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The effect of hydroxyurea on P-glycoprotein/BCRP-mediated transport and CYP3A metabolism of imatinib mesylate

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Abstract

Purpose

It has been reported that the combination therapy of imatinib mesylate, a tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, is associated with remarkable antitumor activity in patients with recurrent glioblastoma multiforme. However, the mechanism of the added activity of hydroxyurea to imatinib is not known. The purpose of this study was to investigate in vitro, whether hydroxyurea could enhance the central nervous system penetration of imatinib, by inhibition of the ATP-dependent transporter proteins P-glycoprotein (ABCB1; MDR1; Pgp) and Breast Cancer Resistance Protein (ABCG2; BCRP), or by inhibition of cytochrome P450 3A (CYP3A) metabolism of imatinib.

Methods

The effect of hydroxyurea on the Pgp and BCRP mediated transport of imatinib was investigated by the sulforhodamine-B (SRB) drug cytotoxicity assay and transepithelial transport assay. In vitro biotransformation studies with supersomes expressing human CYP3A4 were performed to investigate whether hydroxyurea inhibited CYP3A4.

Results

In both in vitro cytotoxicity and transport assays, hydroxyurea did not affect Pgp and BCRP mediated transport of imatinib. In a biotransformation assay, hydroxyurea had no influence on the metabolic degradation of imatinib either.

Conclusion

The results indicate that hydroxyurea does not interact with imatinib by inhibition of Pgp and BCRP mediated transport or by CYP3A4 mediated metabolism of imatinib.

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Authors and Affiliations

  1. Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands

    Roos L. Oostendorp, Serena Marchetti & Jan H. M. Schellens

  2. Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands

    Jan H. M. Schellens

  3. Faculty of Pharmaceutical Sciences, Utrecht University, Sorbonnelaan 16, 3584 CA, Utrecht, The Netherlands

    Jos H. Beijnen & Jan H. M. Schellens

  4. Postgraduate School of oncology, University of Florence, Florence, Italy

    Serena Marchetti & R. Mazzanti

Authors
  1. Roos L. Oostendorp
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  2. Serena Marchetti
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  3. Jos H. Beijnen
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  4. R. Mazzanti
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  5. Jan H. M. Schellens
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Corresponding author

Correspondence to Jan H. M. Schellens.

Additional information

Roos L. Oostendorp, Serena Marchetti contributed equally to this article.

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Oostendorp, R.L., Marchetti, S., Beijnen, J.H. et al. The effect of hydroxyurea on P-glycoprotein/BCRP-mediated transport and CYP3A metabolism of imatinib mesylate. Cancer Chemother Pharmacol 59, 855–860 (2007). https://doi.org/10.1007/s00280-006-0334-2

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  • DOI: https://doi.org/10.1007/s00280-006-0334-2

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