P-Glycoprotein (ABCB1/MDR1) and BCRP (ABCG2) Limit Brain Accumulation and Cytochrome P450-3A (CYP3A) Restricts Oral Exposure of the RET Inhibitor Selpercatinib (RETEVMO).
Slco1a/1b
brain accumulation
cytochrome P450-3A
oral exposure
p-glycoprotein/ABCB1
rearranged during transfection (RET) receptor kinase
selpercatinib
Journal
Pharmaceuticals (Basel, Switzerland)
ISSN: 1424-8247
Titre abrégé: Pharmaceuticals (Basel)
Pays: Switzerland
ID NLM: 101238453
Informations de publication
Date de publication:
27 Oct 2021
27 Oct 2021
Historique:
received:
20
09
2021
revised:
20
10
2021
accepted:
20
10
2021
entrez:
27
11
2021
pubmed:
28
11
2021
medline:
28
11
2021
Statut:
epublish
Résumé
Selpercatinib is a targeted, FDA-approved, oral, small-molecule inhibitor for the treatment of rearranged during transfection (RET) proto-oncogene mutation-positive cancer. Using 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 selpercatinib pharmacokinetics. Selpercatinib was efficiently transported by hABCB1 and mAbcg2, but not hABCG2, and was not a substrate of human OATP1A2, -1B1 or -1B3 in vitro. In vivo, brain and testis penetration were increased by 3.0- and 2.7-fold in
Identifiants
pubmed: 34832869
pii: ph14111087
doi: 10.3390/ph14111087
pmc: PMC8617681
pii:
doi:
Types de publication
Journal Article
Langues
eng
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