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

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Abstract

Purpose

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.

Results

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.

Conclusions

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.

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Fig. 1
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Notes

  1. Bihorel S, Camenisch G, Lemaire M, et al. Influence of Breast Cancer Resistance Protein (Abcg2) and P-glycoprotein (Abcb1a/1b) on imatinib mesylate (Gleevec®) transport across the mouse blood–brain barrier. Submitted for publication.

  2. Wiegand H and Pfaar U, unpublished data

Abbreviations

ABC:

ATP-binding cassette

BB ratio:

Blood/brain concentration ratio

BBB:

Blood–brain barrier

BCRP:

Breast cancer resistance protein

CNS:

Central nervous system

K net :

Net transport coefficient

MG:

Malignant glioma

P-gp:

P-glycoprotein

SD:

Standard deviation

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Acknowledgments

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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Authors and Affiliations

  1. INSERM, U705, CNRS, UMR 7157, Université Paris 7, Université Paris 5, Faculté de Pharmacie, Laboratoire de Pharmacocinétique, Paris, France

    Sébastien Bihorel & Jean-Michel Scherrmann

  2. Department of Drug Metabolism and Pharmacokinetics, Novartis Pharma A.G., Basel, Switzerland

    Gian Camenisch & Michel Lemaire

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  1. Sébastien Bihorel
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  2. Gian Camenisch
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  4. Jean-Michel Scherrmann
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Correspondence to Jean-Michel Scherrmann.

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Bihorel, S., Camenisch, G., Lemaire, M. et al. Modulation of the Brain Distribution of Imatinib and its Metabolites in Mice by Valspodar, Zosuquidar and Elacridar. Pharm Res 24, 1720–1728 (2007). https://doi.org/10.1007/s11095-007-9278-4

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