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 ArticleArticle

The Role of Probenecid-Sensitive Organic Acid Transport in the Pharmacokinetics of N-Methyl-d-Aspartate Receptor Antagonists Acting at the GlycineB-Site: Microdialysis and Maximum Electroshock Seizures Studies

M. B. Hesselink, H. Smolders, B. Eilbacher, A. G. De Boer, D. D. Breimer and W. Danysz
Journal of Pharmacology and Experimental Therapeutics August 1999, 290 (2) 543-550;
M. B. Hesselink
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
H. Smolders
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
B. Eilbacher
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
A. G. De Boer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
D. D. Breimer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
W. Danysz
  • 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

The purpose of the present study was to determine whether the probenecid-sensitive organic acid transporter is responsible for the short duration of action of a new group ofN-methyl-d-aspartate receptor glycineB-site antagonists, MRZ 2/570, 2/571, and 2/576. A prolongation of their anticonvulsant activity from 60 to 180 to 240 min, was found in mice after pretreatment with probenecid (200 mg/kg i.p.). Microdialysis studies in rats showed that this is likely due to a change in central nervous system concentrations of these drugs because cotreatment with probenecid caused an increase in the brain extracellular fluid half-life (0.5- to 4-fold) and the brain area under the curve (1.8- to 3.6-fold). In serum the half-life of MRZ 2/576 (30 mg/kg) was also increased by coadministration of probenecid from 15.6 ± 1.3 to 40.6 ± 6.0 min. At steady state (MRZ 2/576, 20 mg/kg/h i.v.), brain extracellular fluid concentration was elevated 2.5-fold by concomitant administration of probenecid. These results clearly show that these glycineB-site antagonists are rapidly cleared from the systemic circulation and the central nervous system by the probenecid-sensitive organic acid transport system. Moreover, the present data show that MRZ 2/570, 2/571, and 2/576 reach the brain in concentrations (1.34–2.32 μM) above the range of their in vitro potencies at the glycine site of theN-methyl-d-aspartate receptor (0.1–1.0 μM).

Footnotes

  • Send reprint requests to: Dr. Wojciech Danysz, Merz + Co., Dept. of Pharmacological Research, Eckenheimer Landstrasse 100–104; 60318 Frankfurt/Main, Germany. E-mail:wojciech.danysz{at}merz.de

  • ↵1 Current address: Department of Pharmacology, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2300 RA Leiden, the Netherlands.

  • ↵2 On leave from Department of Pharmacology, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2300 RA Leiden, the Netherlands.

  • ↵3 Present address: Department of Neuropharmacology, Cerebrus Ltd., Oakdene Court, 613 Reading Road, Winnersh, Wokingham, RG41 5UA, UK.

  • ↵4 Present address: Department of Pharmacology, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2300 RA Leiden, the Netherlands.

  • Abbreviations:
    NMDA
    N-methyl-d-aspartate
    CNS
    central nervous system
    ECF
    extracellular fluid
    AUC
    area under the curve
    glycineB-site
    strychnine-insensitive glycine coagonist site
    BBB
    blood-brain barrier
    MES
    maximal electroshock
    aCSF
    artificial cerebrospinal fluid
    PNQX
    pyrido[3,4-f]quinoxaline-2,3-dione,1,4,7,8,9,10-hexahydro-9-methyl-6-nitromethanesulfonate
    • Received October 7, 1998.
    • Accepted April 23, 1999.
  • 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.
PreviousNext
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 290 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 290, Issue 2
1 Aug 1999
  • 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 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.
The Role of Probenecid-Sensitive Organic Acid Transport in the Pharmacokinetics of N-Methyl-d-Aspartate Receptor Antagonists Acting at the GlycineB-Site: Microdialysis and Maximum Electroshock Seizures Studies
(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 ArticleArticle

The Role of Probenecid-Sensitive Organic Acid Transport in the Pharmacokinetics of N-Methyl-d-Aspartate Receptor Antagonists Acting at the GlycineB-Site: Microdialysis and Maximum Electroshock Seizures Studies

M. B. Hesselink, H. Smolders, B. Eilbacher, A. G. De Boer, D. D. Breimer and W. Danysz
Journal of Pharmacology and Experimental Therapeutics August 1, 1999, 290 (2) 543-550;

Citation Manager Formats

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

Share
Research ArticleArticle

The Role of Probenecid-Sensitive Organic Acid Transport in the Pharmacokinetics of N-Methyl-d-Aspartate Receptor Antagonists Acting at the GlycineB-Site: Microdialysis and Maximum Electroshock Seizures Studies

M. B. Hesselink, H. Smolders, B. Eilbacher, A. G. De Boer, D. D. Breimer and W. Danysz
Journal of Pharmacology and Experimental Therapeutics August 1, 1999, 290 (2) 543-550;
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

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

Related Articles

Cited By...

More in this TOC Section

  • PST3093 Stimulates SERCA2a and Improves Cardiac Function
  • CRV431 Decreases Liver Fibrosis and Tumor Development
  • Effects of Antidepressants and Benzodiazepine-Type Anxiolytic Agents on Hepatic Porphyrin Accumulation in Primary Cultures of Chick Embryo Liver Cells
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 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