Receptor occupancy and brain free fraction

Jeanette Watson, Sara Wright, Adam Lucas, Kirsten L. Clarke, Jean Viggers, Sharon Cheetham, Phil Jeffrey, Rod Porter, Kevin D. Read (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    104 Citations (Scopus)


    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.

    Original languageEnglish
    Pages (from-to)753-760
    Number of pages8
    JournalDrug Metabolism and Disposition
    Issue number4
    Publication statusPublished - Apr 2009


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