Cancer Chemotherapy and Pharmacology

, Volume 53, Issue 4, pp 313–323

Pharmacokinetics and cellular uptake of imatinib and its main metabolite CGP74588

  • Philipp le Coutre
  • Karl-Anton Kreuzer
  • Stefan Pursche
  • Malte v. Bonin
  • Traugott Leopold
  • Gökben Baskaynak
  • Bernd Dörken
  • Gerhard Ehninger
  • Oliver Ottmann
  • Andreas Jenke
  • Martin Bornhäuser
  • Eberhard Schleyer
Original Article

DOI: 10.1007/s00280-003-0741-6

Cite this article as:
le Coutre, P., Kreuzer, KA., Pursche, S. et al. Cancer Chemother Pharmacol (2004) 53: 313. doi:10.1007/s00280-003-0741-6

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.

Keywords

ImatinibMetaboliteCGP74588N-Desmethyl-imatinibPharmacokineticsCMLALL

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Philipp le Coutre
    • 1
  • Karl-Anton Kreuzer
    • 1
  • Stefan Pursche
    • 2
  • Malte v. Bonin
    • 2
  • Traugott Leopold
    • 2
  • Gökben Baskaynak
    • 1
  • Bernd Dörken
    • 1
  • Gerhard Ehninger
    • 2
  • Oliver Ottmann
    • 3
  • Andreas Jenke
    • 2
  • Martin Bornhäuser
    • 2
  • Eberhard Schleyer
    • 2
    • 4
  1. 1.Medizinische Klinik für Hämatologie und Onkologie, Campus Virchow, CharitéHumboldt Universität BerlinGermany
  2. 2.Universitätsklinikum Carl Gustav CarusAbteilung für Hämatologie und OnkologieDresdenGermany
  3. 3.Medizinische Klinik IIIJohann Wolfgang Goethe UniversitätFrankfurt a.M.Germany
  4. 4.Medizinische Klinik und Poliklinik I an derTechnischen Universität DresdenDresdenGermany