Correlation between the in Vitro and in Vivo Blood-Brain Barrier Permeabilities of H2 Receptor Antagonists

In vitro models of the Blood-Brain Barrier (BBB) offer the possibility of a first level screen on new chemical entities for predicting potential brain permeability in vivo. An in vitro BBB model was established, utilizing cultured bovine brain microvessel endothelial cells (BBMECs). BBMEC cultures were assessed morphologically and biochemically for maintainance of in vivo cerebral microvessel endothelial characteristics. Barrier function was assessed by growing cultures on polycarbonate membrane filter inserts (Costar 12mm two piece SnapwellTM transwell plates; 0.4 um pore size) and placing these inserts between diffusion chambers and measuring permeability of C14- sucrose, a paracellular marker with low permeability and H3-propranolol, a transcellular permeability marker with high permeability. Between 10–15 days in culture, sucrose permeability was the lowest and ranged between 1.6–3.0 × 10−5 cm/sec (0.058–0.12 cm/hr) while propranolol permeability was unchanged from 6–12 days in culture. The validity and usefullness of the model in predicting in vivo brain penetration was assessed by measuring the in vitro permeability of seven H2 receptor antagonists whose in vivo CNS permeability was assessed by Young et al.4 A very good correlation was obtained between the in vitro and in vivo permeability for these molecules (R2=0.898). The results suggest that the in vitro model of the BBB using BBMECs provides a useful screening system for selecting molecules which will possess appropriate characteristics to access the brain.