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 ArticlePerspective

The Conduct of in Vitro Studies to Address Time-Dependent Inhibition of Drug-Metabolizing Enzymes: A Perspective of the Pharmaceutical Research and Manufacturers of America

Scott W. Grimm, Heidi J. Einolf, Steven D. Hall, Kan He, Heng-Keang Lim, Kah-Hiing John Ling, Chuang Lu, Amin A. Nomeir, Eleanore Seibert, Konstantine W. Skordos, George R. Tonn, Robert Van Horn, Regina W. Wang, Y. Nancy Wong, Tian J. Yang and R. Scott Obach
Drug Metabolism and Disposition July 2009, 37 (7) 1355-1370; DOI: https://doi.org/10.1124/dmd.109.026716
Scott W. Grimm
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Heidi J. Einolf
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steven D. Hall
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kan He
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Heng-Keang Lim
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kah-Hiing John Ling
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chuang Lu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Amin A. Nomeir
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eleanore Seibert
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Konstantine W. Skordos
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
George R. Tonn
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert Van Horn
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Regina W. Wang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Y. Nancy Wong
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tian J. Yang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
R. Scott Obach
  • 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 inhibition (TDI) of cytochrome P450 (P450) enzymes caused by new molecular entities (NMEs) is of concern because such compounds can be responsible for clinically relevant drug-drug interactions (DDI). Although the biochemistry underlying mechanism-based inactivation (MBI) of P450 enzymes has been generally understood for several years, significant advances have been made only in the past few years regarding how in vitro time-dependent inhibition data can be used to understand and predict clinical DDI. In this article, a team of scientists from 16 pharmaceutical research organizations that are member companies of the Pharmaceutical Research and Manufacturers of America offer a discussion of the phenomenon of TDI with emphasis on the laboratory methods used in its measurement. Results of an anonymous survey regarding pharmaceutical industry practices and strategies around TDI are reported. Specific topics that still possess a high degree of uncertainty are raised, such as parameter estimates needed to make predictions of DDI magnitude from in vitro inactivation parameters. A description of follow-up mechanistic experiments that can be done to characterize TDI are described. A consensus recommendation regarding common practices to address TDI is included, the salient points of which include the use of a tiered approach wherein abbreviated assays are first used to determine whether NMEs demonstrate TDI or not, followed by more thorough inactivation studies for those that do to define the parameters needed for prediction of DDI.

Footnotes

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

  • doi:10.1124/dmd.109.026716.

  • ABBREVIATIONS: DDI, drug-drug interactions; PhRMA, Pharmaceutical Research and Manufacturers of America; FDA, Food and Drug Administration; P450, cytochrome P450; TDI, time-dependent inhibition; MBI; mechanism-based inactivation; MIC, metabolite-intermediate complex; NME, new molecular entity; IVIVE, in vitro-in vivo extrapolation; AUC, area under the curve; ADME, absorption, distribution, metabolism, and excretion; PK, pharmacokinetic; PBPK, physiologically based pharmacokinetics; MDMA, 3,4-methylenedioxymethamphetamine; SAR, structure activity relationships; HLM, human liver microsome.

    • Accepted April 7, 2009.
    • Received January 13, 2009.
  • 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 (7)
Drug Metabolism and Disposition
Vol. 37, Issue 7
1 Jul 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.
The Conduct of in Vitro Studies to Address Time-Dependent Inhibition of Drug-Metabolizing Enzymes: A Perspective of the Pharmaceutical Research and Manufacturers of America
(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 ArticlePerspective

The Conduct of in Vitro Studies to Address Time-Dependent Inhibition of Drug-Metabolizing Enzymes: A Perspective of the Pharmaceutical Research and Manufacturers of America

Scott W. Grimm, Heidi J. Einolf, Steven D. Hall, Kan He, Heng-Keang Lim, Kah-Hiing John Ling, Chuang Lu, Amin A. Nomeir, Eleanore Seibert, Konstantine W. Skordos, George R. Tonn, Robert Van Horn, Regina W. Wang, Y. Nancy Wong, Tian J. Yang and R. Scott Obach
Drug Metabolism and Disposition July 1, 2009, 37 (7) 1355-1370; DOI: https://doi.org/10.1124/dmd.109.026716

Citation Manager Formats

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

Share
Research ArticlePerspective

The Conduct of in Vitro Studies to Address Time-Dependent Inhibition of Drug-Metabolizing Enzymes: A Perspective of the Pharmaceutical Research and Manufacturers of America

Scott W. Grimm, Heidi J. Einolf, Steven D. Hall, Kan He, Heng-Keang Lim, Kah-Hiing John Ling, Chuang Lu, Amin A. Nomeir, Eleanore Seibert, Konstantine W. Skordos, George R. Tonn, Robert Van Horn, Regina W. Wang, Y. Nancy Wong, Tian J. Yang and R. Scott Obach
Drug Metabolism and Disposition July 1, 2009, 37 (7) 1355-1370; DOI: https://doi.org/10.1124/dmd.109.026716
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
    • The Science of Time-Dependent Inhibition and Predicting DDI
    • Results of the PhRMA Survey
    • Experimental Approaches for TDI Studies: Recommendations
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Regulatory Guidance for P450 Induction from IQ: Part 3
  • Prioritizing NPs as precipitants of NPDIs
  • Regulatory Guidance for P450 Induction from IQ
Show more Perspective

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