In Situ and In Vivo Animal Models

Abstract

An important property in any central nervous system drug is the ability to cross the blood–brain barrier (BBB) and to reach therapeutic concentrations in brain at safe and acceptable doses. Multiple parameters influence brain drug bioavailability, including solubility, membrane permeation, and affinity for influx and efflux transporters. This chapter overviews the primary in vivo methods to assess brain drug distribution in preclinical and clinical reports. In most studies, two parameters, the BBB permeability-surface area product (PS) and brain distribution volume or partition coefficient (K _p,brain), are used to characterize the ability of a drug compound to gain access to and distribute in brain. Together with the time course of systemic drug exposure, these two parameters can be used to predict total drug concentration within brain. Further, because unbound drug concentration often correlates better with drug activity, a number of studies also determine the drug free fraction (f _u) so that the free concentrations can be calculated. Specific methods, such as in situ brain perfusion, brain efflux index, and brain microdialysis, are valuable to dissect specific elements of BBB drug permeation or transport as well as equilibration in brain interstitial fluid and cellular elements. Overall, these approaches complement in vivo drug distribution studies and in vitro BBB permeation methods.