期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 98, 期 1, 页码 122-134出版社
WILEY
DOI: 10.1002/jps.21405
关键词
QSAR; in silico modeling; nonlinear regression; computational ADME; blood-brain barrier; drug transport; passive diffusion; permeability
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 logPS (permeability-surface area product) from in situ perfusion, brain uptake index, and intravenous administration studies. A data set of 280 logPS 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 (RMSE < 0.5) and simple physicochemical interpretations (logP and pKa), thus providing a clear route towards property-based design of new CNS drugs. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:122-134, 2009
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