PT - JOURNAL ARTICLE AU - Scott G. Summerfield AU - Kevin Read AU - David J. Begley AU - Tanja Obradovic AU - Ismael J. Hidalgo AU - Sara Coggon AU - Ann V. Lewis AU - Rod A. Porter AU - Phil Jeffrey TI - Central Nervous System Drug Disposition: The Relationship between in Situ Brain Permeability and Brain Free Fraction AID - 10.1124/jpet.107.121525 DP - 2007 Jul 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 205--213 VI - 322 IP - 1 4099 - http://jpet.aspetjournals.org/content/322/1/205.short 4100 - http://jpet.aspetjournals.org/content/322/1/205.full SO - J Pharmacol Exp Ther2007 Jul 01; 322 AB - 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 (Papp) 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 (R2 = 0.82) between P and Papp, whereas the uptake of more lipophilic compounds seems to be influenced by both Papp and brain free fraction. A nonlinear relationship is observed between logPoct 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. The American Society for Pharmacology and Experimental Therapeutics