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

Metabolic Intermediate Complex Formation of Human Cytochrome P450 3A4 by Lapatinib

Hideo Takakusa, Michelle D. Wahlin, Chunsheng Zhao, Kelsey L. Hanson, Lee Sun New, Eric Chun Yong Chan and Sidney D. Nelson
Drug Metabolism and Disposition June 2011, 39 (6) 1022-1030; DOI: https://doi.org/10.1124/dmd.110.037531
Hideo Takakusa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michelle D. Wahlin
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chunsheng Zhao
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kelsey L. Hanson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lee Sun New
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eric Chun Yong Chan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sidney D. Nelson
  • 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

Lapatinib, an oral breast cancer drug, has recently been reported to be a mechanism-based inactivator of cytochrome P450 (P450) 3A4 and also an idiosyncratic hepatotoxicant. It was suggested that formation of a reactive quinoneimine metabolite was involved in mechanism-based inactivation (MBI) and/or hepatotoxicity. We investigated the mechanism of MBI of P450 3A4 by lapatinib. Liquid chromatography-mass spectrometry analysis of P450 3A4 after incubation with lapatinib did not show any peak corresponding to irreversible modifications. The enzymatic activity inactivated by lapatinib was completely restored by the addition of potassium ferricyanide. These results indicate that the mechanism of MBI by lapatinib is quasi-irreversible and mediated via metabolic intermediate complex (MI complex) formation. This finding was verified by the increase in a signature Soret absorbance at approximately 455 nm. Two amine oxidation products of the metabolism of lapatinib by P450 3A4 were characterized: N-hydroxy lapatinib (M3) and the oxime form of N-dealkylated lapatinib (M2), suggesting that a nitroso or another related intermediate generated from M3 is involved in MI complex formation. In contrast, P450 3A5 was much less susceptible to MBI by lapatinib via MI complex formation than P450 3A4. In addition, P450 3A5 had a significantly lower ability than 3A4 to generate M3, consistent with N-hydroxylation as the initial step in the pathway to MI complex formation. In conclusion, our results demonstrate that the primary mechanism for MBI of P450 3A4 by lapatinib is not irreversible modification by the quinoneimine metabolite, but quasi-irreversible MI complex formation mediated via oxidation of the secondary amine group of lapatinib.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of General Medical Sciences [GM32165]; the Eli Lilly Foundation (to M.D.W.); and Daiichi Sankyo Co., Ltd. (to H.T.).

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

    doi:10.1124/dmd.110.037531.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    DDI
    drug-drug interaction
    MI complex
    metabolic-intermediate complex
    LC
    liquid chromatography
    MBI
    mechanism-based inactivation
    LC
    liquid chromatography
    MS
    mass spectrometry
    ESI
    electrospray ionization
    HLMs
    human liver microsomes
    KPi
    potassium phosphate
    MS/MS
    tandem mass spectrometry.

  • Received December 3, 2010.
  • Accepted February 28, 2011.
  • Copyright © 2011 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: 39 (6)
Drug Metabolism and Disposition
Vol. 39, Issue 6
1 Jun 2011
  • 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.
Metabolic Intermediate Complex Formation of Human Cytochrome P450 3A4 by Lapatinib
(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

Metabolic Intermediate Complex Formation of Human Cytochrome P450 3A4 by Lapatinib

Hideo Takakusa, Michelle D. Wahlin, Chunsheng Zhao, Kelsey L. Hanson, Lee Sun New, Eric Chun Yong Chan and Sidney D. Nelson
Drug Metabolism and Disposition June 1, 2011, 39 (6) 1022-1030; DOI: https://doi.org/10.1124/dmd.110.037531

Citation Manager Formats

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

Metabolic Intermediate Complex Formation of Human Cytochrome P450 3A4 by Lapatinib

Hideo Takakusa, Michelle D. Wahlin, Chunsheng Zhao, Kelsey L. Hanson, Lee Sun New, Eric Chun Yong Chan and Sidney D. Nelson
Drug Metabolism and Disposition June 1, 2011, 39 (6) 1022-1030; DOI: https://doi.org/10.1124/dmd.110.037531
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
    • Results
    • Discussion
    • Authorship Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Ozanimod human metabolism and Disposition
  • High-throughput Characterization of SLCO1B1 Variants of VUS.
  • Poria cocos triterpenes as bile acid transporter inhibitors
Show more Articles

Similar Articles

  • 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