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
  • 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
    • 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

Metabolism of the Active Metabolite of Quetiapine, N-Desalkylquetiapine In Vitro

Gry Vibeke Bakken, Espen Molden, Karoline Knutsen, Niclas Lunder and Monica Hermann
Drug Metabolism and Disposition September 2012, 40 (9) 1778-1784; DOI: https://doi.org/10.1124/dmd.112.045237
Gry Vibeke Bakken
Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway (G.V.B., E.M., N.L., M.H.); and Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway (E.M., K.K., M.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Espen Molden
Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway (G.V.B., E.M., N.L., M.H.); and Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway (E.M., K.K., M.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Karoline Knutsen
Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway (G.V.B., E.M., N.L., M.H.); and Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway (E.M., K.K., M.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Niclas Lunder
Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway (G.V.B., E.M., N.L., M.H.); and Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway (E.M., K.K., M.H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Monica Hermann
Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway (G.V.B., E.M., N.L., M.H.); and Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway (E.M., K.K., M.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
Loading

Abstract

The antipsychotic drug quetiapine has been approved for the treatment of unipolar and bipolar depression. The antidepressant activity is considered to be mediated by the active metabolite N-desalkylquetiapine, which is mainly formed by CYP3A4. Little is known about the subsequent elimination of this metabolite. Therefore, this study investigated the possible involvement of cytochrome P450 (P450) enzymes in the metabolism of N-desalkylquetiapine. Screening for and interpretation of metabolites were performed by incubating N-desalkylquetiapine in human liver microsomes (HLM) followed by liquid chromatography-tandem mass spectrometry. The possible involvement of P450 enzymes in N-desalkylquetiapine metabolism was evaluated by coincubation of selective P450 inhibitors in HLM and subsequent experiments with recombinant human P450 enzymes. In HLM experiments, three chromatographic peaks were interpreted as possible metabolites of N-desalkylquetiapine, namely, N-desalkylquetiapine sulfoxide, 7-hydroxy-N-desalkylquetiapine, and an unrecognized metabolite (denoted M3). Inhibition of CYP2D6 (by quinidine) reduced formation of 7-hydroxy-N-desalkylquetiapine by 81%, whereas the CYP3A4 inhibitor ketoconazole inhibited formation of N-desalkylquetiapine sulfoxide and M3 by 65 and 34%, respectively. Inhibitors of CYP1A2, CYP2C9, and CYP2C19 showed only limited changes in metabolite formation. In recombinant systems, 7-hydroxy-N-desalkylquetiapine was exclusively formed by CYP2D6, whereas N-desalkylquetiapine sulfoxide and M3 were formed by both CYP3A4 and CYP2D6. Overall, intrinsic clearance of N-desalkylquetiapine was 12-fold higher by recombinant CYP2D6 relative to CYP3A4. In conclusion, N-desalkylquetiapine is metabolized by both CYP2D6 and CYP3A4 in vitro with preference for the former enzyme. The pharmacologically active metabolite, 7-hydroxy-N-desalkylquetiapine, was exclusively formed by CYP2D6, whereas the two other metabolites were mainly formed by CYP3A4.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.112.045237.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    M
    metabolite
    CLint
    intrinsic clearance
    HLM
    human liver microsomes
    CI
    confidence interval
    IS
    internal standard.

  • Received February 29, 2012.
  • Accepted June 11, 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.
Metabolism of the Active Metabolite of Quetiapine, N-Desalkylquetiapine In Vitro
(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

METABOLISM OF N-DESALKYLQUETIAPINE IN VITRO

Gry Vibeke Bakken, Espen Molden, Karoline Knutsen, Niclas Lunder and Monica Hermann
Drug Metabolism and Disposition September 1, 2012, 40 (9) 1778-1784; DOI: https://doi.org/10.1124/dmd.112.045237

Citation Manager Formats

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

METABOLISM OF N-DESALKYLQUETIAPINE IN VITRO

Gry Vibeke Bakken, Espen Molden, Karoline Knutsen, Niclas Lunder and Monica Hermann
Drug Metabolism and Disposition September 1, 2012, 40 (9) 1778-1784; DOI: https://doi.org/10.1124/dmd.112.045237
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
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Authorship Contributions
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • 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