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

SPECIES DIFFERENTIAL STEREOSELECTIVE OXIDATION OF A METHYLSULFIDE METABOLITE OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL)PHENYL]METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR DUAL AGONIST

Bindhu V. Karanam, Christopher J. Welch, Vijay G. Reddy, Jennifer Chilenski, Mirlinda Biba and Stella Vincent
Drug Metabolism and Disposition October 2004, 32 (10) 1061-1068; DOI: https://doi.org/10.1124/dmd.104.000224
Bindhu V. Karanam
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christopher J. Welch
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Vijay G. Reddy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jennifer Chilenski
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mirlinda Biba
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stella Vincent
  • 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

MK-0767 [(±)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl)phenyl]methyl]benzamide], a thiazolidinedione (TZD)-containing peroxisome proliferator-activated receptor agonist, is a rapidly interconverting racemate that possesses a chiral center at the five position of the TZD ring. M25 is a methyl sulfide metabolite generated from MK-0767 following CYP3A4-mediated TZD ring opening and subsequent methylation of the sulfide intermediate M22. M25, a major in vitro and in vivo metabolite, was further metabolized in liver microsomes to the methyl sulfoxide amide (M16) with two chiral centers and the methyl sulfone amide (M20) with one chiral center. Previous studies demonstrated that both CYP3A4 and flavin monooxygenase-3 (FMO3) catalyzed the formation of M16, whereas M20 was formed exclusively by CYP3A4. The relative contribution of CYP3A4 and FMO3 in the formation of M16 in human and preclinical species was evaluated by chiral analysis using supercritical fluid chromatography. No stereoselectivity was observed in incubations of M25 with human and rhesus liver and recombinant CYP3A4 microsomes, whereas a high degree of stereoselectivity (63 to >99% enantiomeric excess) was observed in rat and dog liver and human recombinant FMO3 microsomes. Also, polyclonal anti-rat CYP3A2 antibody and cytochrome P450 (P450) chemical inhibitors did not inhibit the oxidation of M25 in rat liver microsomes. Furthermore, M25 oxidation was more sensitive to heat inactivation at pH 8 and 8.7 in rat and dog liver microsomes than in human and monkey liver microsomes, consistent with the species difference in involvement of FMOs. Collectively, these results indicated thatS-oxidation of M25 was catalyzed primarily by P450 enzymes in human and monkey liver microsomes and by FMO enzymes in rat and dog liver microsomes.

Footnotes

  • doi:10.1124/dmd.104.000224.

  • ABBREVIATIONS: MK-0767, (±)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl)phenyl]methyl]benzamide; TZD, thiazolidinedione; PPAR, peroxisome proliferator-activated receptor; P450, cytochrome P450; FMO, flavin monooxygenase; HPLC, high-performance liquid chromatography; TAO, troleandomycin; SFC, supercritical fluid chromatography; CD, circular dichroism; ee, enantioselectivity excess.

    • Received April 9, 2004.
    • Accepted June 24, 2004.
  • 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: 32 (10)
Drug Metabolism and Disposition
Vol. 32, Issue 10
1 Oct 2004
  • Table of Contents
  • About the Cover
  • 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.
SPECIES DIFFERENTIAL STEREOSELECTIVE OXIDATION OF A METHYLSULFIDE METABOLITE OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL)PHENYL]METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR DUAL AGONIST
(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

SPECIES DIFFERENTIAL STEREOSELECTIVE OXIDATION OF A METHYLSULFIDE METABOLITE OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL)PHENYL]METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR DUAL AGONIST

Bindhu V. Karanam, Christopher J. Welch, Vijay G. Reddy, Jennifer Chilenski, Mirlinda Biba and Stella Vincent
Drug Metabolism and Disposition October 1, 2004, 32 (10) 1061-1068; DOI: https://doi.org/10.1124/dmd.104.000224

Citation Manager Formats

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

Share
Research ArticleArticle

SPECIES DIFFERENTIAL STEREOSELECTIVE OXIDATION OF A METHYLSULFIDE METABOLITE OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL)PHENYL]METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR DUAL AGONIST

Bindhu V. Karanam, Christopher J. Welch, Vijay G. Reddy, Jennifer Chilenski, Mirlinda Biba and Stella Vincent
Drug Metabolism and Disposition October 1, 2004, 32 (10) 1061-1068; DOI: https://doi.org/10.1124/dmd.104.000224
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

  • Improved CYP Reaction Phenotyping
  • Multiple-Concentration Chemical Inhibition Design
  • New Dog P450 3A98 in Gut
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