title: High-throughput screening of drug-brain tissue binding and in silico prediction for assessment of central nervous system drug delivery.
abstract: A high-throughput method for rapid screening of in vitro drug-brain homogenate binding is presented. The method is based on a straightforward sample pooling approach combining equilibrium dialysis with liquid chromatography mass spectrometry (LCMS). A strong correlation of fraction unbound in brain (fu) between single compound measurements and 25-pooled compounds (R2 = 0.906) was obtained for a selection of structurally diverse CNS compounds with a wide range of fractions unbound. Effects of brain homogenate dilution and dialysis time were investigated. To the best of our knowledge, it was the first time that we have demonstrated consistent fraction unbound in mouse and rat brain homogenate, revealing the drug-tissue partitioning mechanism predominated by hydrophobic interaction. On the basis of this finding, a generic approach to estimate drug binding to various tissues is proposed. A robust and interpretable QSAR for fu prediction is also presented by statistical modeling.
authors.affiliation: Lead Generation DMPK & Physical Chemistry, AstraZeneca R&D, Mölndal, SE-431 88, Mölndal, Sweden. hong.wan@astrazeneca.com
authors.forename: Hong
authors.initials: H
authors.lastname: Wan
authors.forename: Mikael
authors.initials: M
authors.lastname: Rehngren
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giordanetto
authors.forename: Fredrik
authors.initials: F
authors.lastname: Bergström
authors.forename: Anders
authors.initials: A
authors.lastname: Tunek
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D003956:Dialysis; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D051379:Mice; D015233:Models, Statistical; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D051381:Rats
chemical_list: D002491:Central Nervous System Agents