P-glycoprotein (ABCB1/MDR1) limits brain accumulation and Cytochrome P450-3A (CYP3A) restricts oral availability of the novel FGFR4 inhibitor fisogatinib (BLU-554).
ATP Binding Cassette Transporter, Subfamily B
/ genetics
Administration, Oral
Animals
Biological Availability
Brain
/ metabolism
Carcinoma, Hepatocellular
/ drug therapy
Cytochrome P-450 CYP3A
/ genetics
Humans
Intestinal Mucosa
/ metabolism
Liver
/ metabolism
Liver Neoplasms
/ drug therapy
Male
Mice
Mice, Knockout
Organic Cation Transport Proteins
/ genetics
Protein Kinase Inhibitors
/ administration & dosage
Pyrans
/ pharmacology
Quinazolines
/ pharmacology
Receptor, Fibroblast Growth Factor, Type 4
/ antagonists & inhibitors
Recombinant Proteins
/ genetics
Tissue Distribution
Brain accumulation
Cytochrome P450-3A
Fibroblast growth factor receptor 4
Fisogatinib (BLU-554)
Oatp1a/1b
Oral availability
P-glycoprotein
Journal
International journal of pharmaceutics
ISSN: 1873-3476
Titre abrégé: Int J Pharm
Pays: Netherlands
ID NLM: 7804127
Informations de publication
Date de publication:
05 Jan 2020
05 Jan 2020
Historique:
received:
14
09
2019
revised:
29
10
2019
accepted:
01
11
2019
pubmed:
24
11
2019
medline:
29
7
2020
entrez:
24
11
2019
Statut:
ppublish
Résumé
Fisogatinib (BLU-554) is a highly selective and potent oral fibroblast growth factor receptor 4 (FGFR4) inhibitor currently in Phase I clinical trials for treatment of hepatocellular carcinoma (HCC). Using (male) genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters, and the drug-metabolizing CYP3A complex in fisogatinib pharmacokinetics. In vitro, fisogatinib was modestly transported by hABCB1. Upon oral administration of 10 mg/kg fisogatinib, its brain accumulation was substantially increased in Abcb1a/1b
Identifiants
pubmed: 31759109
pii: S0378-5173(19)30887-7
doi: 10.1016/j.ijpharm.2019.118842
pii:
doi:
Substances chimiques
ATP Binding Cassette Transporter, Subfamily B
0
Organic Cation Transport Proteins
0
Protein Kinase Inhibitors
0
Pyrans
0
Quinazolines
0
Recombinant Proteins
0
fisogatinib
5Q7R99CKV2
multidrug resistance protein 3
9EI49ZU76O
CYP3A protein, mouse
EC 1.14.14.1
Cytochrome P-450 CYP3A
EC 1.14.14.1
CYP3A4 protein, human
EC 1.14.14.55
Fgfr4 protein, mouse
EC 2.7.10.1
Receptor, Fibroblast Growth Factor, Type 4
EC 2.7.10.1
Abcb1b protein, mouse
EC 7.6.2.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
118842Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.