Pharmaceutical Research

, Volume 24, Issue 9, pp 1720–1728 | Cite as

Modulation of the Brain Distribution of Imatinib and its Metabolites in Mice by Valspodar, Zosuquidar and Elacridar

  • Sébastien Bihorel
  • Gian Camenisch
  • Michel Lemaire
  • Jean-Michel Scherrmann
Short Communication



The selective protein tyrosine kinase inhibitor, imatinib, inhibits the growth of glioma cells in preclinical models, but its poor brain distribution limits its efficacy in patients. P-glycoprotein (P-gp, rodent Mdr1a/1b or Abcb1a/1b) and Breast cancer resistance protein (rodent Bcrp1 or Abcg2) were suggested to restrict the delivery of imatinib to the brain. This study evaluates the effect of administering selective inhibitors of these transporters together with imatinib on the systemic and cerebral disposition of imatinib in mice.

Materials and Methods

Wild-type, Mdr1a/1b(/) and Bcrp1(/) mice were given imatinib intravenously, either alone, or with valspodar, zosuquidar (P-gp inhibitors), or elacridar (a P-gp and Bcrp1 inhibitor). The blood and brain concentrations of [14C]imatinib and its radioactive metabolites were determined.


The blockade of P-gp by valspodar or zosuquidar (>3 mg/kg) enhanced the brain uptake of imatinib (∼4-fold) in wild-type mice, but not that of its metabolites. Blockade of both P-gp and Bcrp1 by elacridar (>3 mg/kg) produced significantly greater brain penetration of imatinib (9.3-fold) and its metabolites (2.8-fold). In contrast, only the lack of P-gp enhanced imatinib brain penetration (6.4-fold) in knockout mice. These results of brain uptake correlated reasonably well with those obtained previously by our group using in situ brain perfusion.


Imatinib and its metabolites penetrate into the brain poorly and their penetration is limited by P-gp and (probably) Bcrp1. Administering imatinib together with P-gp (and Bcrp1) transporter inhibitors such as elacridar may improve the delivery of imatinib to the brain, making it potentially more effective against malignant gliomas.

Key words

brain breast cancer resistance protein 1 imatinib metabolites P-glycoprotein 



ATP-binding cassette

BB ratio

Blood/brain concentration ratio


Blood–brain barrier


Breast cancer resistance protein


Central nervous system


Net transport coefficient


Malignant glioma




Standard deviation



We thank Dr. Yves Auberson (Novartis Institutes for Biomedical Research) for providing zosuquidar and elacridar, Dr. Rachael Profit and Dr Owen Parkes for editing the English text. This work was supported by Novartis Pharma AG contract (Novartis-INSERM n° 03035A10) to Dr. Sébastien Bihorel and Dr. Jean-Michel Scherrmann.


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Sébastien Bihorel
    • 1
  • Gian Camenisch
    • 2
  • Michel Lemaire
    • 2
  • Jean-Michel Scherrmann
    • 1
  1. 1.INSERM, U705, CNRS, UMR 7157Université Paris 7, Université Paris 5, Faculté de Pharmacie, Laboratoire de PharmacocinétiqueParisFrance
  2. 2.Department of Drug Metabolism and PharmacokineticsNovartis Pharma A.G.BaselSwitzerland

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