Strategies to assess blood–brain barrier penetration

作者：Li Di, Edward H. Kerns, Guy T. Carter · 发表于：Expert Opinion on Drug Discovery · 年份：2008 · DOI：10.1517/17460441.3.6.677 · 被引用次数：116 · 研究领域：Pharmacological Effects and Toxicity Studies、Drug Transport and Resistance Mechanisms、Neuroscience and Neuropharmacology Research

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.