title: Ionization-specific prediction of blood-brain permeability.
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 log PS (permeability-surface area product) from in situ perfusion, brain uptake index, and intravenous administration studies. A data set of 280 log PS 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 (log P and pKa), thus providing a clear route towards property-based design of new CNS drugs.
authors.affiliation: Pharma Algorithms, Inc., A.Mickeviciaus 29, LT-08117 Vilnius, Lithuania. kiril@pharma-algorithms.com
authors.forename: Kiril
authors.initials: K
authors.lastname: Lanevskij
authors.forename: Pranas
authors.initials: P
authors.lastname: Japertas
authors.forename: Remigijus
authors.initials: R
authors.lastname: Didziapetris
authors.forename: Alanas
authors.initials: A
authors.lastname: Petrauskas
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000737:chemistry* / Q000378:metabolism*; D002199:Capillary Permeability / Q000502:physiology*; D004573:Electrolytes / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D051379:Mice; D008956:Models, Chemical; D015233:Models, Statistical; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013816:Thermodynamics
chemical_list: D004573:Electrolytes; D004364:Pharmaceutical Preparations