ddt2004_BBB pred.pdfVIP

TECHNOLOGIES DRUG DISCOVERY TODAY Drug Discovery Today: Technologies Vol. 1, No. 4 2004 Editors-in-Chief Kelvin Lam – Pfizer, Inc., USA Henk Timmerman – Vrije Universiteit, The Netherlands Lead profilingPrediction of blood–brain barrier permeation in drug discovery from in vivo, in vitro and in silico models N. Joan Abbott Blood–Brain Barrier Group, Wolfson Centre for Age Related Diseases, Hodgkin Building, King’s College London, London, UK SE1 1ULThe properties of the blood–brain barrier (BBB) are important considerations when designing drugs to tar- get or avoid the brain. In vivo models provide some of the most reliable measurements of BBB drug perme- ability, whereas several new cell-based in vitro technol- ogies give valuable mechanistic insights. Higher throughout methods (cell- and non-cell-based; in silico modelling) can help in prediction of permeation, but a combination of techniques is still required to cover the range of BBB drug entry and efflux mechanisms.E-mail address: (N. J. Abbott) joan.abbott@kcl.ac.uk URL: http://www.kcl.ac.uk/depsta/biomedical/CARD/abbott_profile.htm 1740-6749/$
2004 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddtec.2004.11.014Section Editors: Han van de Waterbeemd, Christopher Kohl – Pfizer Global Research Development, Pharmacokinetics, Dynamics and Metabolism (PDM), Sandwich, Kent, UK The central nervous system is an important target for many classes of drugs, such as sleep inducers, sedatives, anti-psychotics and -epileptics. For other drug agents, it may be necessary to limit brain penetration to reduce undesirable side effects. Thus there is considerable interest in developing reliable models for the prediction of blood–brain barrier permeation. In this review Joan Abbott expertly discusses models available in vivo, in vitro and in silico. In vivo models are low throughput, whereas currently there still is no standard in vitro screen for assessing brain uptake. The development of robust in silico models is hampered