Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 53, Issue 4, pp 313–323 | Cite as

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

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

Imatinib Metabolite CGP74588 N-Desmethyl-imatinib Pharmacokinetics CML ALL 

Notes

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.

References

  1. 1.
    Buchdunger E, Zimmermann J, Mett H, et al (1996) Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by 2 phenylaminopyrimidine derivative. Cancer Res 56:100–104PubMedGoogle Scholar
  2. 2.
    Druker BJ, Tamura S, Buchdunger E, et al (1996) Effects of a selective inhibitor of the Abl tyrosinekinase on the growth of BCR-ABL positive cells. Nat Med 2:561–566PubMedGoogle Scholar
  3. 3.
    Gambacorti-Passerini C, le Coutre P, Mologni L (1997) Inhibition of the ABL kinase activity selectively blocks the proliferation of BCR-ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Dis 23:380–394CrossRefPubMedGoogle Scholar
  4. 4.
    Deininger MW, Goldmann JM, Lydon N, Melo J (1997) The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood 90:3691–3698PubMedGoogle Scholar
  5. 5.
    le Coutre P, Mologni L, Cleris L, et al (1999) In vivo eradication of human BCR-ABL-positive leukemia cells with an ABL kinase inhibitor. J Natl Cancer Inst 91:163–168CrossRefPubMedGoogle Scholar
  6. 6.
    Kantarjian H, Sawyers C, Hochhaus A, et al (2002) Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346:645–652PubMedGoogle Scholar
  7. 7.
    O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ (2003) IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348:994–1004CrossRefPubMedGoogle Scholar
  8. 8.
    Druker BJ, Sawyers CL, Kantarjian H (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042PubMedGoogle Scholar
  9. 9.
    Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F, Schiffer CA, Fischer T, Deininger MW, Lennard AL, Hochhaus A, Ottmann OG, Gratwohl A, Baccarani M, Stone R, Tura S, Mahon FX, Fernandes-Reese S, Gathmann I, Capdeville R, Kantarjian HM, Sawyers CL (2002) Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 99:1928–1937CrossRefPubMedGoogle Scholar
  10. 10.
    Gambacorti-Passerini C, Barni R, le Coutre P, et al (2000) Role of α1 acid glycoprotein in the in vivo resistance of human BCR-ABL+ leukemic cells to the Abl inhibitor STI571. J Natl Cancer Inst 92:1641–1650PubMedGoogle Scholar
  11. 11.
    le Coutre P, Kreuzer KA, Na IK, et al (2002) Determination of α-1 acid glycoprotein in patients with Ph+ chronic myeloid leukemia during the first 13 weeks of therapy with STI571. Blood Cells Mol Dis 28:75–85CrossRefPubMedGoogle Scholar
  12. 12.
    Gambacorti-Passerini C, Zucchetti M, Russo D, Frapolli R, Verga M, Bungaro S, Tornaghi L, Rossi F, Pioltelli P, Pogliani E, Alberti D, Corneo G, D’Incalci M (2003) Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin Cancer Res 9:625–632PubMedGoogle Scholar
  13. 13.
    Gambacorti-Passerini CB, Rossi F, Verga M, Ruchatz H, Gunby R, Frapolli R, Zucchetti M, Scapozza L, Bungaro S, Tornaghi L, Rossi F, Pioltelli P, Pogliani E, D’Incalci M, Corneo G (2002) Differences between in vivo and in vitro sensitivity to imatinib of Bcr/Abl+ cells obtained from leukemic patients. Blood Cells Mol Dis 28:361–372CrossRefPubMedGoogle Scholar
  14. 14.
    Ford JM (2002) Imatinib mesilate, investigators’ brochure, 5th edn. Novartis PharmaGoogle Scholar
  15. 15.
    Heinzel G, Hammer R, Wolf M, Koss FW, Bozler G (1977) Model building in pharmacokinetics/Part III: simplified rules for the deduction of analytical solutions for linear compartment models (in German). Arzneimittelforschung 27:904PubMedGoogle Scholar
  16. 16.
    le Coutre P, Tassi E, Varella-Garcia M, et al (2000) Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells trough gene amplification. Blood 95:1758–1766PubMedGoogle Scholar
  17. 17.
    Weisberg E, Griffin JD (2000) Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines. Blood 95:3498–3505PubMedGoogle Scholar
  18. 18.
    Gorre ME, Mohammed M, Ellwood K, et al (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–880CrossRefPubMedGoogle Scholar
  19. 19.
    Bakhtiar R, Lohne J, Ramos L, Khemani M, Hayes M, Tse F (2002) High-throughput quantification of the anti-leukemia drug STI571 (GleevecTM) and its main metabolite (CGP 74588) in human plasma using liquid chromatography-tandem mass spectrometry. J Chromatogr B 768:325–340Google Scholar
  20. 20.
    Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J, Goldman JM, Melo JV (2003) MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 101:2368–2373CrossRefPubMedGoogle Scholar
  21. 21.
    Dai H, Marbach P, Lemaire M, Hayes M, Elmquist WF (2003) Distribution of STI-571 to the brain is limited by p-glycoprotein-mediated efflux. Pharmacol Exp Ther 304:1085–1092CrossRefGoogle Scholar
  22. 22.
    Huang M, Wang Y, Cogut SB, Mitchell BS, Graves LM (2003) Inhibition of nucleoside transport by protein kinase inhibitors. J Pharmacol Exp Ther 304:753–760CrossRefPubMedGoogle Scholar

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

Personalised recommendations