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 ArticleMetabolism, Transport, and Pharmacogenomics

Impact of P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) Gene Dosage on Plasma Pharmacokinetics and Brain Accumulation of Dasatinib, Sorafenib, and Sunitinib

Seng Chuan Tang, Niels de Vries, Rolf W. Sparidans, Els Wagenaar, Jos H. Beijnen and Alfred H. Schinkel
Journal of Pharmacology and Experimental Therapeutics September 2013, 346 (3) 486-494; DOI: https://doi.org/10.1124/jpet.113.205583
Seng Chuan Tang
Division of Molecular Oncology, the Netherlands Cancer Institute, Amsterdam, The Netherlands (S.C.T., E.W., A.H.S.); Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands (R.W.S., J.H.B.); and Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands (N.d.V., J.H.B.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Niels de Vries
Division of Molecular Oncology, the Netherlands Cancer Institute, Amsterdam, The Netherlands (S.C.T., E.W., A.H.S.); Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands (R.W.S., J.H.B.); and Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands (N.d.V., J.H.B.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rolf W. Sparidans
Division of Molecular Oncology, the Netherlands Cancer Institute, Amsterdam, The Netherlands (S.C.T., E.W., A.H.S.); Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands (R.W.S., J.H.B.); and Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands (N.d.V., J.H.B.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Els Wagenaar
Division of Molecular Oncology, the Netherlands Cancer Institute, Amsterdam, The Netherlands (S.C.T., E.W., A.H.S.); Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands (R.W.S., J.H.B.); and Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands (N.d.V., J.H.B.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jos H. Beijnen
Division of Molecular Oncology, the Netherlands Cancer Institute, Amsterdam, The Netherlands (S.C.T., E.W., A.H.S.); Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands (R.W.S., J.H.B.); and Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands (N.d.V., J.H.B.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alfred H. Schinkel
Division of Molecular Oncology, the Netherlands Cancer Institute, Amsterdam, The Netherlands (S.C.T., E.W., A.H.S.); Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands (R.W.S., J.H.B.); and Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands (N.d.V., J.H.B.)
  • 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

Low brain accumulation of anticancer drugs due to efflux transporters may limit chemotherapeutic efficacy, necessitating a better understanding of the underlying mechanisms. P-glycoprotein (Abcb1a/1b) and breast cancer resistance protein (Abcg2) combination knockout mice often display disproportionately increased brain accumulation of shared drug substrates compared with single transporter knockout mice. Recently developed pharmacokinetic models could explain this phenomenon. To experimentally test these models and their wider relevance for tyrosine kinase inhibitors and other drugs, we selected dasatinib, sorafenib, and sunitinib because of their divergent oral availability and brain accumulation profiles: the brain accumulation of dasatinib is mainly restricted by Abcb1, that of sorafenib mainly by Abcg2, and that of sunitinib equally by Abcb1 and Abcg2. We analyzed the effect of halving the efflux activity of these transporters at the blood-brain barrier by generating heterozygous Abcb1a/1b;Abcg2 knockout mice and testing the plasma and brain levels of the drugs after oral administration at 10 mg/kg. Real-time reverse transcription-polymerase chain reaction analysis confirmed the ∼2-fold decreased expression of both transporters in brain. Interestingly, whereas complete knockout of the transporters caused 24- to 36-fold increases in brain accumulation of the drugs, the heterozygous mice only displayed 1.6- to 1.9-fold increases of brain accumulation relative to wild-type mice. These results are well in line with the predictions of the pharmacokinetic models and provide strong support for their validity for a wider range of drugs. Moreover, retrospective analysis of fetal accumulation of drugs across the placenta in Abcb1a/1b heterozygous knockout pups suggests that these models equally apply to the maternal-fetal barrier.

Footnotes

    • Received April 12, 2013.
    • Accepted June 12, 2013.
  • This work was supported by an academic staff training scheme fellowship from the Malaysian Ministry of Science, Technology and Innovation (to S.C.T.), and in part by the Dutch Cancer Society [Grant 2007-3764].

  • dx.doi.org/10.1124/jpet.113.205583.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2013 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: 346 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 346, Issue 3
1 Sep 2013
  • 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.
Impact of P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) Gene Dosage on Plasma Pharmacokinetics and Brain Accumulation of Dasatinib, Sorafenib, and 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

Impact of P-gp and Bcrp Gene Dosage on TKI Brain Penetration

Seng Chuan Tang, Niels de Vries, Rolf W. Sparidans, Els Wagenaar, Jos H. Beijnen and Alfred H. Schinkel
Journal of Pharmacology and Experimental Therapeutics September 1, 2013, 346 (3) 486-494; DOI: https://doi.org/10.1124/jpet.113.205583

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

Impact of P-gp and Bcrp Gene Dosage on TKI Brain Penetration

Seng Chuan Tang, Niels de Vries, Rolf W. Sparidans, Els Wagenaar, Jos H. Beijnen and Alfred H. Schinkel
Journal of Pharmacology and Experimental Therapeutics September 1, 2013, 346 (3) 486-494; DOI: https://doi.org/10.1124/jpet.113.205583
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
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • 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

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