Drug Discovery Methods for Studying Brain Drug Delivery and Distribution

Abstract

Methods used in drug discovery laboratories for assessing the delivery of small molecules to the brain have changed significantly in recent years. There is now more focus on measuring or estimating target unbound drug concentrations in the brain and evaluating the quantitative aspects of drug transport across the bloodbrain barrier (BBB). The techniques for investigation of the rate and extent of BBB transport of new chemical entities (NCEs) are discussed in this chapter. Combinatory methodology for rapid mapping of the extent of brain drug delivery via assessment of the unbound drug brain partitioning coefficient is presented. The chapter also explains the procedures for approximation of subcellular distribution of NCEs, particularly into the lysosomes. The principles, technical issues, advantages, and potential applications of techniques for evaluation of intra-brain distribution, i.e., equilibrium dialysis-based brain homogenate and brain slice methods, are described. The assessment of extent of BBB transport and intracellular distribution of NCEs, the identification of intra-brain distribution patterns, and their integration with pharmacodynamic measurements are valuable implements for candidate evaluation and selection in drug discovery and development. Abbreviations A brainAmount of drug in brain tissue AUC tot,brain Area under the total brain concentration-time curve AUC tot,plasma Area under the total plasma concentration-time curve BBB Blood-brain barrier

Molecular Properties Determining Unbound Intracellular and Extracellular Brain Exposure of CNS Drug Candidates

“…The assessment of steady-state K p,uu,brain was achieved through the combinatory mapping approach ,,, italicK normalp , uu , brain ≈ italicK normalp , brain italicV normalu , brain italicf normalu , plasma where K p,brain is the ratio of total brain to total plasma drug concentrations at steady state. K p,brain was obtained at multiple time points (minimum four) after oral or subcutaneous administration.…”