Participation of CYP2C8 and CYP3A4 in the N-demethylation of imatinib in human hepatic microsomes.

Détails

ID Serval
serval:BIB_5D2272749610
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Participation of CYP2C8 and CYP3A4 in the N-demethylation of imatinib in human hepatic microsomes.
Périodique
British journal of pharmacology
Auteur(s)
Nebot N., Crettol S., d'Esposito F., Tattam B., Hibbs D.E., Murray M.
ISSN
1476-5381 (Electronic)
ISSN-L
0007-1188
Statut éditorial
Publié
Date de publication
11/2010
Peer-reviewed
Oui
Volume
161
Numéro
5
Pages
1059-1069
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Imatinib is a clinically important inhibitor of tyrosine kinases that are dysregulated in chronic myelogenous leukaemia and gastrointestinal stromal tumours. Inter-individual variation in imatinib pharmacokinetics is extensive, and influences drug safety and efficacy. Hepatic cytochrome P450 (CYP) 3A4 has been implicated in imatinib N-demethylation, but the clearance of imatinib decreases during prolonged therapy. CYP3A phenotype correlates with imatinib clearance at the commencement of therapy, but not at steady state. The present study evaluated the possibility that multiple CYPs may contribute to imatinib oxidation in liver.
Imatinib biotransformation in human liver microsomes (n= 20) and by cDNA-expressed CYPs was determined by LC-MS. Relationships between imatinib N-demethylation and other drug metabolizing CYPs were assessed.
N-desmethylimatinib formation was correlated with microsomal oxidation of the CYP3A4 substrates testosterone (ρ= 0.60; P < 0.01) and midazolam (ρ= 0.46; P < 0.05), and the CYP2C8 substrate paclitaxel (ρ= 0.58; P < 0.01). cDNA-derived CYPs 2C8, 3A4, 3A5 and 3A7 supported imatinib N-demethylation, but 10 other CYPs were inactive; in kinetic studies, CYP2C8 was a high-affinity enzyme with a catalytic efficiency ∼15-fold greater than those of CYPs 3A4 and 3A5. The CYP3A inhibitors ketoconazole and troleandomycin, and the CYP2C8 inhibitors quercetin and paclitaxel decreased imatinib oxidation. From molecular modelling, the imatinib structure could be superimposed on a pharmacophore for CYP2C8 substrates.
CYP2C8 and CYPs 3A contribute to imatinib N-demethylation in human liver. The involvement of CYP2C8 may account in part for the wide inter-patient variation in imatinib pharmacokinetics observed in clinical practice.
Mots-clé
Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors, Aryl Hydrocarbon Hydroxylases/metabolism, Benzamides, Chromatography, Liquid, Cytochrome P-450 CYP2C8, Cytochrome P-450 CYP3A/metabolism, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 Enzyme System/metabolism, Enzyme Inhibitors/pharmacology, Humans, Imatinib Mesylate, Microsomes, Liver/metabolism, Models, Molecular, Oxidation-Reduction, Piperazines/metabolism, Protein Kinase Inhibitors/metabolism, Pyrimidines/metabolism, Tandem Mass Spectrometry
Pubmed
Web of science
Création de la notice
05/03/2019 10:25
Dernière modification de la notice
20/08/2019 15:15
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