Drug delivery and in vitro models of the blood-brain barrier.

An understanding of the physiology of the blood-brain barrier (BBB) is crucial when addressing complex issues such as drug delivery, pathogenesis of chronic neurological diseases and bio-defense. Rational central nervous system (CNS) drug design cannot entirely and exclusively rely upon the physicochemical properties of putative neurotherapeutics, since lipophilicity alone is a poor predictor for drug penetration into the CNS. This is particularly true for three large families of CNS drugs: antineoplastics, antivirals and anti-epileptics. For these drugs, in contrast to peripheral acting drugs (eg, antihistamines), negligible penetration across the BBB is preferable in order to avoid CNS side effects. Studies performed using small animals such as rodents cannot be directly extrapolated to human brain tissue, as demonstrated by both clinical and in vitro studies. Furthermore, most of the promising CNS drugs that proved effective in vitro have failed in clinical trials due to misleading predictive permeability data extrapolated from models that were not capable of fully reproducing the functional properties of the BBB in vivo. Therefore, a great effort has been made to develop new in vitro models able to reproduce the physiological, anatomical and functional characteristics of the BBB allowing for a better prediction of drug penetration across the BBB, and enabling the design of new pharmaceutical strategies to bypass the shielding of brain parenchyma. Herein we provide a detailed review and discussion of currently employed in vitro BBB models along with probable future developments.