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
Journal of Pharmacology and Experimental Therapeutics
  • 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
Journal of Pharmacology and Experimental Therapeutics

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 jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleArticle

Microsomal Metabolism of Delavirdine: Evidence for Mechanism-Based Inactivation of Human Cytochrome P450 3A

Richard L. Voorman, Stephen M. Maio, N. Ann Payne, Zhiyang Zhao, Kenneth A. Koeplinger and Xiaohong Wang
Journal of Pharmacology and Experimental Therapeutics October 1998, 287 (1) 381-388;
Richard L. Voorman
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephen M. Maio
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
N. Ann Payne
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zhiyang Zhao
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kenneth A. Koeplinger
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xiaohong Wang
  • 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

Administration of delavirdine, an HIV-1 reverse transcriptase inhibitor, to rats or monkeys resulted in apparent loss of hepatic microsomal CYP3A and delavirdine desalkylation activity. Human CYP3A catalyzes the formation of desalkyl delavirdine and 6′-hydroxy delavirdine, an unstable metabolite, while CYP2D6 catalyzes only desalkyl delavirdine. CYP2D6 catalyzed desalkyl delavirdine formation was linear with time (up to 30 min) but when catalyzed by cDNA expressed CYP3A4 or human liver microsomes the reaction rate declined progressively with time. Coincubation with triazolam showed that delavirdine caused a time- and NADPH-dependent loss of CYP3A4 activity in human liver microsomes as measured by triazolam 1′-hydroxylation. The catalytic activity loss was saturable and was characterized by aKi of 21.6 ± 8.9 μM and a kinact of 0.59 ± 0.08 min−1. An apparent partition ratio of 41 was determined with cDNA expressed CYP3A4, based on the substrate depletion method. Incubation of [14C]delavirdine with microsomes from several species resulted in irreversible association with an approximately 50 kDa protein, as demonstrated by SDS-PAGE/autoradiography. Binding to the protein was NADPH dependent, glutathione insensitive, proportional to the level of CYP3A expression and was inhibited by ketoconazole, a specific CYP3A inhibitor. NADPH-dependent irreversible binding to human and rat total microsomal protein was demonstrated following exhaustive extraction of microsomal protein. Binding was decreased in the presence of glutathione and appeared to be related to expression level of CYP3A. These results suggest that delavirdine can inactivate CYP3A and has the potential to slow the metabolism of coadministered CYP3A substrates.

Footnotes

  • Send reprint requests to: Dr. Richard L. Voorman, Drug Metabolism Research B 300–3, Pharmacia and Upjohn, 301 Henrietta St., Kalamazoo, MI 49007. E-mail: Richard.L.Voorman{at}am.pnu.com

  • ↵1 This work was presented in part at the 9th International Conference on Cytochrome P450, Zurich, Switzerland, 1995.

  • Abbreviations:
    HIV-1
    human immunodeficiency virus type-1
    AIDS
    acquired immune deficiency syndrome
    API
    atmospheric pressure ionization
    ELISA
    enzyme linked immunosorbent assay
    MS
    mass spectrometry
    PCN
    pregnenolone 16α-carbonitrile
    SDS-PAGE
    sodium dodecyl sulfate-polyacrylamide gel electrophoresis
    • Received March 5, 1998.
    • Accepted May 19, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET 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

Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 1
1 Oct 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 Journal of Pharmacology and Experimental Therapeutics 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.
Microsomal Metabolism of Delavirdine: Evidence for Mechanism-Based Inactivation of Human Cytochrome P450 3A
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Microsomal Metabolism of Delavirdine: Evidence for Mechanism-Based Inactivation of Human Cytochrome P450 3A

Richard L. Voorman, Stephen M. Maio, N. Ann Payne, Zhiyang Zhao, Kenneth A. Koeplinger and Xiaohong Wang
Journal of Pharmacology and Experimental Therapeutics October 1, 1998, 287 (1) 381-388;

Citation Manager Formats

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

Share
Research ArticleArticle

Microsomal Metabolism of Delavirdine: Evidence for Mechanism-Based Inactivation of Human Cytochrome P450 3A

Richard L. Voorman, Stephen M. Maio, N. Ann Payne, Zhiyang Zhao, Kenneth A. Koeplinger and Xiaohong Wang
Journal of Pharmacology and Experimental Therapeutics October 1, 1998, 287 (1) 381-388;
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

  • PST3093 Stimulates SERCA2a and Improves Cardiac Function
  • CRV431 Decreases Liver Fibrosis and Tumor Development
  • Antagonist-Induced Reversal of Functional and Structural Measures of Hippocampal Benzodiazepine Tolerance
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 JPET
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics