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
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
    • 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 jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleMetabolism, Transport, and Pharmacogenomics

P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) Restrict Brain Accumulation of the Active Sunitinib Metabolite N-Desethyl Sunitinib

Seng Chuan Tang, Nienke A. G. Lankheet, Birk Poller, Els Wagenaar, Jos H. Beijnen and Alfred H. Schinkel
Journal of Pharmacology and Experimental Therapeutics April 2012, 341 (1) 164-173; DOI: https://doi.org/10.1124/jpet.111.186908
Seng Chuan Tang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nienke A. G. Lankheet
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Birk Poller
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Els Wagenaar
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jos H. Beijnen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alfred H. Schinkel
  • 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 + SI
  • PDF
Loading

Abstract

N-desethyl sunitinib is a major and pharmacologically active metabolite of the tyrosine kinase inhibitor and anticancer drug sunitinib. Because the combination of N-desethyl sunitinib and sunitinib represents total active drug exposure, we investigated the impact of several multidrug efflux transporters on plasma pharmacokinetics and brain accumulation of N-desethyl sunitinib after sunitinib administration to wild-type and transporter knockout mice. In vitro, N-desethyl sunitinib was a good transport substrate of human ABCB1 and ABCG2 and murine Abcg2, but not ABCC2 or Abcc2. At 5 μM, ABCB1 and ABCG2 contributed almost equally to N-desethyl sunitinib transport. In vivo, the systemic exposure of N-desethyl sunitinib after oral dosing of sunitinib malate (10 mg/kg) was unchanged when Abcb1 and/or Abcg2 were absent. However, brain accumulation of N-desethyl sunitinib was markedly increased (13.7-fold) in Abcb1a/1b(−/−)/Abcg2(−/−) mice, but not in Abcb1a/1b(−/−) or Abcg2(−/−) mice. In the absence of the ABCB1 and ABCG2 inhibitor elacridar, brain concentrations of N-desethyl sunitinib were detectable only in Abcb1a/1b(−/−)/Abcg2(−/−) mice after sunitinib administration. Combined elacridar plus N-desethyl sunitinib treatment increased N-desethyl sunitinib plasma and brain exposures, but not brain-to-plasma ratios in wild-type mice. In conclusion, brain accumulation of N-desethyl sunitinib is effectively restricted by both Abcb1 and Abcg2. The effect of elacridar treatment in improving brain accumulation of N-desethyl sunitinib in wild-type mice was limited compared with its effect on sunitinib brain accumulation.

Footnotes

  • This work was supported by the Dutch Cancer Society [Grant 2007-3764]; an academic staff training scheme fellowship from the Malaysian Ministry of Science, Technology, and Innovation (to S.C.T.); and a postdoctoral fellowship from the Swiss National Science Foundation [Grant PBBSP3-128567] (to B.P.).

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

    http://dx.doi.org/10.1124/jpet.111.186908.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    ABC
    ATP-binding cassette
    ANOVA
    analysis of variance
    AUC
    area under the plasma concentration-time curve
    BBB
    blood-brain barrier
    Cmax
    maximum drug concentration in plasma
    LLQ
    lower limit of quantification
    MDCKII
    Madin-Darby canine kidney II
    Pbrain
    relative brain accumulation
    TKI
    tyrosine kinase inhibitor
    GF120918
    N-4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide hydrochloride
    LY-335979
    (R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo-(a,e)cyclopropa(c)cycloheptan-6-yl)-α-((5-quinoloyloxy)methyl)-1-piperazine ethanol trihydrochloride
    Ko143
    (3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1′,2′:1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester.

  • Received August 11, 2011.
  • Accepted January 9, 2012.
  • Copyright © 2012 by 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: 341 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 341, Issue 1
1 Apr 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 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.
P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) Restrict Brain Accumulation of the Active Sunitinib Metabolite N-Desethyl Sunitinib
(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 ArticleMetabolism, Transport, and Pharmacogenomics

ABCB1 and ABCG2 Limit N-Desethyl Sunitinib Brain Disposition

Seng Chuan Tang, Nienke A. G. Lankheet, Birk Poller, Els Wagenaar, Jos H. Beijnen and Alfred H. Schinkel
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 164-173; DOI: https://doi.org/10.1124/jpet.111.186908

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleMetabolism, Transport, and Pharmacogenomics

ABCB1 and ABCG2 Limit N-Desethyl Sunitinib Brain Disposition

Seng Chuan Tang, Nienke A. G. Lankheet, Birk Poller, Els Wagenaar, Jos H. Beijnen and Alfred H. Schinkel
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 164-173; DOI: https://doi.org/10.1124/jpet.111.186908
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
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Authorship Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • HDL Mimetic 4F Modulates Aβ Distribution in Brain and Plasma
  • AOX1 Inhibition by Gefitinib, Erlotinib, and Metabolites
  • Catalytic Activity of CYP2C9 Variants
Show more Metabolism, Transport, and Pharmacogenomics

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 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 © 2021 by the American Society for Pharmacology and Experimental Therapeutics