The influence of distributional kinetics into a peripheral compartment on the pharmacokinetics of substrate partitioning between blood and brain tissue

Development of CNS-targeted agents often focuses on identifying compounds with "good" CNS exposure (brain-to-blood partitioning [1). Some compounds undergoing enterohepatic recycling (ER) evidence a partition coefficient, K _p,brain (expressed as C _brain/C _plasma), that exceeds and then decreases to (i.e., overshoots) a plateau (distribution equilibrium) value, rather than increasing monotonically to this value. This study tested the hypothesis that overshoot in K _p,brain is due to substrate residence in a peripheral compartment. Simulations were based on a 3-compartment model with distributional clearances between central and brain (CL _br) and central and peripheral (CL _d) compartments and irreversible clearance from the central compartment (CL). Parameters were varied to investigate the relationship between overshoot and peripheral compartment volume ( V _p), and how this relationship was modulated by other model parameters. Overshoot magnitude and duration were characterized as peak C _brain/C _plasma relative to the plateau value (%OS) and time to reach plateau (TRP). Except for systems with high CL _d, increasing V _p increased TRP and %OS. Increasing brain ( V _br) or central ( V _c) distribution volumes eliminated V _p-related OS. Parallel increases in all clearances shortened TRP, but did not alter %OS. Increasing either CL or CL _d individually increased %OS related to V _p, while increasing CL _br decreased %OS. Under realistic peripheral distribution scenarios, C _brain/C _plasma may overshoot substantially K _p,brain at distribution equilibrium. This observation suggests potential for erroneous assessment of brain disposition, particularly for compounds which exhibit a large apparent V _p, and emphasizes the need for complete understanding of distributional kinetics when evaluating brain uptake.