Receptor occupancy and brain free fraction

TY - JOUR

T1 - Receptor occupancy and brain free fraction

AU - Watson, Jeanette

AU - Wright, Sara

AU - Lucas, Adam

AU - Clarke, Kirsten L.

AU - Viggers, Jean

AU - Cheetham, Sharon

AU - Jeffrey, Phil

AU - Porter, Rod

AU - Read, Kevin D.

PY - 2009/4

Y1 - 2009/4

N2 - This study was designed to investigate whether brain unbound concentration (C-u,C-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,C-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,C-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,C-brain of selected antipsychotic agents is a good predictor of D-2 receptor occupancy in rats. Furthermore, C-u,C-brain seems to provide a better prediction of D-2 receptor occupancy than C-CSF or C-u,C-blood for those compounds whose mechanism of entry into brain tissue is influenced by factors other than simple passive diffusion.

AB - This study was designed to investigate whether brain unbound concentration (C-u,C-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,C-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,C-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,C-brain of selected antipsychotic agents is a good predictor of D-2 receptor occupancy in rats. Furthermore, C-u,C-brain seems to provide a better prediction of D-2 receptor occupancy than C-CSF or C-u,C-blood for those compounds whose mechanism of entry into brain tissue is influenced by factors other than simple passive diffusion.

UR - https://www.scopus.com/pages/publications/63849337048

U2 - 10.1124/dmd.108.022814

DO - 10.1124/dmd.108.022814

M3 - Article

C2 - 19158315

SN - 0090-9556

VL - 37

SP - 753

EP - 760

JO - Drug Metabolism and Disposition

JF - Drug Metabolism and Disposition

IS - 4

ER -