Fig. 1: Conceptual overview for mapping the extent of unbound drug transport across the BBB.
a The in vivo rat neuropharmacokinetic (neuroPK) study provides measurements of the total concentration of a drug in the brain tissue (Ctot,brain,ss) and blood (Ctot,plasma,ss) under steady-state conditions achieved by a 4-h continuous intravenous infusion of the drug. b The in vitro rat brain-slice method provides measurements of the total concentration of a drug in a brain slice (Ctot,br,slice,ss) and buffer (Cu,buffer,ss) under steady-state conditions established by incubating brain slices in the buffer with the drug. c, d Key compartments when analyzing drug distribution in the brain: blood/buffer, brain interstitial fluid (ISF), and parenchymal cells. c Schematic depiction of the in vivo distribution of an unbound drug in the virtually protein-free brain ISF, including passage across the brain endothelial (BBB) and parenchymal cellular (CB) barriers, as well as specific and nonspecific binding to tissue constituents. d Under in vitro conditions, distributional processes are analogous, apart from the absence of functional BBB. e, f Estimation of the extent of unbound drug transport. e Kp,uu,brain is assessed as the ratio of Ctot,brain,ss to Ctot,br,slice,ss. The underlying assumption is that the steady-state unbound plasma concentration (Cu,plasma,ss) is equal to the buffer concentration (Cu,buffer,ss). If this condition is not satisfied, a correction factor (CF) equal to the ratio of Cu,buffer,ss to Cu,plasma,ss is used. f Interpretation of BBB transport based on Kp,uu,brain values.
