Blood-Brain Barrier in Drug Discovery

Contributors ix Preface xiii 1 Introduction and Overview 1 Li Di and Edward H. Kerns Part 1 Pharmacokinetics of Brain Exposure 5 2 Pharmacokinetics of CNS Penetration 7 Andreas Reichel 3 Free Drug Hypothesis for CNS Drug Candidates 42 Xingrong Liu and Cuiping Chen 4 Species Differences and Impact of Disease State on BBB_66 Jean-Marie Nicolas Part 2 Mechanisms of Drugs Across the Blood-Brain Barrier 95 5 Passive Diffusion Permeability of the BBB--Examples and SAR_97 Scott Summerfield, Phil Jeffrey, Jasminder Sahi, and Liangfu Chen 6 Establishment of P-Glycoprotein Structure-Transport Relationships to Optimize CNS Exposure in Drug Discovery 113 Jerome H. Hochman, Sookhee N. Ha, and Robert P. Sheridan 7 Uptake Transport at the BBB--Examples and SAR_125 Ziqiang Cheng and Qian Liu 8 Transport of Protein and Antibody Therapeutics across the Blood-Brain Barrier 146 William M. Pardridge Part 3 Predicting and Measuring Brain Exposure of Drugs 167 9 In Silico Tools for Predicting Brain Exposure of Drugs 169 Hongming Chen, Susanne Winiwarter, and Ola Engkvist 10 In Vitro Assays for Assessing BBB Permeability: Artificial Membrane and Cell Culture Models 188 Alex Avdeef, Mária A. Deli, and Winfried Neuhaus 11 Human-Based In Vitro Brain Endothelial Cell Models 238 Hannah K. Wilson and Eric V. Shusta 12 Methods for Assessing Brain Binding 274 Li Di and Cheng Chang 13 In Vivo Studies of Brain Exposure in Drug Discovery 284 Edward H. Kerns 14 PBPK Modeling Approach for Predictions of Human CNS Drug Brain Distribution 296 Elizabeth C.M. de Lange 15 PK/PD Modeling of CNS Drug Candidates 324 Johan Gabrielsson, Stephan Hjorth, and Lambertus A. Peletier 16 Microdialysis to Assess Free Drug Concentration in Brain 351 William Kielbasa and Robert E. Stratford, Jr. 17 Imaging Techniques for Central Nervous System (CNS) Drug Discovery 365 Lei Zhang and Anabella Villalobos Part 4 Modulating Brain Penetration of Leads During Drug Discovery 385 18 Designing CNS Drugs for Optimal Brain Exposure 387 Zoran Rankovic 19 Case Studies of CNS Drug Optimization--Medicinal Chemistry and CNS Biology Perspectives 425 Kevin J. Hodgetts 20 Designing Peripheral Drugs for Minimal Brain Exposure 446 Peter Bungay, Sharan Bagal, and Andy Pike 21 Case Studies of Non-CNS Drugs to Minimize Brain Penetration--Nonsedative Antihistamines 463 Andrew Crowe Part 5 Case Studies in CNS Drug Discovery 483 22 Case Study 1: The Discovery and Development of Perampanel 485 Antonio Laurenza, Jim Ferry, Haichen Yang, Shigeki Hibi, Takahisa Hanada, and Andrew Satlin 23 Case Study 2: The Discovery and Development of the Multimodal Acting Antidepressant Vortioxetine 505 Christoffer Bundgaard, Alan L. Pehrson, Connie Sánchez, and Benny Bang-Andersen Part 6 Drug Delivery Techniques to CNS 521 24 Brain Delivery Using Nanotechnology 523 Huile Gao and Xinguo Jiang 25 Intranasal Delivery to the Central Nervous System 535 Lisbeth Illum Part 7 Future Prospects in Blood-Brain Barrier UNDERSTANDING AND DRUG DISCOVERY 567 26 Future Perspectives 569 N. Joan Abbott Index 580