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

Progress Curve Mechanistic Modeling Approach for Assessing Time-Dependent Inhibition of CYP3A4

Howard J. Burt, Henry Pertinez, Carolina Säll, Claire Collins, Ruth Hyland, J. Brian Houston and Aleksandra Galetin
Drug Metabolism and Disposition September 2012, 40 (9) 1658-1667; DOI: https://doi.org/10.1124/dmd.112.046078
Howard J. Burt
Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom (H.J.B., H.P., C.S., J.B.H., A.G.); and Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Sandwich, Kent, United Kingdom (C.C., R.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Henry Pertinez
Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom (H.J.B., H.P., C.S., J.B.H., A.G.); and Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Sandwich, Kent, United Kingdom (C.C., R.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Carolina Säll
Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom (H.J.B., H.P., C.S., J.B.H., A.G.); and Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Sandwich, Kent, United Kingdom (C.C., R.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Claire Collins
Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom (H.J.B., H.P., C.S., J.B.H., A.G.); and Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Sandwich, Kent, United Kingdom (C.C., R.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ruth Hyland
Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom (H.J.B., H.P., C.S., J.B.H., A.G.); and Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Sandwich, Kent, United Kingdom (C.C., R.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
J. Brian Houston
Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom (H.J.B., H.P., C.S., J.B.H., A.G.); and Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Sandwich, Kent, United Kingdom (C.C., R.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Aleksandra Galetin
Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom (H.J.B., H.P., C.S., J.B.H., A.G.); and Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Sandwich, Kent, United Kingdom (C.C., R.H.)
  • 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

A progress curve method for assessing time-dependent inhibition of CYP3A4 is based on simultaneous quantification of probe substrate metabolite and inhibitor concentrations during the experiment. Therefore, it may overcome some of the issues associated with the traditional two-step method and estimation of inactivation rate (kinact) and irreversible inhibition (KI) constants. In the current study, seven time-dependent inhibitors were investigated using a progress curve method and recombinant CYP3A4. A novel mechanistic modeling approach was applied to determine inhibition parameters using both inhibitor and probe metabolite data. Progress curves generated for clarithromycin, erythromycin, diltiazem, and N-desmethyldiltiazem were described well by the mechanistic mechanism-based inhibition (MBI) model. In contrast, mibefradil, ritonavir, and verapamil required extension of the model and inclusion of competitive inhibition term for the metabolite. In addition, this analysis indicated that verapamil itself causes minimal MBI, and the formation of inhibitory metabolites was responsible for the irreversible loss of CYP3A4 activity. The kinact and KI estimates determined in the current study were compared with literature data generated using the conventional two-step method. In the current study, the inactivation efficiency (kinact/KI) for clarithromycin, ritonavir, and erythromycin were up to 7-fold higher, whereas kinact/KI for mibefradil, N-desmethyldiltiazem, and diltiazem were, on average, 2- to 4.8-fold lower than previously reported estimates. Use of human liver microsomes instead of recombinant CYP3A4 resulted in 5-fold lower kinact/KI for erythromycin. In conclusion, the progress curve method has shown a greater mechanistic insight when determining kinetic parameters for MBI in addition to providing a more comprehensive experimental protocol.

Footnotes

  • This work was supported by Pfizer Pharmacokinetics, Dynamics, and Metabolism at Department (Sandwich, UK) 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.

    http://dx.doi.org/10.1124/dmd.112.046078.

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

  • ABBREVIATIONS:

    MBI
    mechanism-based inhibition
    DDI
    drug-drug interaction
    P450
    cytochrome P450
    HLMs
    human liver microsomes
    fuinc
    fraction unbound in incubation
    MIC
    metabolite intermediate complex
    Km
    Michaelis-Menten constant
    kinact
    inactivation rate constant
    KI
    irreversible inhibition constant
    Ki
    reversible inhibition constant
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry.

  • Received April 5, 2012.
  • Accepted May 23, 2012.
  • Copyright © 2012 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: 40 (9)
Drug Metabolism and Disposition
Vol. 40, Issue 9
1 Sep 2012
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • 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.
Progress Curve Mechanistic Modeling Approach for Assessing Time-Dependent Inhibition of CYP3A4
(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

PROGRESS CURVE ASSESSMENT OF TIME-DEPENDENT INHIBITION

Howard J. Burt, Henry Pertinez, Carolina Säll, Claire Collins, Ruth Hyland, J. Brian Houston and Aleksandra Galetin
Drug Metabolism and Disposition September 1, 2012, 40 (9) 1658-1667; DOI: https://doi.org/10.1124/dmd.112.046078

Citation Manager Formats

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

Share
Research ArticleArticle

PROGRESS CURVE ASSESSMENT OF TIME-DEPENDENT INHIBITION

Howard J. Burt, Henry Pertinez, Carolina Säll, Claire Collins, Ruth Hyland, J. Brian Houston and Aleksandra Galetin
Drug Metabolism and Disposition September 1, 2012, 40 (9) 1658-1667; DOI: https://doi.org/10.1124/dmd.112.046078
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

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

Related Articles

Cited By...

More in this TOC Section

  • Ontogeny of CPPGL
  • Expression of AKR and SDR Isoforms in the Human Intestine
  • Metabolism of Lufotrelvir in Humans
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