Receptor occupancy and brain free fraction.
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.
Watson
Jeanette
J
Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, Scotland, UK.
Wright
Sara
S
Lucas
Adam
A
Clarke
Kirsten L
KL
Viggers
Jean
J
Cheetham
Sharon
S
Jeffrey
Phil
P
Porter
Rod
R
Read
Kevin D
KD
D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism*; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D008297:Male; D020891:Raclopride / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
D014150:Antipsychotic Agents; D017448:Receptors, Dopamine D2; D020891:Raclopride