Metabolism of the dual FLT-3/Aurora kinase inhibitor CCT241736 in preclinical and human in vitro models: Implication for the choice of toxicology species.
Animals
Aurora Kinases
/ antagonists & inhibitors
Cytochrome P-450 Enzyme System
/ metabolism
Dogs
Drug Evaluation, Preclinical
Female
Hepatocytes
/ metabolism
Humans
Male
Mice, Inbred ICR
Microsomes, Liver
/ metabolism
Piperazines
/ pharmacokinetics
Protein Kinase Inhibitors
/ pharmacokinetics
Rats, Sprague-Dawley
Species Specificity
Swine
Swine, Miniature
Toxicity Tests
fms-Like Tyrosine Kinase 3
/ antagonists & inhibitors
In vitro metabolism
Metabolite identification
Reaction phenotyping
Toxicology species
Journal
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
ISSN: 1879-0720
Titre abrégé: Eur J Pharm Sci
Pays: Netherlands
ID NLM: 9317982
Informations de publication
Date de publication:
01 Nov 2019
01 Nov 2019
Historique:
received:
05
12
2018
revised:
26
02
2019
accepted:
02
04
2019
pubmed:
7
4
2019
medline:
27
2
2020
entrez:
7
4
2019
Statut:
ppublish
Résumé
CCT241736 is a dual fms-like tyrosine kinase 3 (FLT3)/Aurora kinase inhibitor in development for the treatment of acute myeloid leukaemia. The successful development of any new drug relies on adequate safety testing including preclinical toxicology studies. Selection of an appropriate preclinical species requires a thorough understanding of the compound's metabolic clearance and pathways, as well as other pharmacokinetic and pharmacodynamic considerations. In addition, elucidation of the metabolising enzymes in human facilitates improved clinical prediction based on population pharmacokinetics and can inform drug-drug interaction studies. Intrinsic clearance (CL
Identifiants
pubmed: 30953752
pii: S0928-0987(19)30142-3
doi: 10.1016/j.ejps.2019.04.004
pmc: PMC6892276
pii:
doi:
Substances chimiques
Piperazines
0
Protein Kinase Inhibitors
0
Cytochrome P-450 Enzyme System
9035-51-2
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
Aurora Kinases
EC 2.7.11.1
Types de publication
Comparative Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
104899Informations de copyright
Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.
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