Abstract
This study was designed to investigate whether brain unbound concentration (Cu,brain) is a better predictor of dopamine D2 receptor occupancy than total brain concentration, cerebrospinal fluid concentration (CCSF), or blood unbound concentration (Cu,blood). The ex vivo D2 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 Cu,brain was estimated from the product of total brain concentration and unbound fraction, which was determined using a brain homogenate method. In conclusion, the Cu,brain of selected antipsychotic agents is a good predictor of D2 receptor occupancy in rats. Furthermore, Cu,brain seems to provide a better prediction of D2 receptor occupancy than CCSF or Cu,blood for those compounds whose mechanism of entry into brain tissue is influenced by factors other than simple passive diffusion.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.022814.
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ABBREVIATIONS: CNS, central nervous system; PD, pharmacodynamic; Cu,brain, brain unbound concentration; CCSF, cerebrospinal fluid concentration; CSF, cerebrospinal fluid; BBB, blood-brain barrier; Cu,blood, blood unbound concentration; HPLC, high-performance liquid chromatography; MS/MS, tandem mass spectrometry; fu,brain, unbound fraction in brain tissue; P-gp, P-glycoprotein; PET, positron emission tomography; ANOVA, analysis of variance; FLB-457, (S)-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-bromo-2,3-dimethoxybenzamide.
- Received June 10, 2008.
- Accepted January 15, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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