-to-medium total drug concentration ratio
    Kpu
    hepatocyte-to-medium unbound drug concentration ratio
    Kpi
    measure of total cellular drug concentration relative to cytosolic drug concentration
    Pdiff
    passive uptake clearance
    P450
    cytochrome P450.

  • Received May 6, 2011.
  • Accepted June 28, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

 

DMD 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

Drug Metabolism and Disposition: 39 (10)
Drug Metabolism and Disposition
Vol. 39, Issue 10
1 Oct 2011
  • 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 Drug Metabolism & Disposition 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.
Kinetic Characterization of Rat Hepatic Uptake of 16 Actively Transported Drugs
(Your Name) has forwarded a page to you from Drug Metabolism & Disposition
(Your Name) thought you would be interested in this article in Drug Metabolism & Disposition.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

HEPATOCELLULAR UPTAKE OF 16 DRUGS IN RAT HEPATOCYTES

Yoshiyuki Yabe, Aleksandra Galetin and J. Brian Houston
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1808-1814; DOI: https://doi.org/10.1124/dmd.111.040477

Citation Manager Formats

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

Share
Research ArticleArticle

HEPATOCELLULAR UPTAKE OF 16 DRUGS IN RAT HEPATOCYTES

Yoshiyuki Yabe, Aleksandra Galetin and J. Brian Houston
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1808-1814; DOI: https://doi.org/10.1124/dmd.111.040477
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Results
    • Discussion
    • Authorship Contributions
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Expression of AKR and SDR Isoforms in the Human Intestine
  • Factors Affecting Drug Metabolism by AO
  • Interaction of Human OATP1B1 with PDZK1
Show more Articles

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

ASPET's Other Journals

  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-009X (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics