OATP1A/1B, CYP3A, ABCB1, and ABCG2 limit oral availability of the NTRK inhibitor larotrectinib, while ABCB1 and ABCG2 also restrict its brain accumulation.

ABSTRACT:

Background and purpose

Larotrectinib is a FDA-approved oral small-molecule inhibitor for treatment of neurotrophic tropomyosin receptor kinase fusion-positive cancer. We here investigated the functions of the multidrug efflux transporters ABCB1 and ABCG2, the SLCO1A/1B (OATP1A/1B) uptake transporters, and the multispecific drug-metabolizing enzyme CYP3A in larotrectinib pharmacokinetic behaviour.

Experimental approach

In vitro, transepithelial drug transport and uptake assays were performed. In vivo, larotrectinib (10 mg·kg^-1 ) was administered orally to relevant genetically modified mouse models. Cell medium, plasma samples, and organ homogenates were measured by a sensitive and specific LC-MS/MS larotrectinib assay.

Key results

In vitro, larotrectinib was

SUBMITTER: Wang Y 

PROVIDER: S-EPMC7279963 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature