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
OtherAccelerated Communication

An Unexpected Synergist Role of P-Glycoprotein and Breast Cancer Resistance Protein on the Central Nervous System Penetration of the Tyrosine Kinase Inhibitor Lapatinib (N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016)

Joseph W. Polli, Katie L. Olson, John P. Chism, Lisa St. John-Williams, Russell L. Yeager, Sesha M. Woodard, Vicky Otto, Stephen Castellino and Victoria E. Demby
Drug Metabolism and Disposition February 2009, 37 (2) 439-442; DOI: https://doi.org/10.1124/dmd.108.024646
Joseph W. Polli
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Katie L. Olson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John P. Chism
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lisa St. John-Williams
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Russell L. Yeager
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sesha M. Woodard
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Vicky Otto
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephen Castellino
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Victoria E. Demby
  • 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

Lapatinib is a tyrosine kinase inhibitor approved for use in combination with capecitabine to treat advanced or metastatic breast cancers overexpressing human epidermal receptor 2 (ErbB2). This work investigated the role of P-glycoprotein (Pgp; the protein from the Mdr1a/b gene) and breast cancer resistance protein (Bcrp; the protein from the Bcrp1 gene) in modulating the central nervous system penetration of lapatinib at steady-state conditions in FVBn mice (wild-type), Mdr1a/b(–/–), Bcrp1(–/–), and Mdr1a/b(–/–)/Bcrp1(–/–) knockout mice. After an intravenous infusion of lapatinib for 24 h to a targeted steady-state plasma concentration of 700 ng/ml (0.3 mg/kg/h) or 7000 ng/ml (3 mg/kg/h), lapatinib brain-to-plasma ratios were approximately 3- to 4-fold higher in Mdr1a/b(–/–) knockout mice (ratio range from 0.09 to 0.16) compared with wild-type mice (ratio range from 0.03 to 0.04). There was no difference in the brain-to-plasma ratio in the Bcrp1(–/–) knockout mice (ratio range from 0.03 to 0.04) compared with wild-type mice. In contrast, Mdr1a/b(–/–)/Bcrp1(–/–) triple knockout mice had a 40-fold higher brain-to-plasma ratio (ratio range from 1.2 to 1.7), suggesting that Pgp and Bcrp work in concert to limit the brain-to-plasma ratio of lapatinib in mice. This finding has important potential consequences for the treatment of brain tumors in breast cancer patients treated with tyrosine kinase inhibitors as well as the basic understanding of ATP binding cassette transporters expressed in the blood-brain barrier on the central nervous system disposition of drugs.

Footnotes

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

  • doi:10.1124/dmd.108.024646.

  • ABBREVIATIONS: Lapatinib, GW572016, N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; TKI, tyrosine kinase inhibitor; HER, human epidermal receptor; CNS, central nervous system; Pgp, P-glycoprotein; Bcrp and BCRP, breast cancer resistance protein; Mdr1, gene encoding the Pgp protein; Bcrp1, gene encoding Bcrp protein; t1/2, plasma half-life; Cmax, maximum plasma concentration; C(0), extrapolated estimate of plasma concentration at end of bolus dose; Css, steady-state plasma concentration; HPLC, high-performance liquid chromatography; CLp, plasma clearance; 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.

    • Received September 16, 2008.
    • Accepted November 26, 2008.
  • 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: 37 (2)
Drug Metabolism and Disposition
Vol. 37, Issue 2
1 Feb 2009
  • 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.
An Unexpected Synergist Role of P-Glycoprotein and Breast Cancer Resistance Protein on the Central Nervous System Penetration of the Tyrosine Kinase Inhibitor Lapatinib (N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}met…
(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
OtherAccelerated Communication

An Unexpected Synergist Role of P-Glycoprotein and Breast Cancer Resistance Protein on the Central Nervous System Penetration of the Tyrosine Kinase Inhibitor Lapatinib (N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016)

Joseph W. Polli, Katie L. Olson, John P. Chism, Lisa St. John-Williams, Russell L. Yeager, Sesha M. Woodard, Vicky Otto, Stephen Castellino and Victoria E. Demby
Drug Metabolism and Disposition February 1, 2009, 37 (2) 439-442; DOI: https://doi.org/10.1124/dmd.108.024646

Citation Manager Formats

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

Share
OtherAccelerated Communication

An Unexpected Synergist Role of P-Glycoprotein and Breast Cancer Resistance Protein on the Central Nervous System Penetration of the Tyrosine Kinase Inhibitor Lapatinib (N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016)

Joseph W. Polli, Katie L. Olson, John P. Chism, Lisa St. John-Williams, Russell L. Yeager, Sesha M. Woodard, Vicky Otto, Stephen Castellino and Victoria E. Demby
Drug Metabolism and Disposition February 1, 2009, 37 (2) 439-442; DOI: https://doi.org/10.1124/dmd.108.024646
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 and Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Use of CYP Transgenic Mouse Models
  • Nonlinear Metabolite Kinetics of Verapamil
  • Production of Recombinant hsa-mir-27b
Show more Accelerated Communication

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