Receptor occupancy and brain free fraction

TY - JOUR

T1 - Receptor occupancy and brain free fraction

A1 - Watson,Jeanette

A1 - Wright,Sara

A1 - Lucas,Adam

A1 - Clarke,Kirsten L.

A1 - Viggers,Jean

A1 - Cheetham,Sharon

A1 - Jeffrey,Phil

A1 - Porter,Rod

A1 - Read,Kevin D.

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 - <p>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.</p>

AB - <p>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.</p>

U2 - 10.1124/dmd.108.022814

DO - 10.1124/dmd.108.022814

M1 - Article

JO - Drug Metabolism and Disposition

JF - Drug Metabolism and Disposition

SN - 0090-9556

IS - 4

VL - 37

SP - 753

EP - 760

ER -