Download Blood-Brain Barrier in Drug Discovery: Optimizing Brain by Li Di, Edward H. Kerns PDF

By Li Di, Edward H. Kerns

Focused on valuable fearful method (CNS) drug discovery efforts, this booklet educates drug researchers concerning the blood-brain barrier (BBB) to allow them to impact very important advancements in a single of the main major – and such a lot difficult – parts of drug discovery.

• Written by way of international specialists to supply useful recommendations to extend mind penetration or reduce CNS side-effects
• Reviews state of the art in silico, in vitro, and in vivo instruments to evaluate mind penetration and complicated CNS drug supply strategies
• Covers BBB body structure, medicinal chemistry layout ideas, loose drug speculation for the BBB, and delivery mechanisms together with passive diffusion, uptake/efflux transporters, and receptor-mediated processes
• Highlights the advances in modelling BBB pharmacokinetics and dynamics relationships (PK/PD) and physiologically-based pharmacokinetics (PBPK)
• Discusses case reviews of winning CNS and non-CNS medicinal drugs, classes realized and paths to the market

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Extra resources for Blood-Brain Barrier in Drug Discovery: Optimizing Brain Exposure of CNS Drugs and Minimizing Brain Side Effects for Peripheral Drugs

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34 Pharmacokinetics of CNS Penetration [13] Reichel A (2009) Addressing central nervous system (CNS) penetration in drug discovery: basics and implications of the evolving new concept. Chem Biodivers 6(11):2030–2049. [14] Summerfield SG, Lucas AJ, Porter RA, Jeffrey P, Gunn RN, Read KR, Stevens AJ, Metcalf AC, Osuna MC, Kilford PJ, Passchier J, Ruffo AD (2008) Toward an improved prediction of human in vivo brain penetration. Xenobiotica 38(12):1518–1535. [15] Abbott NJ, Rönnbäck L, Hansson E (2006) Astrocyte–endothelial interactions at the blood-brain barrier.

For compounds where the concentration–time profiles in plasma and brain do not run in parallel, unbound brain concentrations cannot directly be taken from unbound plasma concentrations and Kp,uu. Therefore, the unbound brain concentrations of such compounds carry much more uncertainty compared to compounds with a parallel concentration–time profile. Whenever possible, preference should therefore 21 Parallel Non-parallel c–t profiles in plasma and brain c–t profiles in plasma and brain Concentration Concentration NEUROPK Total brain Total plasma Time Unbound plasma and Brain Cu,brain = Cu,plasma × Kp,uu Total brain ?

Academic Press, Amsterdam, p. 552. [67] Summerfield S, Jeffrey P. (2009) Discovery DMPK: changing paradigms in the eighties, nineties and noughties. Exp Opin Drug Discov 4(3):207–218. [68] Zhang D, Surapaneni S (2012) ADME-Enabling Technologies in Drug Design and Development. John Wiley & Sons, NJ, p. 622. [69] Liu X, Smith BJ, Chen C, Callegari E, Becker SL, Chen X, Cianfrogna J, Doran AC, Doran SD, Gibbs JP, Hosea N, Liu J, Nelson FR, Szewc MA, Van Deusen J. (2005) Use of a physiologically based pharmacokinetic model to study the time to reach brain equilibrium: an experimental analysis of the role of blood-brain barrier permeability, plasma protein binding, and brain tissue binding.

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