P-glycoprotein (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) limit brain accumulation of the FLT3 inhibitor quizartinib in mice.
ATP Binding Cassette Transporter, Subfamily B
/ genetics
ATP Binding Cassette Transporter, Subfamily G, Member 2
/ genetics
Animals
Antineoplastic Agents
/ administration & dosage
Benzothiazoles
/ administration & dosage
Biological Availability
Brain
/ metabolism
Dogs
Female
Humans
Madin Darby Canine Kidney Cells
Mice
Mice, Knockout
Mice, Transgenic
Neoplasm Proteins
/ genetics
Phenylurea Compounds
/ administration & dosage
Tissue Distribution
fms-Like Tyrosine Kinase 3
/ antagonists & inhibitors
ABCB1
ABCG2
Brain penetration
CYP3A enzymes
FLT3
Quizartinib
Journal
International journal of pharmaceutics
ISSN: 1873-3476
Titre abrégé: Int J Pharm
Pays: Netherlands
ID NLM: 7804127
Informations de publication
Date de publication:
10 Feb 2019
10 Feb 2019
Historique:
received:
21
09
2018
revised:
27
11
2018
accepted:
03
12
2018
pubmed:
16
12
2018
medline:
5
4
2019
entrez:
16
12
2018
Statut:
ppublish
Résumé
Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mAbcg2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mAbcg2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b
Identifiants
pubmed: 30553002
pii: S0378-5173(18)30920-7
doi: 10.1016/j.ijpharm.2018.12.014
pii:
doi:
Substances chimiques
ABCB1 protein, human
0
ABCG2 protein, human
0
ATP Binding Cassette Transporter, Subfamily B
0
ATP Binding Cassette Transporter, Subfamily G, Member 2
0
Abcg2 protein, mouse
0
Antineoplastic Agents
0
Benzothiazoles
0
Neoplasm Proteins
0
Phenylurea Compounds
0
quizartinib
7LA4O6Q0D3
FLT3 protein, human
EC 2.7.10.1
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
172-180Informations de copyright
Copyright © 2018 Elsevier B.V. All rights reserved.