The discovery of tyrosine kinase inhibitors (TKIs) brought a major breakthrough in the treatment of patients with chronic myeloid leukemia (CML). Pathogenetic CML events are closely linked with the Bcr-Abl protein with tyrosine kinase activity. TKIs block the ATP-binding site; therefore, the signal pathways leading to malignant transformation are no longer active. However, there is limited information about the impact of TKI treatment on the metabolome of CML patients. Using liquid chromatography mass spectrometric metabolite profiling and multivariate statistical methods, we analyzed plasma and leukocyte samples of patients newly diagnosed with CML, patients treated with hydroxyurea and TKIs (imatinib, dasatinib, nilotinib), and healthy controls. The global metabolic profiles clearly distinguished the newly diagnosed CML patients and the patients treated with hydroxyurea from those treated with TKIs and the healthy controls. The major changes were found in glycolysis, the citric acid cycle, and amino acid metabolism. We observed differences in the levels of amino acids and acylcarnitines between those patients responding to imatinib treatment and those who were resistant to it. According to our findings, the metabolic profiling may be potentially used as an additional tool for the assessment of response/resistance to imatinib.

• MeSH
• aminokyseliny metabolismus   MeSH
• chronická myeloidní leukemie krev   metabolismus   MeSH
• citrátový cyklus účinky léků   MeSH
• glykolýza účinky léků   MeSH
• hydroxymočovina farmakologie   terapeutické užití   MeSH
• imatinib mesylát farmakologie   terapeutické užití   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• krevní plazma chemie   metabolismus   MeSH
• leukocyty chemie   metabolismus   MeSH
• lidé MeSH
• metabolom * MeSH
• metabolomika metody   MeSH
• monitorování léčiv metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Modern high resolution mass spectrometry offers unique identification capability in drug metabolism studies. In this work detailed imatinib metabolization in the plasma of patients with chronic myeloid leukemia is presented. The metabolites were separated by liquid chromatography on a C18 column with mass spectrometry detection via an Orbitrap Elite instrument (Thermo Scientific) based on exact mass measurement. A scan range of m/z 350-1200 resolution of 60,000 was applied (mass accuracy of 5ppm). The data were evaluated using the advanced software for mass spectrometry Mass Frontier and MetWorks. In all plasma samples, studied 90 metabolites in the concentration range of 0.0001-1μmol/L were identified by m/z values and confirmed by exact mass measurement of the MS(2) and MS(3) fragmentations. In order to achieve optimal clinical response and avoid toxicity, current therapeutic monitoring of parent drug is a useful tool for the individualization of treatment. Current high-resolution mass spectrometry possesses the potential to broaden this approach by monitoring number of potentially clinically relevant drug metabolites.

• MeSH
• antitumorózní látky krev   terapeutické užití   MeSH
• chromatografie kapalinová metody   MeSH
• chronická myeloidní leukemie krev   farmakoterapie   MeSH
• hmotnostní spektrometrie metody   MeSH
• imatinib mesylát krev   terapeutické užití   MeSH
• lidé MeSH
• molekulová hmotnost MeSH
• software MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH