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

Influence of Enterohepatic Recycling on the Time Course of Brain-to-Blood Partitioning of Valproic Acid in Rats

Jeannie M. Padowski and Gary M. Pollack
Drug Metabolism and Disposition September 2012, 40 (9) 1846-1853; DOI: https://doi.org/10.1124/dmd.112.045500
Jeannie M. Padowski
Curriculum in Toxicology, School of Medicine, and Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gary M. Pollack
Curriculum in Toxicology, School of Medicine, and Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  • 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 widely used metric of substrate exposure in brain is the brain-to-serum partition coefficient (Kp,brain; Cbrain/Cserum), most appropriately determined at distribution equilibrium between brain tissue and serum. In some cases, Cbrain/Cserum can peak and then decrease, as opposed to monotonically increasing to a plateau, precluding accurate estimation of partitioning. This “overshoot” has been observed with compounds that undergo enterohepatic recycling (ER), such as valproic acid (VPA). Previous simulation experiments identified a relationship between overshoot in the Cbrain/Cserum versus time profile and distribution into a peripheral “compartment” (e.g., the ER loop). This study was conducted to evaluate model predictions of that relationship. Initial experiments tested the ability of activated charcoal, antibiotics, or Mrp2 deficiency to impair VPA ER in rats, thereby limiting the apparent volume of distribution associated with ER. Mrp2 deficiency (significantly) and antibiotics (moderately) interrupted VPA ER. Subsequently, brain partitioning was evaluated in the presence versus absence of ER modulation. Although overshoot was not eliminated completely, deconvolution revealed that overshoot was reduced in Mrp2-deficient and antibiotic-treated rats. Consistent with model predictions, overshoot was higher after antibiotic treatment (moderate ER interruption) than in Mrp2 deficiency (substantial ER interruption). Steady-state Kp,brain was unaffected by experimental manipulation, also consistent with model predictions. These data support the hypothesis that Cbrain/Cserum may overshoot Kp,brain based on the extent of peripheral sequestration. Consideration of this information, particularly for compounds that undergo significant extravascular distribution, may be necessary to avoid erroneous estimation of Kp,brain.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM61191]; the National Institutes of Health National Institute of Environmental Health Sciences [Grant T32-ES007126]; and Eli Lilly and Company.

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

    http://dx.doi.org/10.1124/dmd.112.045500.

  • ABBREVIATIONS:

    CNS
    central nervous system
    Kp,brain and Cbrain/Cserum
    brain/serum partition coefficient
    ER
    enterohepatic recycling
    VPA
    valproic acid
    CCA
    cyclohexanecarboxylic acid
    DE
    distribution equilibrium
    φER
    fraction of the dose undergoing enterohepatic recirculation
    BBB
    blood-brain barrier
    AUC
    area under the concentration-time curve
    AUC0–8 h
    area under the concentration-time profile calculated by the trapezoidal method.

  • Received March 5, 2012.
  • Accepted June 19, 2012.
  • Copyright © 2012 by 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: 40 (9)
Drug Metabolism and Disposition
Vol. 40, Issue 9
1 Sep 2012
  • 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 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.
Influence of Enterohepatic Recycling on the Time Course of Brain-to-Blood Partitioning of Valproic Acid in Rats
(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

ENTEROHEPATIC RECYCLING INFLUENCES VPA BRAIN PARTITIONING

Jeannie M. Padowski and Gary M. Pollack
Drug Metabolism and Disposition September 1, 2012, 40 (9) 1846-1853; DOI: https://doi.org/10.1124/dmd.112.045500

Citation Manager Formats

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

Share
Research ArticleArticle

ENTEROHEPATIC RECYCLING INFLUENCES VPA BRAIN PARTITIONING

Jeannie M. Padowski and Gary M. Pollack
Drug Metabolism and Disposition September 1, 2012, 40 (9) 1846-1853; DOI: https://doi.org/10.1124/dmd.112.045500
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

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

Related Articles

Cited By...

More in this TOC Section

  • CYP3A-mediated oxidation of DABE and BIBR0951
  • Adipocyte PXR does not play an essential role in obesity.
  • Biodistribution of Lipid in Rats
Show more Articles

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