Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 501, Issue 1-2, Pages 102-111Publisher
ELSEVIER
DOI: 10.1016/j.ijpharm.2016.01.074
Keywords
Blood-brain barrier; Central nervous system; PAMPA; High-throughput screening; Apparent permeability
Categories
Funding
- FEDER funds through the Operational Programme Competitiveness Factors-COMPETE
- FCT-Foundation for Science and Technology [SFRH/BD/78256/2011]
- BIAL-Portela Ca S.A.
- Fundação para a Ciência e a Tecnologia [SFRH/BD/78256/2011] Funding Source: FCT
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The determination of the permeability of drug candidates across the blood-brain barrier (BBB) is a fundamental step during drug discovery programs. The parallel artificial membrane permeability assay (PAMPA) is a high throughput screening tool applied to evaluate the passive permeability and adapted to predict BBB penetration. Herein, a new PAMPA model was developed using an in-house brain lipid extract capable of discriminating BBB permeable from non-permeable compounds. The apparent permeability (Papp) of 18 reference molecules and 10 test compounds was assessed and compared with phosphatidylcholine and commercial porcine polar brain lipid (PBL). The physicochemical selectivity of the in-house brain lipid extract was demonstrated by correlating Papp values with physicochemical properties and its predictive capacity estimated by establishing in vitro-in vivo correlations. The strong correlations achieved between 2% (w/v) in-house lipid extract and PBL for reference (r(2) = 0.77) and test compounds (r(2) = 0.94) support an equivalent discriminatory capacity and validate the presented model. Moreover, PAMPA studies performed with PBL and in-house lipid extract exhibited a higher correlation with the in vivo parameter logBB (r(2) = 0.76 and r(2) = 0.72, respectively) than phosphatidylcholine (r(2) = 0.51). Overall, the applied lipid extraction process was reproducible, economical and provided lipid extracts that can be used to reliably assess BBB permeation. (C) 2016 Published by Elsevier B.V.
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