title: In vitro primary human and animal cell-based blood-brain barrier models as a screening tool in drug discovery.
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 × 10⁻⁴) 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.
authors: Laboratoires Fournier S.A., Daix, France.
authors: Olivier
authors: O
authors: Lacombe
authors: Orianne
authors: O
authors: Videau
authors: Delphine
authors: D
authors: Chevillon
authors: Anne-Cécile
authors: AC
authors: Guyot
authors: Christelle
authors: C
authors: Contreras
authors: Sandrine
authors: S
authors: Blondel
authors: Laurence
authors: L
authors: Nicolas
authors: Aurélie
authors: A
authors: Ghettas
authors: Henri
authors: H
authors: Bénech
authors: Etienne
authors: E
authors: Thevenot
authors: Alain
authors: A
authors: Pruvost
authors: Sébastien
authors: S
authors: Bolze
authors: Lucie
authors: L
authors: Krzaczkowski
authors: Colette
authors: C
authors: Prévost
authors: Aloïse
authors: A
authors: Mabondzo
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D008297:Male; D008954:Models, Biological; D051381:Rats; D019108:Tight Junctions / Q000378:metabolism