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BACKGROUND: The principles and screening strategies for brain penetration in drug discovery are important in identifying drug candidates with desirable CNS properties. OBJECTIVE: Define key variables and assays that are essential for determining brain penetration. METHODS: This review covers issues, methods, and strategies for assessing brain penetration of small molecules in drug discovery. RESULTS/CONCLUSION: 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.
Di et al. (2008) studied this question.