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
  • 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
    • 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

Prediction of Human Drug-Drug Interactions from Time-Dependent Inactivation of CYP3A4 in Primary Hepatocytes Using a Population-Based Simulator

Lilly Xu, Yuping Chen, Yvonne Pan, Gary L. Skiles and Magang Shou
Drug Metabolism and Disposition December 2009, 37 (12) 2330-2339; DOI: https://doi.org/10.1124/dmd.108.025494
Lilly Xu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yuping Chen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yvonne Pan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gary L. Skiles
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Magang Shou
  • 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

Time-dependent inactivation (TDI) of human cytochromes P450 3A4 (CYP3A4) is a major cause of clinical drug-drug interactions (DDIs). Human liver microsomes (HLM) are commonly used as an enzyme source for evaluating the inhibition of CYP3A4 by new chemical entities. The inhibition data can then be extrapolated to assess the risk of human DDIs. Using this approach, under- and overpredictions of in vivo DDIs have been observed. In the present study, human hepatocytes were used as an alternative to HLM. Hepatocytes incorporate the effects of other mechanisms of drug metabolism and disposition (i.e., phase II enzymes and transporters) that may modulate the effects of TDI on clinical DDIs. The in vitro potency (KI and kinact) of five known CYP3A4 TDI drugs (clarithromycin, diltiazem, erythromycin, verapamil, and troleandomycin) was determined in HLM (pooled, n = 20) and hepatocytes from two donors (D1 and D2), and the results were extrapolated to predict in vivo DDIs using a Simcyp population trial-based simulator. Compared with observed DDIs, the predictions derived from HLM appeared to be overestimated. The predictions based on TDI measured in hepatocytes were better correlated with the DDIs (n = 37) observed in vivo (R2 = 0.601 for D1 and 0.740 for D2) than those from HLM (R2 = 0.451). In addition, with the use of hepatocytes a greater proportion of the predictions were within a 2-fold range of the clinical DDIs compared with using HLM. These results suggest that DDI predictions from CYP3A4 TDI kinetics in hepatocytes could provide an alternative approach to balance HLM-based predictions that can sometimes substantially overestimate DDIs and possibly lead to erroneous conclusions about clinical risks.

Footnotes

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

    doi:10.1124/dmd.108.025494

  • DDI
    drug-drug interaction
    P450
    cytochrome P450
    TDI
    time-dependent inactivation
    HLM
    human liver microsomes
    IVIVE
    in vitro-in vivo extrapolation
    PK
    pharmacokinetic
    CLA
    clarithromycin
    DIL
    diltiazem
    ERY
    erythromycin
    VER
    verapamil
    TAO
    troleandomycin
    ABT
    1-aminobenzotriazole
    KHB
    Krebs-Henseleit buffer
    MDZ
    midazolam
    1-OH-MDZ
    1-hydroxymidazolam
    LC
    liquid chromatography
    MS
    mass spectrometry
    MS/MS
    tandem mass spectrometry
    ANOVA
    analysis of variance
    ADME
    absorption, distribution, metabolism, and excretion
    RMRSS
    root mean residual sum of square
    MRS
    mean residual sum
    AUC
    area under the curve.

    • Received November 3, 2008.
    • Accepted September 16, 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.
Prediction of Human Drug-Drug Interactions from Time-Dependent Inactivation of CYP3A4 in Primary Hepatocytes Using a Population-Based Simulator
(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

Prediction of Human Drug-Drug Interactions from Time-Dependent Inactivation of CYP3A4 in Primary Hepatocytes Using a Population-Based Simulator

Lilly Xu, Yuping Chen, Yvonne Pan, Gary L. Skiles and Magang Shou
Drug Metabolism and Disposition December 1, 2009, 37 (12) 2330-2339; DOI: https://doi.org/10.1124/dmd.108.025494

Citation Manager Formats

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

Share
Research ArticleArticle

Prediction of Human Drug-Drug Interactions from Time-Dependent Inactivation of CYP3A4 in Primary Hepatocytes Using a Population-Based Simulator

Lilly Xu, Yuping Chen, Yvonne Pan, Gary L. Skiles and Magang Shou
Drug Metabolism and Disposition December 1, 2009, 37 (12) 2330-2339; DOI: https://doi.org/10.1124/dmd.108.025494
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
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments.
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Series-Compartment Models of Hepatic Elimination
  • Warfarin PBPK Model with TMDD Mechanism
  • Identification of payload-containing catabolites of ADCs
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