Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • 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
  • 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
    • 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
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

Investigation of the Mechanism of Enhancement of Central Nervous System Delivery of 2′-β-Fluoro-2′,3′-Dideoxyinosine Via a Blood-Brain Barrier Adenosine Deaminase-Activated Prodrug

Mark D. Johnson, Jian Chen and Bradley D. Anderson
Drug Metabolism and Disposition February 2002, 30 (2) 191-198; DOI: https://doi.org/10.1124/dmd.30.2.191
Mark D. Johnson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jian Chen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bradley D. Anderson
  • 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

Enhanced central nervous system (CNS) delivery of certain poorly penetrating 2′,3′-dideoxynucleosides has been achieved by designing prodrugs that are substrates for enzymes, such as adenosine deaminase (ADA), that are present at high activities in brain tissue. In this study, the potential role of adenosine deaminase localized within the endothelial cells of the blood-brain barrier (BBB) in providing enhanced intracellular and CNS delivery of an ADA-activated prodrug is assessed in vitro using cell culture models of the BBB. The kinetics of uptake and bioconversion of 2′-β-fluoro-2′,3′-dideoxyadenosine (F-ddA), a model ADA-activated prodrug of 2′-β-fluoro-2′,3′-dideoxyinosine, were determined in primary cultured bovine brain microvascular endothelial cells. Model-based simulations of CNS availability derived from in vitro estimates of parameters for simple passive diffusion and ADA-catalyzed deamination suggest that ADA that is localized within the BBB plays an important role in the conversion of F-ddA to 2′-β-fluoro-2′,3′-dideoxyinosine during its passage across the BBB. Consistent with in vivo observations, these simulations demonstrate that elevated levels of certain enzymes, such as ADA, in the brain microvascular endothelial cells of the BBB may be exploited in the design of brain-targeted prodrugs or drug-carrier conjugates, which brain tissue selectively converts.

Footnotes

  • ↵1 Present address: Whitehall-Robbins Healthcare, Richmond, Virginia.

  • This work was supported by National Institutes of Health Grants AI-34133 and NS-39178. Mark Johnson also received support as a recipient of an Advanced Predoctoral Fellowship in Pharmaceutics from the Pharmaceutical Research and Manufacturers of America Foundation.

  • Abbreviations used are::
    BBB
    blood-brain barrier
    HIV
    human immunodeficiency virus
    CNS
    central nervous system
    ddI
    2′,3′-dideoxyinosine
    ADA
    adenosine deaminase
    F-ddA
    2′-β-fluoro-2′,3′-dideoxyadenosine
    ddA
    2′,3′-dideoxyadenosine
    F-ddI
    2′-β-fluoro-2′,3′-dideoxyinosine
    PNP
    purine nucleoside phosphorylase
    BBMEC
    bovine brain microvascular endothelial cell
    EHNA
    (+)-erythro-9-(2-hydroxy-2-nonyl)adenine
    HPLC
    high-performance liquid chromatography
    • Received August 9, 2001.
    • Accepted November 9, 2001.
  • 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: 30 (2)
Drug Metabolism and Disposition
Vol. 30, Issue 2
1 Feb 2002
  • 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.
Investigation of the Mechanism of Enhancement of Central Nervous System Delivery of 2′-β-Fluoro-2′,3′-Dideoxyinosine Via a Blood-Brain Barrier Adenosine Deaminase-Activated Prodrug
(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

Investigation of the Mechanism of Enhancement of Central Nervous System Delivery of 2′-β-Fluoro-2′,3′-Dideoxyinosine Via a Blood-Brain Barrier Adenosine Deaminase-Activated Prodrug

Mark D. Johnson, Jian Chen and Bradley D. Anderson
Drug Metabolism and Disposition February 1, 2002, 30 (2) 191-198; DOI: https://doi.org/10.1124/dmd.30.2.191

Citation Manager Formats

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

Investigation of the Mechanism of Enhancement of Central Nervous System Delivery of 2′-β-Fluoro-2′,3′-Dideoxyinosine Via a Blood-Brain Barrier Adenosine Deaminase-Activated Prodrug

Mark D. Johnson, Jian Chen and Bradley D. Anderson
Drug Metabolism and Disposition February 1, 2002, 30 (2) 191-198; DOI: https://doi.org/10.1124/dmd.30.2.191
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • In Vivo Functional Effects of CYP2C9 M1L
  • Clearance pathways: fevipiprant with probenecid perpetrator
  • Predicting Volume of Distribution from In Vitro Parameters
Show more Article

Similar Articles

  • 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 © 2021 by the American Society for Pharmacology and Experimental Therapeutics