In vitro prediction of brain penetration - a case for free thinking?

Realising adequate brain penetration is a major obstacle in the design of drugs that target the CNS. Much of the understanding at present is derived from studies in rodents and it is difficult to translate many of these measurements to the clinical setting. The complex nature of the brain means that there are numerous compartments to consider when trying to understand brain penetration; these include regional differences in brain tissue morphology and composition, flow of fluid around the CNS network and the protective barriers between the brain and the periphery. A consequence of this complexity is that several parameters can be measured to assess different aspects of brain penetration and until recently no coherent model of brain penetration had been proposed. This review examines the understanding so far of the factors influencing brain penetration and the progress made as a result of in vitro studies. The shift towards thinking in terms of free brain concentrations and free brain fractions has not only provided a new insight into the nature of brain penetration, but also offers the future prospect of providing a better link between efficacy and a relevant unbound measure of brain penetration.