Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2487218 | Journal of Pharmaceutical Sciences | 2009 | 13 Pages |
Abstract
This study presents a mechanistic QSAR analysis of passive blood-brain barrier permeability of drugs and drug-like compounds in rats and mice. The experimental data represented in vivo logâPS (permeability-surface area product) from in situ perfusion, brain uptake index, and intravenous administration studies. A data set of 280 logâPS values was compiled. A subset of 178 compounds was assumed to be driven by passive transport that is free of plasma protein binding and carrier-mediated effects. This subset was described in terms of nonlinear lipophilicity and ionization dependences, that account for multiple kinetic and thermodynamic effects: (i) drug's kinetic diffusion, (ii) ion-specific partitioning between plasma and brain capillary endothelial cell membranes, and (iii) hydrophobic entrapment in phospholipid bilayer. The obtained QSAR model provides both good statistical significance (RMSEâ<â0.5) and simple physicochemical interpretations (logâP and pKa), thus providing a clear route towards property-based design of new CNS drugs. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:122-134, 2009
Keywords
Related Topics
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Pharmacology, Toxicology and Pharmaceutical Science
Drug Discovery
Authors
Kiril Lanevskij, Pranas Japertas, Remigijus Didziapetris, Alanas Petrauskas,