Central nervous system (CNS) drug disposition is dictated by a drug's physicochemical
properties and its ability to permeate physiological barriers. The blood–brain barrier (BBB),
blood-cerebrospinal fluid barrier and centrally located drug transporter proteins influence
drug disposition within the central nervous system. Attainment of adequate brain-to-plasma
and cerebrospinal fluid-to-plasma partitioning is important in determining the efficacy of
centrally acting therapeutics. We have developed a physiologically-based pharmacokinetic …

ABSTRACT A whole-body physiologically based pharmacokinetic (PBPK) model was
developed for the prediction of unbound drug concentration-time profiles in the rat brain, in
which drug transfer across the blood–brain barrier (BBB) was treated mechanistically by
separating the parameters governing the rate (permeability) of BBB transfer from brain
binding. An in vitro–in vivo scaling strategy based on Caco-2 cell permeability was proposed
to extrapolate the active transporter-driven component of this permeability, in which a …