It has long been recognized that relative plasma and tissue binding largely determine drug distribution. In this work, we demonstrate that unbound brain (fub) and unbound plasma (fup) fraction paired with a measure of equilibrium brain and plasma exposure can be used as an indirect model for the assessment of brain penetration and for the direct estimation of free brain concentrations. Preclinical brain-to-plasma ratio's (B/P) for the majority of over 100 proprietary and marketed CNS agents examined thus far can be accurately predicted via fup/fub ratio measured in vitro. In instances where brain distribution is known to be impaired via efflux transport, the degree of impairment is quantitatively indicated by the discrepancy between B/P ratio and fup/fub. Application of this approach to multiple species suggests that the degree of tissue binding and distributional impairment (due to P-gp) are quantitatively similar among species. In addition, PK-PD exercises indicate that the concentration of drug available to interact with CNS targets can be accurately estimated through the product of fub and total brain concentrations. These results indicate that this approach offers a simple and nonspecific (species and mechanism) means for determining CNS penetration and free drug exposure.
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