title: Pharmacokinetics and cellular uptake of imatinib and its main metabolite CGP74588.
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 microg.h/ml for an oral dose of 400 mg daily), the t(1/2) (18.2 h) and the peak concentration (1.92 micro/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.
authors.affiliation: Medizinische Klinik für Hämatologie und Onkologie, Campus Virchow, Charité, Humboldt Universität Berlin, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: le Coutre
authors.forename: Karl-Anton
authors.initials: KA
authors.lastname: Kreuzer
authors.forename: Stefan
authors.initials: S
authors.lastname: Pursche
authors.forename: Malte v
authors.initials: Mv
authors.lastname: Bonin
authors.forename: Traugott
authors.initials: T
authors.lastname: Leopold
authors.forename: Gökben
authors.initials: G
authors.lastname: Baskaynak
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.forename: Oliver
authors.initials: O
authors.lastname: Ottmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Jenke
authors.forename: Martin
authors.initials: M
authors.lastname: Bornhäuser
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schleyer
mesh_terms: D000284:Administration, Oral; D000368:Aged; D001549:Benzamides; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D018922:HL-60 Cells; D006207:Half-Life; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D010879:Piperazines / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000652:urine; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D011743:Pyrimidines / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D001549:Benzamides; C464561:CGP 74588; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate