Strategies to assess blood–brain barrier penetration

Abstract

The principles and screening strategies for brain penetration in drug discovery are important in identifying drug candidates with desirable CNS properties. Define key variables and assays that are essential for determining brain penetration. This review covers issues, methods, and strategies for assessing brain penetration of small molecules in drug discovery. Brain penetration is assessed using both initial rate and extent at steady-state. Unbound drug is the active species that exerts pharmacological effects. Low brain penetration can be due to low blood-brain barrier (BBB) permeability, P-glycoprotein (Pgp) efflux, or high plasma protein binding. Successful methods include: parallel artificial membrane permeability assay (PAMPA)-BBB permeability, MDR1-MDCKII for Pgp efflux, B-P dialysis for fraction unbound, and in vivo B/P ratio to extrapolate unbound brain drug concentration.