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

UDP-GLUCURONOSYLTRANSFERASE 2B7 IS THE MAJOR ENZYME RESPONSIBLE FOR GEMCABENE GLUCURONIDATION IN HUMAN LIVER MICROSOMES

Jonathan N. Bauman, Theunis C. Goosen, Meera Tugnait, Vincent Peterkin, Susan I. Hurst, Lee C. Menning, Mark Milad, Michael H. Court and J. Andrew Williams
Drug Metabolism and Disposition September 2005, 33 (9) 1349-1354; DOI: https://doi.org/10.1124/dmd.105.005108
Jonathan N. Bauman
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Theunis C. Goosen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Meera Tugnait
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Vincent Peterkin
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Susan I. Hurst
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lee C. Menning
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark Milad
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael H. Court
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
J. Andrew Williams
  • 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 predominant metabolic pathway of gemcabene in humans is glucuronidation. The principal human UDP-glucuronosyltransferases (UGTs) involved in the glucuronidation of gemcabene were determined in this study. Glucuronidation of gemcabene was catalyzed by recombinant UGT1A3, recombinant UGT2B7, and recombinant UGT2B17, as well as by human liver microsomes (HLM). Gemcabene glucuronidation in recombinant UGTs and HLM followed non-Michaelis-Menten kinetics consistent with homotropic activation, but pharmacokinetics in humans were linear over the dose range tested (total plasma Cmax, 0.06–0.88 mM). Gemcabene showed similar affinity (S50) for recombinant UGTs (0.92–1.45 mM) and HLM (1.37 mM). S-Flurbiprofen was identified as a more selective inhibitor of recombinant UGT2B7-catalyzed gemcabene glucuronidation (>23-fold lower IC50) when compared with recombinant UGT1A3- or recombinant UGT2B17-catalyzed gemcabene glucuronidation. The IC50 for S-flurbiprofen inhibition of gemcabene glucuronidation was similar in HLM (60.6 μM) compared with recombinant UGT2B7 (27.4 μM), consistent with a major role for UGT2B7 in gemcabene glucuronidation in HLM. In addition, 5,6,7,3′,4′,5′-hexamethoxyflavone inhibited recombinant UGT1A3 and recombinant UGT2B17-catalyzed gemcabene glucuronidation (with 4-fold greater potency for recombinant UGT1A3) but did not inhibit gemcabene glucuronidation in HLM, suggesting that UGT1A3 and UGT2B17 do not contribute significantly to gemcabene glucuronidation. Reaction rates for gemcabene glucuronidation from a human liver bank correlated well (r2 = 0.722, P < 0.0001; n = 24) with rates of glucuronidation of the UGT2B7 probe substrate 3′-azido-3′-deoxythymidine. In conclusion, using the three independent experimental approaches typically used for cytochrome P450 reaction phenotyping, UGT2B7 is the major enzyme contributing to gemcabene glucuronidation in human liver microsomes.

Footnotes

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

  • doi:10.1124/dmd.105.005108.

  • ABBREVIATIONS: UGT, UDP-glucuronosyltransferase; HPLC, high-performance liquid chromatography; UDPGA, uridine 5′-diphosphoglucuronic acid; HLM, human liver microsome(s); AZT, zidovudine, 3′-azido-3′-deoxythymidine; HMF, 5,6,7,3′,4′,5′-hexamethoxyflavone.

    • Received April 8, 2005.
    • Accepted June 17, 2005.
  • 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: 33 (9)
Drug Metabolism and Disposition
Vol. 33, Issue 9
1 Sep 2005
  • 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.
UDP-GLUCURONOSYLTRANSFERASE 2B7 IS THE MAJOR ENZYME RESPONSIBLE FOR GEMCABENE GLUCURONIDATION IN 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

UDP-GLUCURONOSYLTRANSFERASE 2B7 IS THE MAJOR ENZYME RESPONSIBLE FOR GEMCABENE GLUCURONIDATION IN HUMAN LIVER MICROSOMES

Jonathan N. Bauman, Theunis C. Goosen, Meera Tugnait, Vincent Peterkin, Susan I. Hurst, Lee C. Menning, Mark Milad, Michael H. Court and J. Andrew Williams
Drug Metabolism and Disposition September 1, 2005, 33 (9) 1349-1354; DOI: https://doi.org/10.1124/dmd.105.005108

Citation Manager Formats

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

Share
Research ArticleArticle

UDP-GLUCURONOSYLTRANSFERASE 2B7 IS THE MAJOR ENZYME RESPONSIBLE FOR GEMCABENE GLUCURONIDATION IN HUMAN LIVER MICROSOMES

Jonathan N. Bauman, Theunis C. Goosen, Meera Tugnait, Vincent Peterkin, Susan I. Hurst, Lee C. Menning, Mark Milad, Michael H. Court and J. Andrew Williams
Drug Metabolism and Disposition September 1, 2005, 33 (9) 1349-1354; DOI: https://doi.org/10.1124/dmd.105.005108
Reddit logo Twitter logo Facebook 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

  • A PBPK model for CBD in adults and children
  • Olanzapine Glucuronidation in Humanized Mice
  • rs2242480 Regulates the Expression of CYP3A4 and CYP3A5
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 © 2023 by the American Society for Pharmacology and Experimental Therapeutics