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

BRAIN CYCLOSPORIN A LEVELS ARE DETERMINED BY ONTOGENIC REGULATION OF MDR1A EXPRESSION

Kerry B. Goralski, Philip D. Acott, Albert D. Fraser, David Worth and Christopher J. Sinal
Drug Metabolism and Disposition February 2006, 34 (2) 288-295; DOI: https://doi.org/10.1124/dmd.105.007427
Kerry B. Goralski
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Philip D. Acott
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Albert D. Fraser
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David Worth
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christopher J. Sinal
  • 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

Cyclosporin A (CyA) toxicity is a common occurrence in pediatric organ transplant patients. We hypothesized that reduced mdr1a expression in newborn and developing mice would affect CyA accumulation within organs and/or toxicity. For functional studies, CyA was administered (5 mg kg–1 i.p.) to 1-, 12-, and 19-day, and adult male and female mdr1a+/+ and mdr1a–/– mice. Peak blood CyA was lower in 1-, 12-, and 19-day-old (1000 ng ml–1) versus adult (1500 ng ml–1) mice but was similar in mdr1a+/+ and mdr1a–/– mice. Kidney mdr1a expression (measured by quantitative polymerase chain reaction) increased 2.5-fold in 19-day-old male and female mice and increased another 4-fold in adult females compared with adult males. Liver mdr1a expression increased 6-fold by day 12 compared with neonatal mice. Thereafter, maintenance of hepatic mdr1a expression in females and a reduction to neonatal levels in males was observed. Kidney/blood (8- to 9-fold) and liver/blood (12- to 15-fold) CyA levels were highest on days 12 and 19 and were not dependent on maturational changes in mdr1a mRNA levels. Adults had higher brain expression of mdr1a mRNA (3-fold), a corresponding 5-fold increase in immunodetectable P-glycoprotein, and 80% lower brain accumulation of CyA compared with 1-day-old mice. Conversely, in mdr1a-null mice, brain/blood CyA was similar in newborn and adult mice. A similar pattern was observed for the brain accumulation of the mdr1a substrate 3H-digoxin. We conclude that the risk for central nervous system drug toxicity could be higher in neonates or young children as a consequence of underdeveloped P-glycoprotein.

Footnotes

  • This work was supported by operating grants from the Canadian Institutes of Health Research. K.B.G. was supported by postdoctoral fellowships from The IWK Health Centre, The Canadian Institutes of Health Research, and the Reynolds Foundation.

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

  • doi:10.1124/dmd.105.007427.

  • ABBREVIATIONS: P-gp, P-glycoprotein; CyA, cyclosporin A; PCR, polymerase chain reaction; Q-PCR, quantitative PCR; CNS, central nervous system; zfy, Y-chromosome-specific zinc finger protein; mEH, mitochondrial expoxide hydrolase; CT, threshold cycle; rpII, ribosome polymerase II; TBS-T, Tris-buffered saline with Tween 20; ANOVA, analysis of variance; C2, cyclosporine concentration measured 2 h after dosing; HSD, honestly significantly different.

    • Received September 16, 2005.
    • Accepted November 9, 2005.
  • 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: 34 (2)
Drug Metabolism and Disposition
Vol. 34, Issue 2
1 Feb 2006
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • 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.
BRAIN CYCLOSPORIN A LEVELS ARE DETERMINED BY ONTOGENIC REGULATION OF MDR1A EXPRESSION
(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

BRAIN CYCLOSPORIN A LEVELS ARE DETERMINED BY ONTOGENIC REGULATION OF MDR1A EXPRESSION

Kerry B. Goralski, Philip D. Acott, Albert D. Fraser, David Worth and Christopher J. Sinal
Drug Metabolism and Disposition February 1, 2006, 34 (2) 288-295; DOI: https://doi.org/10.1124/dmd.105.007427

Citation Manager Formats

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

Share
Research ArticleArticle

BRAIN CYCLOSPORIN A LEVELS ARE DETERMINED BY ONTOGENIC REGULATION OF MDR1A EXPRESSION

Kerry B. Goralski, Philip D. Acott, Albert D. Fraser, David Worth and Christopher J. Sinal
Drug Metabolism and Disposition February 1, 2006, 34 (2) 288-295; DOI: https://doi.org/10.1124/dmd.105.007427
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
    • 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 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 © 2022 by the American Society for Pharmacology and Experimental Therapeutics