Characterization of an "in vitro" blood-brain barrier: effects of molecular size and lipophilicity on cerebrovascular endothelial transport rates of drugs.

The in vitro blood-brain barrier model described consisted of confluent monolayers of bovine cerebrovascular cells in primary cultures. Aim of the study was to investigate whether this type of model exhibits transport characteristics comparable to the in vivo blood-brain barrier and whether the cells in the cultured monolayers were able to form tight junctions, the most typical feature of the in vivo blood-brain barrier. Endothelial permeability of fluorescein-conjugated dextrans with increasing molecular size was correlated to monolayer pore shape, size and abundance by means of a mathematical model. Results showed that the in vitro pores had a longitudinal appearance with an effective pore size of 81 A and fractional pore area of 0.04%. These data indicate that the properties of the in vitro pores and in vivo tight junctions are comparable. The monolayer model was applied successfully to establish a relationship between endothelial permeability and drug lipophilicity, using several beta blocking agents and nonsteroidal anti-inflammatory drugs as model drugs. Results showed a sigmoidal relationship between these parameters, indicating the existence of a threshold lipophilicity for passive transendothelial transport.