cgp-74588 and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

To determine blood binding parameters of imatinib and its metabolite CGP74588 in humans and non-human species.. The blood distribution and protein binding of imatinib and CGP74588 were determined in vitro using (14)C labelled compounds.. The mean fraction of imatinib in plasma (f(p)) was 45% in dog, 50% in mouse, 65% in rat, 70% in healthy humans and up to 92% in acute lymphatic leukaemia (AML) patients. Similarly, f(p) for CGP74588 was low in dog and monkey (30%), higher in rat, mouse and humans (70%) and highest in some AML patients (90%). The unbound fraction of imatinib and CGP74588 in plasma was lower in rat, mouse, healthy humans and AML patients (2.3-6.5% at concentrations < or = 5000 ng ml(-1)) compared to monkey and dog (7.6-19%). Both compounds displayed high binding to human alpha(1)-acid glycoprotein. AML patients had a reduced haematocrit and showed greatest variability in their blood binding parameters.. Imatinib and CGP74588 displayed very similar blood binding parameters within all species/groups investigated. The five species clustered into two distinct groups with rat, mouse and humans being clearly different from dog and monkey. For both compounds, higher protein binding was associated with a decreased partitioning into blood cells.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Benzamides; Dogs; Female; Humans; Imatinib Mesylate; Macaca fascicularis; Male; Mice; Middle Aged; Piperazines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Binding; Pyrimidines; Rats; Rats, Wistar

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.

Topics: Administration, Oral; Aged; Benzamides; Biological Availability; Chromatography, High Pressure Liquid; Half-Life; HL-60 Cells; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Metabolic Clearance Rate; Piperazines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines