Successful Prediction of Human Steady-State Unbound Brain-to-Plasma Concentration Ratio of P-gp Substrates Using the Proteomics-Informed Relative Expression Factor Approach.

ABSTRACT: In order to optimize central nervous system (CNS) drug development, accurate prediction of the drug's human steady-state unbound brain interstitial fluid-to-plasma concentration ratio (K_p,uu,brain ) is critical, especially for drugs that are effluxed by the multiple drug resistance transporters (e.g., P-glycoprotein, P-gp). Due to lack of good in vitro human blood-brain barrier models, we and others have advocated the use of a proteomics-informed relative expressive factor (REF) approach to predict K_p,uu,brain . Therefore, we tested the success of this approach in humans, with a focus on P-gp substrates, using brain positron emission tomography imaging data for verification. To do so, the efflux ratio (ER) of verapamil, N-desmethyl loperamide, and metoclopramide was d

SUBMITTER: Storelli F 

PROVIDER: S-EPMC8360000 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature