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
OtherArticle

Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics

Mary Alexandra Schleiff, Noah R. Flynn, Sasin Payakachat, Benjamin Mark Schleiff, Anna O. Pinson, Dennis W. Province, S. Joshua Swamidass, Gunnar Boysen and Grover P. Miller
Drug Metabolism and Disposition November 25, 2020, DMD-AR-2020-000254; DOI: https://doi.org/10.1124/dmd.120.000254
Mary Alexandra Schleiff
1Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, United States of America
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Noah R. Flynn
2Washington University - St. Louis, United States of America
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sasin Payakachat
3Chemistry, Hendrix College, United States of America
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Benjamin Mark Schleiff
4Independent Researcher, United States of America
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anna O. Pinson
5Chemistry and Biochemistry, Harding University, United States of America
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dennis W. Province
5Chemistry and Biochemistry, Harding University, United States of America
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
S. Joshua Swamidass
6Washington University - St Louis, United States of America
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gunnar Boysen
7Environmental & Occupational Health, University of Arkansas for Medical Sciences, United States of America
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Grover P. Miller
1Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, United States of America
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Grover P. Miller
  • For correspondence: millergroverp@uams.edu
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

Abstract

Meclofenamate is a non-steroidal anti-inflammatory drug used in the treatment of mild to moderate pain yet poses a rare risk of hepatotoxicity through an unknown mechanism. NSAID bioactivation is a common molecular initiating event for hepatotoxicity. Thus, we hypothesized a similar mechanism for meclofenamate and leveraged computational and experimental approaches to identify and characterize its bioactivation. Analyses employing our XenoNet model indicated possible pathways to meclofenamate bioactivation into 19 reactive metabolites subsequently trapped into glutathione adducts. We describe the first reported bioactivation kinetics for meclofenamate and relative importance of those pathways using human liver microsomes. The findings validated only four of the many bioactivation pathways predicted by modeling. For experimental studies, dansyl glutathione was a critical trap for reactive quinone metabolites and provided a way to characterize adduct structures by mass spectrometry and quantitate yields during reactions. Of the four quinone adducts, we were able to characterize structures for three of them. Based on kinetics, the most efficient bioactivation pathway led to the monohydroxy para-quinone-imine followed by the dechloro-ortho-quinone-imine. Two very inefficient pathways led to the dihydroxy ortho-quinone and a likely multiply adducted quinone. When taken together, bioactivation pathways for meclofenamate accounted for approximately 13% of total metabolism. In sum, XenoNet facilitated prediction of reactive metabolite structures while quantitative experimental studies provided a tractable approach to validate actual bioactivation pathways for meclofenamate. Our results provide a foundation for assessing reactive metabolite load more accurately for future comparative studies with other NSAIDs and drugs in general.

Significance Statement Meclofenamate bioactivation may initiate hepatotoxicity yet common risk assessment approaches are often cumbersome and inefficient and yield qualitative insights that do not scale relative bioactivation risks. We developed and applied innovative combined modeling and quantitative kinetics to identify and validate meclofenamate bioactivation pathways and relevance as a function of time and concentration. This strategy yielded novel insights on meclofenamate bioactivation and provides a tractable approach to more accurately and efficiently assess other drug bioactivations and correlate risks to toxicological outcomes.

  • bioactivation
  • computer modeling and simulation
  • Cytochrome P450 (CYP)
  • enzyme kinetics
  • glutathione conjugates
  • kinetic modeling
  • liver microsomes
  • non-steroidal anti-inflammatory drugs (NSAIDs)
  • reactive metabolites
  • © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.
PreviousNext
Back to top

In this issue

Drug Metabolism and Disposition: 49 (1)
Drug Metabolism and Disposition
Vol. 49, Issue 1
1 Jan 2021
  • 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.
Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics
(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
OtherArticle

Models and Experiments Reveal Meclofenamate Bioactivation

Mary Alexandra Schleiff, Noah R. Flynn, Sasin Payakachat, Benjamin Mark Schleiff, Anna O. Pinson, Dennis W. Province, S. Joshua Swamidass, Gunnar Boysen and Grover P. Miller
Drug Metabolism and Disposition November 25, 2020, DMD-AR-2020-000254; DOI: https://doi.org/10.1124/dmd.120.000254

Citation Manager Formats

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

Models and Experiments Reveal Meclofenamate Bioactivation

Mary Alexandra Schleiff, Noah R. Flynn, Sasin Payakachat, Benjamin Mark Schleiff, Anna O. Pinson, Dennis W. Province, S. Joshua Swamidass, Gunnar Boysen and Grover P. Miller
Drug Metabolism and Disposition November 25, 2020, DMD-AR-2020-000254; DOI: https://doi.org/10.1124/dmd.120.000254
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
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Candesartan glucuronide serves as a CYP2C8 inhibitor
  • Role of AADAC on eslicarbazepine acetate hydrolysis
  • Gene expression profile of human intestinal epithelial cells
Show more Article

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