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, Kp,brain (expressed as Cbrain/Cplasma), 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 Kp,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 (CLbr) and central and peripheral (CLd) compartments and irreversible clearance from the central compartment (CL). Parameters were varied to investigate the relationship between overshoot and peripheral compartment volume (Vp), and how this relationship was modulated by other model parameters. Overshoot magnitude and duration were characterized as peak Cbrain/Cplasma relative to the plateau value (%OS) and time to reach plateau (TRP). Except for systems with high CLd, increasing Vp increased TRP and %OS. Increasing brain (Vbr) or central (Vc) distribution volumes eliminated Vp-related OS. Parallel increases in all clearances shortened TRP, but did not alter %OS. Increasing either CL or CLd individually increased %OS related to Vp, while increasing CLbr decreased %OS. Under realistic peripheral distribution scenarios, Cbrain/Cplasma may overshoot substantially Kp,brain at distribution equilibrium. This observation suggests potential for erroneous assessment of brain disposition, particularly for compounds which exhibit a large apparent Vp, and emphasizes the need for complete understanding of distributional kinetics when evaluating brain uptake.