ABSTRACT:This study was designed to investigate whether brain unbound concentration (C u,brain ) is a better predictor of dopamine D 2 receptor occupancy than total brain concentration, cerebrospinal fluid concentration (C CSF ), or blood unbound concentration (C u,blood ). The ex vivo D 2 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 C u,brain was estimated from the product of total brain concentration and unbound fraction, which was determined using a brain homogenate method. In conclusion, the C u,brain of selected antipsychotic agents is a good predictor of D 2 receptor occupancy in rats. Furthermore, C u,brain seems to provide a better prediction of D 2 receptor occupancy than C CSF or C u,blood for those compounds whose mechanism of entry into brain tissue is influenced by factors other than simple passive diffusion.
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