The impact of individual human cytochrome P450 enzymes on oxidative metabolism of anticancer drug lenvatinib.
Animals
Antineoplastic Agents
/ metabolism
Chromatography, High Pressure Liquid
Cytochrome P-450 Enzyme Inhibitors
/ pharmacology
Cytochrome P-450 Enzyme System
/ drug effects
Drug Interactions
Female
Humans
Male
Mass Spectrometry
Mice
Mice, Inbred C57BL
Microsomes, Liver
/ enzymology
Oxidation-Reduction
Phenylurea Compounds
/ metabolism
Protein Kinase Inhibitors
/ metabolism
Quinolines
/ metabolism
Rabbits
Rats
Rats, Wistar
Cytochrome P450
Lenvatinib
Metabolism
Tyrosine kinase inhibitor
Journal
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
ISSN: 1950-6007
Titre abrégé: Biomed Pharmacother
Pays: France
ID NLM: 8213295
Informations de publication
Date de publication:
Jan 2022
Jan 2022
Historique:
received:
03
09
2021
revised:
20
10
2021
accepted:
02
11
2021
pubmed:
1
12
2021
medline:
15
3
2022
entrez:
30
11
2021
Statut:
ppublish
Résumé
Lenvatinib, a small molecule tyrosine kinase inhibitor (TKI), exhibits good inhibitory effect in several types of carcinomas. Specifically, it is the most effective TKI used for treatment of thyroid cancer. To extend pharmacokinetics data on this anticancer agent, we aimed to identify the metabolites of lenvatinib formed during in vitro incubation of lenvatinib with human hepatic microsomes or recombinant cytochromes P450 (CYPs) by using high performance liquid chromatography and mass spectrometry. The role of CYPs in the oxidation of lenvatinib was initially investigated in hepatic microsomes using specific CYP inhibitors. CYP-catalytic activities in each microsomal sample were correlated with the amounts of lenvatinib metabolites formed by these samples. Further, human recombinant CYPs were employed in the metabolic studies. Based on our data, lenvatinib is metabolized to O-desmethyl lenvatinib, N-descyclopropyl lenvatinib and lenvatinib N-oxide. In the presence of cytochrome b
Identifiants
pubmed: 34847475
pii: S0753-3322(21)01177-X
doi: 10.1016/j.biopha.2021.112391
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Cytochrome P-450 Enzyme Inhibitors
0
Phenylurea Compounds
0
Protein Kinase Inhibitors
0
Quinolines
0
Cytochrome P-450 Enzyme System
9035-51-2
lenvatinib
EE083865G2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
112391Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.