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
  • Log out
  • 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
  • Log out
  • 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
Abstract

Use of rat and human in vitro systems to assess the effectiveness and enzymology of deoxyguanine analogs as prodrugs of an antiviral agent.

A W Harrell, S M Wheeler, P East, S E Clarke and R J Chenery
Drug Metabolism and Disposition March 1994, 22 (2) 189-193;
A W Harrell
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
S M Wheeler
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
P East
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
S E Clarke
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
R J Chenery
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

BRL 55792, BRL 55791, and BRL 55039 are prodrugs of an active antiviral agent 9-(3-hydroxypropoxy) guanine (BRL 44385). The prodrugs were 6-deoxygenated analogs of BRL 44385, with ether groups substituted at the 9-position: BRL 55792 with an (isopropoxymethyloxy)propoxy group, BRL 55791 with a (methoxymethyloxy)propoxy group, and BRL 55039 with an ethoxypropoxy group. Conversion of the prodrugs to BRL 44385 had been demonstrated in vivo in the rat and involved 6-oxidation followed by dealkylation. Metabolism was studied in rat liver in vitro systems to find a model to evaluate BRL 44385 production. Rat hepatocytes performed both reaction steps and were used to assess which of the three prodrugs demonstrated greatest production of the active drug. BRL 55792 demonstrated greatest conversion in vitro, and this was in agreement with in vivo data. The production of BRL 44385 from BRL 55792 was also demonstrated in human hepatocyte incubations, providing evidence that these reactions can occur in humans, thereby increasing confidence that BRL 55792 would be suitable prodrug for human therapy. Further experiments were performed to investigate the enzymes involved in these conversions. The 6-oxidation step occurred in the cytosol. Use of allopurinol and menadione (xanthine and aldehyde oxidase inhibitors) indicated that these conversions were catalyzed exclusively by xanthine oxidase in the rat but mainly by aldehyde oxidase in humans. The dealkylation reaction was detected in hepatocytes but not in homogenates or subcellular fractions. Inhibition of this reaction by aminobenzotriazole and ketoconazole (P-450 inhibitors) indicated that it was mediated by cytochrome P-450.

 

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. 22, Issue 2
1 Mar 1994
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author
  • Back Matter (PDF)
  • 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.
Use of rat and human in vitro systems to assess the effectiveness and enzymology of deoxyguanine analogs as prodrugs of an antiviral agent.
(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
Abstract

Use of rat and human in vitro systems to assess the effectiveness and enzymology of deoxyguanine analogs as prodrugs of an antiviral agent.

A W Harrell, S M Wheeler, P East, S E Clarke and R J Chenery
Drug Metabolism and Disposition March 1, 1994, 22 (2) 189-193;

Citation Manager Formats

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

Share
Abstract

Use of rat and human in vitro systems to assess the effectiveness and enzymology of deoxyguanine analogs as prodrugs of an antiviral agent.

A W Harrell, S M Wheeler, P East, S E Clarke and R J Chenery
Drug Metabolism and Disposition March 1, 1994, 22 (2) 189-193;
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
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

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