In vitro primary human and animal cell-based blood-brain barrier models as a screening tool in drug discovery.
Mol Pharm
; 8(3): 651-63, 2011 Jun 06.
Article
em En
| MEDLINE
| ID: mdl-21438632
ABSTRACT
Brain penetration is characterized by its extent and rate and is influenced by drug physicochemical properties, plasma exposure, plasma and brain protein binding and BBB permeability. This raises questions related to physiology, interspecies differences and in vitro/in vivo extrapolation. We herein discuss the use of in vitro human and animal BBB model as a tool to improve CNS compound selection. These cell-based BBB models are characterized by low paracellular permeation, well-developed tight junctions and functional efflux transporters. A study of twenty drugs shows similar compound ranking between rat and human models although with a 2-fold higher permeability in rat. cLogP < 5, PSA < 120 Å, MW < 450 were confirmed as essential for CNS drugs. An in vitro/in vivo correlation in rat (R² = 0.67; P = 2 × 10â»4) was highlighted when in vitro permeability and efflux were considered together with plasma exposure and free fraction. The cell-based BBB model is suitable to optimize CNS-drug selection, to study interspecies differences and then to support human brain exposure prediction.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Barreira Hematoencefálica
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Mol Pharm
Assunto da revista:
BIOLOGIA MOLECULAR
/
FARMACIA
/
FARMACOLOGIA
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
França