Physiology of the blood–brain barrier and its consequences for drug transport to the brain

Abstract

The brain endothelium forms the blood–brain barrier (BBB) and is the chief site regulating molecular traffic between blood and brain. The ‘barrier phenotype’ includes tight junctions restricting paracellular flux and a range of transport mechanisms controlling transcellular flux. The barrier is induced by cell types associated with the microvessels and is subject to regulation. The composition of the BBB membranes will influence the permeability of lipid-soluble compounds. Specific transporter systems for solute uptake are present on both the apical (luminal) and basal (abluminal) membranes and efflux transporters of broader specificity are also present. Certain larger molecules may cross via transcytotic vesicular mechanisms. Potential drug molecules designed to enter the brain may use or interact with one or more of these routes—better understanding is needed before it will be possible to establish the optimal means of delivery for specific compounds and to design or modify them accordingly. Many lipid-soluble drugs are substrates for efflux transporters, making it difficult to guarantee CNS delivery or calculate free concentration in the brain interstitial fluid (ISF). The dynamics of the flowing ISF also complicate modelling and prediction of CNS pharmacokinetics. Finally, many disease states involve BBB dysfunction, which needs to be taken into account in designing appropriate therapies.