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

Bioactivation of Flutamide Metabolites by Human Liver Microsomes

Ping Kang, Deepak Dalvie, Evan Smith, Sue Zhou, Alan Deese and James A. Nieman
Drug Metabolism and Disposition July 2008, 36 (7) 1425-1437; DOI: https://doi.org/10.1124/dmd.108.020370
Ping Kang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Deepak Dalvie
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Evan Smith
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sue Zhou
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alan Deese
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
James A. Nieman
  • 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

Flutamide, a widely used nonsteroidal antiandrogen drug for the treatment of prostate cancer, has been associated with rare incidences of hepatotoxicity in patients. It is believed that bioactivation of flutamide and subsequent covalent binding to cellular proteins is responsible for its toxicity. A novel N-S glutathione adduct has been identified in a previous bioactivation study of flutamide (Kang et al., 2007). Due to the extensive first pass metabolism, flutamide metabolites such as 2-hydroxyflutamide and 4-nitro-3-(trifluoromethyl)phenylamine (Flu-1) have achieved plasma concentrations higher than the parent in prostate cancer patients. In vitro studies in human liver microsomes were conducted to probe the cytochrome P450 (P450)-mediated bioactivation of flutamide metabolites and identify the possible reactive species using reduced glutathione (GSH) as a trapping agent. Several GSH adducts (G1, Flu-1-G1, Flu-1-G2, Flu-6-Gs) derived from the metabolites of flutamide were identified and characterized. A comprehensive bioactivation mechanism was proposed to account for the formation of the observed GSH adducts. Of interest were the formation of a reactive intermediate by the desaturation of the isopropyl group of M5 and the unusual bioactivation of Flu-1. Studies using recombinant P450s suggested that the major P450 isozymes involved in the bioactivation of flutamide and its metabolites were CYP1A2, CYP3A4, and CYP2C19. These findings suggested that, in addition to the direct bioactivation of flutamide, the metabolites of flutamide could also be bioactivated and contribute to flutamide-induced hepatotoxicity.

Footnotes

  • Part of this work was presented at the 8th International ISSX Meeting, Sendai, Japan, October 9–12, 2007.

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

  • doi:10.1124/dmd.108.020370.

  • ABBREVIATIONS: flutamide, 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide; P450, cytochrome P450; Flu-1, 4-nitro-3-(trifluoromethyl)phenylamine; Flu-2, N-[4-nitro-3-(trifluoromethyl)phenyl]-acetamide; Flu-1-N-OH, N-[4-nitro-3-(trifluoromethyl)phenyl]hydroxylamine; Flu-6, 2-methyl-N-[4-amino-3-(trifluoromethyl)phenyl]-propanamide; GSH, reduced glutathione; ESI, electrospray ionization; LC/MS, liquid chromatography/mass spectrometry; amu, atomic mass unit; NMR, nuclear magnetic resonance; HPLC, high-performance liquid chromatography; COSY, correlation spectroscopy; DCM, dichloromethane.

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

  • ↵1 Current affiliation: Genentech, Inc., South San Francisco, CA.

    • Received January 7, 2008.
    • Accepted April 11, 2008.
  • 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: 36 (7)
Drug Metabolism and Disposition
Vol. 36, Issue 7
1 Jul 2008
  • 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.
Bioactivation of Flutamide Metabolites by Human Liver Microsomes
(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

Bioactivation of Flutamide Metabolites by Human Liver Microsomes

Ping Kang, Deepak Dalvie, Evan Smith, Sue Zhou, Alan Deese and James A. Nieman
Drug Metabolism and Disposition July 1, 2008, 36 (7) 1425-1437; DOI: https://doi.org/10.1124/dmd.108.020370

Citation Manager Formats

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

Share
Research ArticleArticle

Bioactivation of Flutamide Metabolites by Human Liver Microsomes

Ping Kang, Deepak Dalvie, Evan Smith, Sue Zhou, Alan Deese and James A. Nieman
Drug Metabolism and Disposition July 1, 2008, 36 (7) 1425-1437; DOI: https://doi.org/10.1124/dmd.108.020370
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
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Determination of Acyl-, O-, and N-Glucuronide
  • TMDD Affects PK of IL-10 Fc-fusion Proteins
  • Uptake as the RDS in Pevonedistat Hepatic 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 © 2022 by the American Society for Pharmacology and Experimental Therapeutics