Cytochromes P450 2C8 and 3A Catalyze the Metabolic Activation of the Tyrosine Kinase Inhibitor Masitinib.
Journal
Chemical research in toxicology
ISSN: 1520-5010
Titre abrégé: Chem Res Toxicol
Pays: United States
ID NLM: 8807448
Informations de publication
Date de publication:
19 09 2022
19 09 2022
Historique:
pubmed:
2
9
2022
medline:
21
9
2022
entrez:
1
9
2022
Statut:
ppublish
Résumé
Masitinib is a small molecule tyrosine kinase inhibitor under investigation for the treatment of amyotrophic lateral sclerosis, mastocytosis, and COVID-19. Hepatotoxicity has been reported in some patients while taking masitinib. The liver injury is thought to involve hepatic metabolism of masitinib by cytochrome P450 (P450) enzymes to form chemically reactive, potentially toxic metabolites. The goal of the current investigation was to determine the P450 enzymes involved in the metabolic activation of masitinib in vitro. In initial studies, masitinib (30 μM) was incubated with pooled human liver microsomes in the presence of NADPH and potassium cyanide to trap reactive iminium ion metabolites as cyano adducts. Masitinib metabolites and cyano adducts were analyzed using reversed-phase liquid chromatography-tandem mass spectrometry. The primary active metabolite,
Identifiants
pubmed: 36048877
doi: 10.1021/acs.chemrestox.2c00057
pmc: PMC10226528
mid: NIHMS1898962
doi:
Substances chimiques
Benzamides
0
Piperidines
0
Protein Kinase Inhibitors
0
Pyridines
0
Thiazoles
0
NADP
53-59-8
Cytochrome P-450 Enzyme System
9035-51-2
masitinib
M59NC4E26P
Potassium Cyanide
MQD255M2ZO
Banques de données
ClinicalTrials.gov
['NCT03127267', 'NCT04333108', 'NCT05441488', 'NCT05047783', 'NCT04622865', 'NCT05449444']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1467-1481Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM143044
Pays : United States
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