Development of a High-Throughput Brain Slice Method for Studying Drug Distribution in the Central Nervous System

切片制备 药物发现 中枢神经系统 药品 脑组织 分布(数学) 化学 药理学 计算生物学 神经科学 生物 生物化学 数学 数学分析
作者
Markus Fridén,Frederic Ducrozet,Brian Middleton,Madeleine Antonsson,Ulf Bredberg,Margareta Hammarlund-Udenæs
出处
期刊:Drug Metabolism and Disposition [American Society for Pharmacology and Experimental Therapeutics]
卷期号:37 (6): 1226-1233 被引量:115
标识
DOI:10.1124/dmd.108.026377
摘要

New, more efficient methods of estimating unbound drug concentrations in the central nervous system (CNS) combine the amount of drug in whole brain tissue samples measured by conventional methods with in vitro estimates of the unbound brain volume of distribution (V(u,brain)). Although the brain slice method is the most reliable in vitro method for measuring V(u,brain), it has not previously been adapted for the needs of drug discovery research. The aim of this study was to increase the throughput and optimize the experimental conditions of this method. Equilibrium of drug between the buffer and the brain slice within the 4 to 5 h of incubation is a fundamental requirement. However, it is difficult to meet this requirement for many of the extensively binding, lipophilic compounds in drug discovery programs. In this study, the dimensions of the incubation vessel and mode of stirring influenced the equilibration time, as did the amount of brain tissue per unit of buffer volume. The use of cassette experiments for investigating V(u,brain) in a linear drug concentration range increased the throughput of the method. The V(u,brain) for the model compounds ranged from 4 to 3000 ml . g brain(-1), and the sources of variability are discussed. The optimized setup of the brain slice method allows precise, robust estimation of V(u,brain) for drugs with diverse properties, including highly lipophilic compounds. This is a critical step forward for the implementation of relevant measurements of CNS exposure in the drug discovery setting.
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