Entrectinib, a TRK/ROS1 inhibitor with anti-CNS tumor activity: differentiation from other inhibitors in its class due to weak interaction with P-glycoprotein.

ABSTRACT:

Background

Studies evaluating the CNS penetration of a novel tyrosine kinase inhibitor, entrectinib, proved challenging, particularly due to discrepancies across earlier experiments regarding P-glycoprotein (P-gp) interaction and brain distribution. To address this question, we used a novel "apical efflux ratio" (AP-ER) model to assess P-gp interaction with entrectinib, crizotinib, and larotrectinib, and compared their brain-penetration properties.

Methods

AP-ER was designed to calculate P-gp interaction with the 3 drugs in vitro using P-gp-overexpressing cells. Brain penetration was studied in rat plasma, brain, and cerebrospinal fluid (CSF) samples after intravenous drug infusion. Unbound brain concentrations were estimated through kinetic lipid membrane binding assays and

SUBMITTER: Fischer H 

PROVIDER: S-EPMC7283026 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature