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 ArticleSpecial Section on Prediction of Human Pharmacokinetic Parameters from In Vitro Systems

Stereoselective Inhibition of CYP2C19 and CYP3A4 by Fluoxetine and Its Metabolite: Implications for Risk Assessment of Multiple Time-Dependent Inhibitor Systems

Justin D. Lutz, Brooke M. VandenBrink, Katipudi N. Babu, Wendel L. Nelson, Kent L. Kunze and Nina Isoherranen
Drug Metabolism and Disposition December 2013, 41 (12) 2056-2065; DOI: https://doi.org/10.1124/dmd.113.052639
Justin D. Lutz
Department of Pharmaceutics (J.D.L., N.I.) and Department of Medicinal Chemistry (B.M.V., K.N.B., W.L.N., K.L.K.), School of Pharmacy, University of Washington, Seattle, Washington
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Brooke M. VandenBrink
Department of Pharmaceutics (J.D.L., N.I.) and Department of Medicinal Chemistry (B.M.V., K.N.B., W.L.N., K.L.K.), School of Pharmacy, University of Washington, Seattle, Washington
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Katipudi N. Babu
Department of Pharmaceutics (J.D.L., N.I.) and Department of Medicinal Chemistry (B.M.V., K.N.B., W.L.N., K.L.K.), School of Pharmacy, University of Washington, Seattle, Washington
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wendel L. Nelson
Department of Pharmaceutics (J.D.L., N.I.) and Department of Medicinal Chemistry (B.M.V., K.N.B., W.L.N., K.L.K.), School of Pharmacy, University of Washington, Seattle, Washington
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kent L. Kunze
Department of Pharmaceutics (J.D.L., N.I.) and Department of Medicinal Chemistry (B.M.V., K.N.B., W.L.N., K.L.K.), School of Pharmacy, University of Washington, Seattle, Washington
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nina Isoherranen
Department of Pharmaceutics (J.D.L., N.I.) and Department of Medicinal Chemistry (B.M.V., K.N.B., W.L.N., K.L.K.), School of Pharmacy, University of Washington, Seattle, Washington
  • 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

Recent guidance on drug-drug interaction (DDI) testing recommends evaluation of circulating metabolites. However, there is little consensus on how to quantitatively predict and/or assess the risk of in vivo DDIs by multiple time-dependent inhibitors (TDIs) including metabolites from in vitro data. Fluoxetine was chosen as the model drug to evaluate the role of TDI metabolites in DDI prediction because it is a TDI of both CYP3A4 and CYP2C19 with a circulating N-dealkylated inhibitory metabolite, norfluoxetine. In pooled human liver microsomes, both enantiomers of fluoxetine and norfluoxetine were TDIs of CYP2C19, (S)-norfluoxetine was the most potent inhibitor with time-dependent inhibition affinity constant (KI) of 7 μM, and apparent maximum time-dependent inhibition rate (kinact,app) of 0.059 min−1. Only (S)-fluoxetine and (R)-norfluoxetine were TDIs of CYP3A4, with (R)-norfluoxetine being the most potent (KI = 8 μM, and kinact,app = 0.011 min−1). Based on in-vitro-to-in-vivo predictions, (S)-norfluoxetine plays the most important role in in vivo CYP2C19 DDIs, whereas (R)-norfluoxetine is most important in CYP3A4 DDIs. Comparison of two multiple TDI prediction models demonstrated significant differences between them in in-vitro-to-in-vitro predictions but not in in-vitro-to-in-vivo predictions. Inclusion of all four inhibitors predicted an in vivo decrease in CYP2C19 (95%) and CYP3A4 (60–62%) activity. The results of this study suggest that adequate worst-case risk assessment for in vivo DDIs by multiple TDI systems can be achieved by incorporating time-dependent inhibition by both parent and metabolite via simple addition of the in vivo time-dependent inhibition rate/cytochrome P450 degradation rate constant (λ/kdeg) values, but quantitative DDI predictions will require a more thorough understanding of TDI mechanisms.

Footnotes

    • Received April 30, 2013.
    • Accepted June 19, 2013.
  • ↵1 Current affiliation: Amgen, Inc., Seattle, Washington.

  • ↵2 Current affiliation: Sri Lakshmi Barghavi Pharma, Pvt. Ltd., Pashamylaram, India.

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants P01 GM32165 and T32 GM007750].

  • dx.doi.org/10.1124/dmd.113.052639.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 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: 41 (12)
Drug Metabolism and Disposition
Vol. 41, Issue 12
1 Dec 2013
  • 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.
Stereoselective Inhibition of CYP2C19 and CYP3A4 by Fluoxetine and Its Metabolite: Implications for Risk Assessment of Multiple Time-Dependent Inhibitor Systems
(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 ArticleSpecial Section on Prediction of Human Pharmacokinetic Parameters from In Vitro Systems

Prediction of Fluoxetine Drug-Drug Interactions

Justin D. Lutz, Brooke M. VandenBrink, Katipudi N. Babu, Wendel L. Nelson, Kent L. Kunze and Nina Isoherranen
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2056-2065; DOI: https://doi.org/10.1124/dmd.113.052639

Citation Manager Formats

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

Share
Research ArticleSpecial Section on Prediction of Human Pharmacokinetic Parameters from In Vitro Systems

Prediction of Fluoxetine Drug-Drug Interactions

Justin D. Lutz, Brooke M. VandenBrink, Katipudi N. Babu, Wendel L. Nelson, Kent L. Kunze and Nina Isoherranen
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2056-2065; DOI: https://doi.org/10.1124/dmd.113.052639
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
    • Materials and Methods
    • Results
    • Discussion
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Clearance Prediction Using HepatoPac
  • In Vitro–In Vivo Correlation of P-gp Efflux Ratio
  • Heterotropic Activation of CYP3A by a Novel mGlu5 PAM
Show more Special Section on Prediction of Human Pharmacokinetic Parameters from In Vitro Systems

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