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

Physiologically Based Pharmacokinetic Modeling of Intestinal First-Pass Metabolism of CYP3A Substrates with High Intestinal Extraction

Michael Gertz, J. Brian Houston and Aleksandra Galetin
Drug Metabolism and Disposition September 2011, 39 (9) 1633-1642; DOI: https://doi.org/10.1124/dmd.111.039248
Michael Gertz
  • 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
Aleksandra Galetin
  • 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

Abstract

Prediction of intestinal availability (FG), in conjunction with hepatic metabolism, is of considerable importance in drug disposition to assess oral clearance and liability to drug-drug interactions. In the current study, FG predictions were performed within a physiologically based pharmacokinetic (PBPK) model using in vitro permeability and clearance data. The prediction success was assessed in comparison with the QGut model. In addition, apparent oral clearance values, predicted using the PBPK model, were compared with in vivo observations from meta-analyses. Finally, unbound intrinsic clearance values (CLuint) were determined for 12 CYP3A substrates in eight individual human jejunal microsome (HJM) samples to assess interindividual variability in intestinal intrinsic clearance and subsequent FG predictions. Overall, the PBPK model improved FG predictions in comparison with the QGut model; this was apparent by a reduced bias and increased precision. In particular, FG predictions of indinavir, saquinavir, and terfenadine were model-dependent. The predicted oral clearance values of the drugs investigated ranged from 8.79 to 6320 l/h for tacrolimus and simvastatin, respectively, and were overall within 3-fold of the observed data with the exception of indinavir, atorvastatin, and buspirone. The individual HJM CLuint values ranged from 17 to 14,000 μl · min−1 · mg−1 for atorvastatin and saquinavir, respectively, and corresponding interindividual variability in CLuint estimates ranged from 41 to 67%. These in vitro data resulted in predicted FG values ranging from 0.03 to 0.94 for simvastatin and indinavir, respectively. The largest interindividual variability of FG was predicted for terfenadine (65%) in contrast with the low variability in the case of indinavir (3%).

Footnotes

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

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

    doi:10.1124/dmd.111.039248.

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

  • ABBREVIATIONS:

    FG
    intestinal availability
    QGut
    hybrid parameter of enterocytic blood flow and drug permeability
    PBPK
    physiologically based pharmacokinetic
    HJM
    human jejunal microsomes
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    MDCK-MDR1
    Madin-Darby canine kidney cells transfected with human MDR1 gene
    CL
    clearance
    fu
    fraction unbound
    HIM
    human intestinal microsomes
    HLM
    human liver microsomes
    CV
    coefficient of variation.

  • Received March 2, 2011.
  • Accepted June 1, 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 (9)
Drug Metabolism and Disposition
Vol. 39, Issue 9
1 Sep 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.
Physiologically Based Pharmacokinetic Modeling of Intestinal First-Pass Metabolism of CYP3A Substrates with High Intestinal Extraction
(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

Physiologically Based Pharmacokinetic Modeling of Intestinal First-Pass Metabolism of CYP3A Substrates with High Intestinal Extraction

Michael Gertz, J. Brian Houston and Aleksandra Galetin
Drug Metabolism and Disposition September 1, 2011, 39 (9) 1633-1642; DOI: https://doi.org/10.1124/dmd.111.039248

Citation Manager Formats

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

Share
Research ArticleArticle

Physiologically Based Pharmacokinetic Modeling of Intestinal First-Pass Metabolism of CYP3A Substrates with High Intestinal Extraction

Michael Gertz, J. Brian Houston and Aleksandra Galetin
Drug Metabolism and Disposition September 1, 2011, 39 (9) 1633-1642; DOI: https://doi.org/10.1124/dmd.111.039248
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

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

Related Articles

Cited By...

More in this TOC Section

  • Oral PBPK Modeling of Vismodegib
  • Transporter-enzyme interplay in PK of PF-06835919
  • PBPK Model of Vit D3 and Metabolites
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 © 2022 by the American Society for Pharmacology and Experimental Therapeutics