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.