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Pharmacokinetics and cellular uptake of imatinib and its main metabolite CGP74588

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Abstract

Despite the remarkable clinical response rates to imatinib in the treatment of bcr-abl leukemic patients, pharmacokinetic data on this relatively novel substance are needed to improve our understanding of the emergence of resistance, the interindividual variations of clinical response and the clinical and biologic relevance of its main metabolite N-desmethyl-imatinib. We present here pharmacokinetic data obtained with a newly designed HPLC approach in 97 patients with chronic myeloid leukemia or acute lymphatic leukemia (ALL) under treatment with imatinib that allowed us to calculate the AUC (39.5 μg·h/ml for an oral dose of 400 mg daily), the t1/2 (18.2 h) and the peak concentration (1.92 μ/ml for an oral dose of 400 mg daily) of imatinib in plasma. In a subgroup of patients, the same parameters were analyzed for N-desmethyl-imatinib. We also provide data on the imatinib concentration in the cerebrospinal fluid (CSF) of ALL patients and demonstrate that oral administration of imatinib resulted only in a marginal flux across the blood-brain barrier. Finally, in an in vitro setting, we determined cellular concentrations of imatinib in HL-60 cells and showed an over-proportional uptake both in RPMI medium and in human plasma. Using an arithmetical approach combining all parameters obtained in imatinib-treated patients, we finally provide a conclusive approximation of basic pharmacokinetic data for both imatinib and its main metabolite N-desmethyl-imatinib.

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Acknowledgement

P. le Coutre, K.-A. Kreuzer, O. Ottmann and G. Ehninger are principal investigators/coinvestigators of clinical trials with imatinib carried out by Novartis Pharmaceuticals.

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Authors and Affiliations

  1. Medizinische Klinik für Hämatologie und Onkologie, Campus Virchow, Charité, Humboldt Universität Berlin, Germany

    Philipp le Coutre, Karl-Anton Kreuzer, Gökben Baskaynak & Bernd Dörken

  2. Universitätsklinikum Carl Gustav Carus, Abteilung für Hämatologie und Onkologie, Dresden, Germany

    Stefan Pursche, Malte v. Bonin, Traugott Leopold, Gerhard Ehninger, Andreas Jenke, Martin Bornhäuser & Eberhard Schleyer

  3. Medizinische Klinik III, Johann Wolfgang Goethe Universität, Frankfurt a.M., Germany

    Oliver Ottmann

  4. Medizinische Klinik und Poliklinik I an der, Technischen Universität Dresden, Fetscherstr. 48, 01307, Dresden, Germany

    Eberhard Schleyer

Authors
  1. Philipp le Coutre
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  2. Karl-Anton Kreuzer
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  3. Stefan Pursche
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  4. Malte v. Bonin
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  5. Traugott Leopold
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  6. Gökben Baskaynak
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  7. Bernd Dörken
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  8. Gerhard Ehninger
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  9. Oliver Ottmann
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  10. Andreas Jenke
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  11. Martin Bornhäuser
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  12. Eberhard Schleyer
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Correspondence to Eberhard Schleyer.

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le Coutre, P., Kreuzer, KA., Pursche, S. et al. Pharmacokinetics and cellular uptake of imatinib and its main metabolite CGP74588. Cancer Chemother Pharmacol 53, 313–323 (2004). https://doi.org/10.1007/s00280-003-0741-6

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  • DOI: https://doi.org/10.1007/s00280-003-0741-6

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