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 ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Use of a Physiologically Based Pharmacokinetic Model to Study the Time to Reach Brain Equilibrium: An Experimental Analysis of the Role of Blood-Brain Barrier Permeability, Plasma Protein Binding, and Brain Tissue Binding

Xingrong Liu, Bill J. Smith, Cuiping Chen, Ernesto Callegari, Stacey L. Becker, Xi Chen, Julie Cianfrogna, Angela C. Doran, Shawn D. Doran, John P. Gibbs, Natilie Hosea, Jianhua Liu, Frederick R. Nelson, Mark A. Szewc and Jeffery Van Deusen
Journal of Pharmacology and Experimental Therapeutics June 2005, 313 (3) 1254-1262; DOI: https://doi.org/10.1124/jpet.104.079319
Xingrong Liu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bill J. Smith
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cuiping Chen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ernesto Callegari
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stacey L. Becker
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xi Chen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Julie Cianfrogna
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Angela C. Doran
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shawn D. Doran
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John P. Gibbs
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Natilie Hosea
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jianhua Liu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Frederick R. Nelson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark A. Szewc
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jeffery Van Deusen
  • 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

This study was designed 1) to examine the effects of blood-brain barrier (BBB) permeability [quantified as permeability-surface area product (PS)], unbound fraction in plasma (fu,plasma), and brain tissue (fu,brain) on the time to reach equilibrium between brain and plasma and 2) to investigate the drug discovery strategies to design and select compounds that can rapidly penetrate the BBB and distribute to the site of action. The pharmacokinetics of seven model compounds: caffeine, CP-141938 [methoxy-3-[(2-phenyl-piperadinyl-3-amino)-methyl]-phenyl-N-methyl-methane-sulfonamide], fluoxetine, NFPS [N[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine], propranolol, theobromine, and theophylline in rat brain and plasma after subcutaneous administration were studied. The in vivo log PS and log fu,brain calculated using a physiologically based pharmacokinetic model correlates with in situ log PS (R2 = 0.83) and in vitro log fu,brain (R2 = 0.69), where the in situ PS and in vitro fu,brain was determined using in situ brain perfusion and equilibrium dialysis using brain homogenate, respectively. The time to achieve brain equilibrium can be quantitated with a proposed parameter, intrinsic brain equilibrium half-life [t1/2eq,in = Vbln2/(PS · fu,brain)], where Vb is the physiological volume of brain. The in vivo log t1/2eq,in does not correlate with in situ log PS (R2 < 0.01) but correlates inversely with log(PS · fu,brain) (R2 = 0.85). The present study demonstrates that rapid brain equilibration requires a combination of high BBB permeability and low brain tissue binding. A high BBB permeability alone cannot guarantee a rapid equilibration. The strategy to select compounds with rapid brain equilibration in drug discovery should identify compounds with high BBB permeability and low nonspecific binding in brain tissue.

Footnotes

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

  • doi:10.1124/jpet.104.079319.

  • ABBREVIATIONS: BBB, blood-brain barrier; CNS, central nervous system; NFPS, N[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine; CP-141938, methoxy-3-[(2-phenyl-piperadinyl-3-amino)-methyl]-phenyl-N-methyl-methane-sulfonamide; HPLC, high-performance liquid chromatography; PBPK, physiologically based pharmacokinetics; PS, permeability-surface area product; BP, brain-to-plasma concentration ratio.

    • Received October 14, 2004.
    • Accepted February 28, 2005.
  • 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.
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • 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 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.
Use of a Physiologically Based Pharmacokinetic Model to Study the Time to Reach Brain Equilibrium: An Experimental Analysis of the Role of Blood-Brain Barrier Permeability, Plasma Protein Binding, and Brain Tissue Binding
(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 ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Use of a Physiologically Based Pharmacokinetic Model to Study the Time to Reach Brain Equilibrium: An Experimental Analysis of the Role of Blood-Brain Barrier Permeability, Plasma Protein Binding, and Brain Tissue Binding

Xingrong Liu, Bill J. Smith, Cuiping Chen, Ernesto Callegari, Stacey L. Becker, Xi Chen, Julie Cianfrogna, Angela C. Doran, Shawn D. Doran, John P. Gibbs, Natilie Hosea, Jianhua Liu, Frederick R. Nelson, Mark A. Szewc and Jeffery Van Deusen
Journal of Pharmacology and Experimental Therapeutics June 1, 2005, 313 (3) 1254-1262; DOI: https://doi.org/10.1124/jpet.104.079319

Citation Manager Formats

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

Share
Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Use of a Physiologically Based Pharmacokinetic Model to Study the Time to Reach Brain Equilibrium: An Experimental Analysis of the Role of Blood-Brain Barrier Permeability, Plasma Protein Binding, and Brain Tissue Binding

Xingrong Liu, Bill J. Smith, Cuiping Chen, Ernesto Callegari, Stacey L. Becker, Xi Chen, Julie Cianfrogna, Angela C. Doran, Shawn D. Doran, John P. Gibbs, Natilie Hosea, Jianhua Liu, Frederick R. Nelson, Mark A. Szewc and Jeffery Van Deusen
Journal of Pharmacology and Experimental Therapeutics June 1, 2005, 313 (3) 1254-1262; DOI: https://doi.org/10.1124/jpet.104.079319
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
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Transport Is Not Rate-Limiting in Morphine Glucuronidation in the Single-Pass Perfused Rat Liver Preparation
  • Enhanced Hepatic Uptake and Bioactivity of Type α1(I) Collagen Gene Promoter-Specific Triplex-Forming Oligonucleotides after Conjugation with Cholesterol
  • Characterization of P-glycoprotein Inhibition by Major Cannabinoids from Marijuana
Show more ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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