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
  • Log out
  • 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
  • Log out
  • My Cart
Drug Metabolism & Disposition

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

Inhibition and Stimulation of Intestinal and Hepatic CYP3A Activity: Studies in Humanized CYP3A4 Transgenic Mice Using Triazolam

Robert A. B. van Waterschoot, Rogier W. Rooswinkel, Rolf W. Sparidans, Antonius E. van Herwaarden, Jos H. Beijnen and Alfred H. Schinkel
Drug Metabolism and Disposition December 2009, 37 (12) 2305-2313; DOI: https://doi.org/10.1124/dmd.109.029397
Robert A. B. van Waterschoot
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rogier W. Rooswinkel
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rolf W. Sparidans
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Antonius E. van Herwaarden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jos H. Beijnen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alfred H. Schinkel
  • 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

CYP3A4 is an important determinant of drug-drug interactions. In this study, we evaluated whether cytochrome P450 3A knockout mice [Cyp3a(−/−)] and CYP3A4 transgenic (CYP3A4-Tg) mice can be used to study drug-drug interactions in the liver and intestine. Triazolam was used as a probe drug because it is a highly specific CYP3A substrate and not a P-glycoprotein substrate. Triazolam metabolism was profoundly reduced in Cyp3a(−/−) mice both in vitro and in vivo. In vitro studies revealed clear species differences in humans and mice, but triazolam metabolism in microsomes derived from CYP3A4-Tg “humanized” mice closely resembled that in human microsomes. It is interesting to note that studies with tissue-specific CYP3A4-Tg mice revealed that intestinal CYP3A4 has a major impact on oral triazolam exposure, whereas the effect of hepatic CYP3A4 was limited. To mimic a drug-drug interaction, we coadministered triazolam with the prototypical CYP3A inhibitor ketoconazole, which increased triazolam exposure in all the CYP3A-proficient mouse strains but not in Cyp3a(−/−) mice. We further found that the anticancer drug gefitinib is a potent stimulator of 1′-OH triazolam formation in vitro. It is noteworthy that we could also show in vivo stimulation of triazolam metabolism by gefitinib, resulting in a lower oral triazolam exposure. To our knowledge, this is the first in vivo example of direct stimulation of CYP3A4 activity after oral drug administration. Overall, this study illustrates how Cyp3a(−/−) and CYP3A4-Tg mice can be used to study drug-drug interactions. The data clarify that for drugs that are not P-glycoprotein substrates, intestinal metabolism also can be more important than hepatic metabolism after oral administration.

Footnotes

  • This work was supported by the Technical Sciences Foundation of the Netherlands Organization for Scientific Research.

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

    doi:10.1124/dmd.109.029397

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

  • Cyp3a(−/−)
    cytochrome P450 3A knockout mice
    Tg
    transgenic
    P-gp
    P-glycoprotein
    P450
    cytochrome P450
    Cyp3a(−/−)Tg-3A4Hep
    Cyp3a knockout mice with liver-specific transgenic expression of human CYP3A4
    Cyp3a(−/−)Tg-3A4Int
    Cyp3a knockout mice with intestine-specific transgenic expression of human CYP3A4
    HPLC
    high-performance liquid chromatography
    PEG
    polyethylene glycol
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    AUC
    area under the curve.

    • Received July 13, 2009.
    • Accepted September 9, 2009.
  • Copyright © 2009 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: 37 (12)
Drug Metabolism and Disposition
Vol. 37, Issue 12
1 Dec 2009
  • 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.
Inhibition and Stimulation of Intestinal and Hepatic CYP3A Activity: Studies in Humanized CYP3A4 Transgenic Mice Using Triazolam
(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

Inhibition and Stimulation of Intestinal and Hepatic CYP3A Activity: Studies in Humanized CYP3A4 Transgenic Mice Using Triazolam

Robert A. B. van Waterschoot, Rogier W. Rooswinkel, Rolf W. Sparidans, Antonius E. van Herwaarden, Jos H. Beijnen and Alfred H. Schinkel
Drug Metabolism and Disposition December 1, 2009, 37 (12) 2305-2313; DOI: https://doi.org/10.1124/dmd.109.029397

Citation Manager Formats

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

Inhibition and Stimulation of Intestinal and Hepatic CYP3A Activity: Studies in Humanized CYP3A4 Transgenic Mice Using Triazolam

Robert A. B. van Waterschoot, Rogier W. Rooswinkel, Rolf W. Sparidans, Antonius E. van Herwaarden, Jos H. Beijnen and Alfred H. Schinkel
Drug Metabolism and Disposition December 1, 2009, 37 (12) 2305-2313; DOI: https://doi.org/10.1124/dmd.109.029397
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
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments.
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Retroconversion of PQ and Its N-Oxide Metabolites
  • Deoxycholate Oxidation Is Predictive of CYP3A Activity
  • REF vs RAF Prediction of Renal Clearance
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 © 2021 by the American Society for Pharmacology and Experimental Therapeutics