TY - JOUR T1 - Receptor Occupancy and Brain Free Fraction JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 753 LP - 760 DO - 10.1124/dmd.108.022814 VL - 37 IS - 4 AU - Jeanette Watson AU - Sara Wright AU - Adam Lucas AU - Kirsten L. Clarke AU - Jean Viggers AU - Sharon Cheetham AU - Phil Jeffrey AU - Rod Porter AU - Kevin D. Read Y1 - 2009/04/01 UR - http://dmd.aspetjournals.org/content/37/4/753.abstract N2 - This study was designed to investigate whether brain unbound concentration (Cu,brain) is a better predictor of dopamine D2 receptor occupancy than total brain concentration, cerebrospinal fluid concentration (CCSF), or blood unbound concentration (Cu,blood). The ex vivo D2 receptor occupancy and concentration-time profiles in cerebrospinal fluid, blood, and brain of six marketed antipsychotic drugs were determined after oral administration in rats at a range of dose levels. The Cu,brain was estimated from the product of total brain concentration and unbound fraction, which was determined using a brain homogenate method. In conclusion, the Cu,brain of selected antipsychotic agents is a good predictor of D2 receptor occupancy in rats. Furthermore, Cu,brain seems to provide a better prediction of D2 receptor occupancy than CCSF or Cu,blood for those compounds whose mechanism of entry into brain tissue is influenced by factors other than simple passive diffusion. The American Society for Pharmacology and Experimental Therapeutics ER -