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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Antipsychotic drugs (APD) are widely prescribed for the treatment of schizophrenia. The APD are differentiated into typical and atypical based on the lower incidence of extra-pyramidal side-effects associated with the newer atypical APD. It was suggested that atypicality may arise from an interaction with the 5-hydroxytryptamine (5-HT)(2) receptor and specifically on the 5-HT(2):dopamine D(2) affinity ratio. It is now realised that multiple subtypes of these receptors exist and that in addition, atypical APD interact with many monoamine receptors. The aim of the present study was to characterise the interaction of APD with a variety of monoamine receptors in terms of both affinity and efficacy. The data produced has highlighted that the atypical profile of APD such as olanzapine and clozapine may reflect antagonism of the 5-HT(2A) and 5-HT(2C) receptors, whilst that of, ziprasidone and quetiapine may reflect partial agonist activity at the 5-HT(1A) receptor, and that of aripiprazole may reflect partial agonist activity at the 5-HT(1A) receptor as well as is its claimed partial agonist activity at the dopamine D(2) receptor.

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