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

Oxidation of a Metabolite of Indomethacin (Desmethyldeschlorobenzoylindomethacin) to Reactive Intermediates by Activated Neutrophils, Hypochlorous Acid, and the Myeloperoxidase System

C. Ju and J. P. Uetrecht
Drug Metabolism and Disposition July 1998, 26 (7) 676-680;
C. Ju
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
J. P. Uetrecht
  • 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 use of indomethacin is associated with a relatively high incidence of adverse reactions such as agranulocytosis. Many other drugs associated with agranulocytosis are metabolized to reactive metabolites by activated neutrophils. Therefore, we studied the oxidation of indomethacin and its metabolites by activated neutrophils, myeloperoxidase (MPO) (the major oxidizing enzyme in neutrophils), and HOCl (the major oxidant produced by activated neutrophils). No oxidation of indomethacin by activated neutrophils was observed. However, desmethyldeschlorobenzoylindomethacin (DMBI), a major metabolite of indomethacin, was oxidized to a reactive iminoquinone that could be trapped with glutathione (GSH) orN-acetylcysteine (NAC) to form conjugates, with MH+ ions at m/z 511 and 367, respectively. No metabolism was detected in neutrophils that had not been activated, and the oxidation was inhibited by azide (which inhibits MPO) and by catalase (which catalyzes the breakdown of H2O2). In reactions with HOCl, the same reactive intermediate was formed; its mass spectrum, with a MH+ ion at m/z204, was obtained by using a flow system in which the reactants were fed into a mixing chamber and the products flowed directly into the mass spectrometer. The same GSH and NAC conjugates were also observed when DMBI was oxidized by HOCl or by the MPO system, followed by addition of GSH or NAC. NMR data for the NAC conjugate indicated that the sulfur was substituted in the 4-position on the aromatic ring. The reactive intermediate generated from DMBI by activated neutrophils may be responsible for indomethacin-induced agranulocytosis.

Footnotes

  • Send reprint requests to: Dr. Jack Uetrecht, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada M5S 2S2.

  • This work was supported by the Medical Research Council of Canada (grant MT 13478). A preliminary report of this work was presented at the Society of Toxicology 36th Annual Meeting, Cincinnati, OH.

  • Abbreviations used are::
    MPO
    myeloperoxidase
    GSH
    glutathione
    NAC
    N-acetylcysteine
    DMBI
    desmethyldeschlorobenzoylindomethacin
    DMI
    O-desmethylindomethacin
    • Received November 12, 1997.
    • Accepted March 17, 1998.
  • 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
Vol. 26, Issue 7
1 Jul 1998
  • Table of Contents
  • Index by author
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.
Oxidation of a Metabolite of Indomethacin (Desmethyldeschlorobenzoylindomethacin) to Reactive Intermediates by Activated Neutrophils, Hypochlorous Acid, and the Myeloperoxidase System
(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

Oxidation of a Metabolite of Indomethacin (Desmethyldeschlorobenzoylindomethacin) to Reactive Intermediates by Activated Neutrophils, Hypochlorous Acid, and the Myeloperoxidase System

C. Ju and J. P. Uetrecht
Drug Metabolism and Disposition July 1, 1998, 26 (7) 676-680;

Citation Manager Formats

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

Share
Research ArticleArticle

Oxidation of a Metabolite of Indomethacin (Desmethyldeschlorobenzoylindomethacin) to Reactive Intermediates by Activated Neutrophils, Hypochlorous Acid, and the Myeloperoxidase System

C. Ju and J. P. Uetrecht
Drug Metabolism and Disposition July 1, 1998, 26 (7) 676-680;
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
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Human ADME Properties of Abrocitinib
  • MSCs Pharmacokinetics under liver diseases
  • In Vitro-In Vivo Extrapolation Using Empirical Scaling
Show more Article

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