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

First-Pass Disposition of (−)-6-Aminocarbovir in Rats: II. Inhibition of Intestinal First-Pass Metabolism

Cheryl L. Zimmerman, Yandong Wen and Rory P. Remmel
Drug Metabolism and Disposition June 2000, 28 (6) 672-679;
Cheryl L. Zimmerman
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yandong Wen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rory P. Remmel
  • 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

A CBV [(−)-carbovir, (−)-carbocyclic 2′,3′-didehydro-2′,3′-dideoxyguanosine] prodrug, 6AC [(−)-6-aminocarbovir, (−)-carbocyclic 2′,3′-didehydro-2′,3′-dideoxy-6-deoxy-6-aminoguanosine], was previously evaluated in rats, and it exhibited superiority to the parent drug in increasing systemic and central nervous system exposure to CBV. The gut wall was determined to be the dominant site of the first-pass activation of 6AC after lumenal administration. If subsequent delivery to the brain is desired, then such a first-pass effect might not be viewed favorably. Because the first-pass conversion of 6AC primarily takes place in the intestine by adenosine deaminase (ADA), quenching of the intestinal activation of 6AC by oral administration of ADA inhibitors may result in an increased 6AC bioavailability, and thus an improved brain exposure to CBV. The objectives of the study were to determine whether the ADA inhibitors 2′-deoxycoformycin anderythro-9-(2-hydroxy-3-nonyl)adenine were capable of achieving a substantial and selective inhibition of gut wall activation of 6AC, and to determine whether the systemic concentrations of 6AC would be thus increased. Thirty-nine male Sprague-Dawley rats were divided into two groups. One group received 6AC by either the portal vein or intralumenally with the coadministration of intralumenal 2′-deoxycoformycin. Similarly, the other group received 6AC with coadministration oferythro-9-(2-hydroxy-3-nonyl)adenine. Substantial suppression of the first-pass conversion of 6AC was achieved with both inhibitors. This inhibition appeared to be relatively selective, allowing the choice of dose of inhibitor that would sufficiently inhibit the first-pass metabolism while leaving the activation capacity in the systemic circulation unaltered. The systemic level of 6AC increased with the escalating dose of inhibitors, thus increasing the driving force for passive uptake into the brain.

Footnotes

  • Send reprint requests to: Cheryl L. Zimmerman, Ph.D., Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 308 Harvard St. S.E., Minneapolis, MN 55455. E-mail:zimme005{at}tc.umn.edu

  • ↵1 Present address: Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Department of Metabolism and Pharmacokinetics, F13–08, Princeton, NJ 08543-4000.

  • This work was partially supported by United States Public Health Service Grant R01-AI28236 and the University of Minnesota International Student Work Opportunities Program.

  • Abbreviations used are::
    CBV (−)-carbovir
    (−)-carbocyclic 2′,3′-didehydro-2′,3′-dideoxyguanosine
    6AC
    (−)-6-aminocarbovir, (−)-carbocyclic 2′,3′-didehy dro-2′,3′-dideoxy-6-deoxy-6-aminoguanosine
    ADA, adenosine deaminase
    DCF, 2′-deoxycoformycin, pentostatin
    EHNA
    erythro-9-(2-hydroxy-3-nonyl)adenine
    • Received September 10, 1999.
    • Accepted March 2, 2000.
  • 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: 28 (6)
Drug Metabolism and Disposition
Vol. 28, Issue 6
1 Jun 2000
  • 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.
First-Pass Disposition of (−)-6-Aminocarbovir in Rats: II. Inhibition of Intestinal First-Pass Metabolism
(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

First-Pass Disposition of (−)-6-Aminocarbovir in Rats: II. Inhibition of Intestinal First-Pass Metabolism

Cheryl L. Zimmerman, Yandong Wen and Rory P. Remmel
Drug Metabolism and Disposition June 1, 2000, 28 (6) 672-679;

Citation Manager Formats

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

Share
Research ArticleArticle

First-Pass Disposition of (−)-6-Aminocarbovir in Rats: II. Inhibition of Intestinal First-Pass Metabolism

Cheryl L. Zimmerman, Yandong Wen and Rory P. Remmel
Drug Metabolism and Disposition June 1, 2000, 28 (6) 672-679;
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
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Role of Human MSRA on Sulindac Activation
  • Determination of Acyl-, O-, and N-Glucuronide
  • Uptake as the RDS in Pevonedistat Hepatic Clearance
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 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