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.