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.