Central nervous system drug disposition: the relationship between in situ brain permeability and brain free fraction

The dispositions of 50 marketed central nervous system (CNS) drugs into the brain have been examined in terms of their rat in situ (P) and in vitro apparent membrane permeability (P(app)) alongside lipophilicity and free fraction in rat brain tissue. The inter-relationship between these parameters highlights that both permeability and brain tissue binding influence the uptake of drugs into the CNS. Hydrophilic compounds characterized by low brain tissue binding display a strong correlation (R(2) = 0.82) between P and P(app), whereas the uptake of more lipophilic compounds seems to be influenced by both P(app) and brain free fraction. A nonlinear relationship is observed between logP(oct) and P over the 6 orders of magnitude range in lipophilicity studied. These findings corroborate recent reports in the literature that brain penetration is a function of both rate and extent of drug uptake into the CNS.