title: In vitro biotransformation of imatinib by the tumor expressed CYP1A1 and CYP1B1.
abstract: The main objective of the study was to examine the biotransformation of the anticancer drug imatinib in target cells by incubating it with oxidoreductases expressed in tumor cells. The second objective was to obtain an in silico prediction of the potential activity of imatinib metabolites. An in vitro enzyme kinetic study was performed with cDNA expressed human oxidoreductases and LC-MS/MS analysis. The kinetic parameters (Km and Vmax) were determined for six metabolites. A molecular modeling approach was used to dock these metabolites to the target Abl or Bcr-Abl kinases. CYP3A4 isozyme showed the broadest metabolic capacity, whereas CYP1A1, CYP1B1 and FMO3 isozymes biotransformed imatinib with a high intrinsic clearance. The predicted binding modes for the metabolites to Abl were comparable to that of the parent drug, suggesting potential activity. These findings indicate that CYP1A1 and CYP1B1, which are known to be overexpressed in a wide range of tumors, are involved in the biotransformation of imatinib. They could play a role in imatinib disposition in the targeted stem, progenitor and differentiated cancer cells, with a possible contribution of the metabolites toward the activity of the drug.
authors.affiliation: Quantitative Mass Spectrometry Facility, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland. bertrand.rochat@chuv.ch
authors.forename: Bertrand
authors.initials: B
authors.lastname: Rochat
authors.forename: Vincent
authors.initials: V
authors.lastname: Zoete
authors.forename: Aurélien
authors.initials: A
authors.lastname: Grosdidier
authors.forename: Sandrine
authors.initials: S
authors.lastname: von Grünigen
authors.forename: Marc
authors.initials: M
authors.lastname: Marull
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology*; D001549:Benzamides; D001711:Biotransformation; D019363:Cytochrome P-450 CYP1A1 / Q000502:physiology*; D065633:Cytochrome P-450 CYP1B1; D006801:Humans; D000068877:Imatinib Mesylate; D007700:Kinetics; D013058:Mass Spectrometry; D009369:Neoplasms / Q000378:metabolism*; D010879:Piperazines / Q000493:pharmacokinetics*; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology; D011743:Pyrimidines / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D016315:Proto-Oncogene Proteins c-abl