Drug Discovery Methods for Studying Brain Drug Delivery and Distribution
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 evalu
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Drug Discovery Methods for Studying Brain Drug Delivery and Distribution Irena Loryan and Margareta Hammarlund-Udenaes
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 blood– brain 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 Abrain AUCtot,brain AUCtot,plasma BBB
Amount of drug in brain tissue Area under the total brain concentration–time curve Area under the total plasma concentration–time curve Blood–brain barrier
I. Loryan (*) • M. Hammarlund-Udenaes Translational PKPD Research Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden e-mail: [email protected] M. Hammarlund-Udenaes et al. (eds.), Drug Delivery to the Brain, AAPS Advances in the Pharmaceutical Sciences Series 10, DOI 10.1007/978-1-4614-9105-7_10, © American Association of Pharmaceutical Scientists 2014
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BCRP Breast cancer resistance-associated protein BCSFB Blood-CSF barrier CB Cellular barrier Cbuffer Concentration of compound in the buffer (brain slice method) CNS Central nervous system CSF Cerebrospinal fluid Ctot,blood Total drug concentration in blood Ctot,brain Total drug concentration in brain Total drug concentration in plasma Ctot,plasma Cu,brainISF Unbound drug concentration in brain interstitial fluid Cu,cell Unbound drug concentration in intracellular fluid Cu,cyto Unbound drug concentration in cytosol Cu,lyso Unbound drug concentration in lysosomes Cu,plasma Unbound drug concentration in plasma DMPK Drug metabolism and pharmacokinetics ECF Extracellular fluid (same as ISF) ED Equilibrium dialysis ER Efflux ratio fu,brain Fraction of unbound drug in brain homogenate fu,brain,corrected fu,brain Corrected for pH partitioning into cells fu,hD Fraction of unbound drug in diluted brain homogenate fu,plasma Fraction of unbound drug in plasma HTS High-throughput screening ICF Int
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