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Drug Metabolism and Disposition Fast Forward
First published on January 21, 2009; DOI: 10.1124/dmd.108.022814

0090-9556/09/3704-753-760$20.00
DMD 37:753-760, 2009

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Receptor Occupancy and Brain Free Fraction

Jeanette Watson, Sara Wright, Adam Lucas, Kirsten L. Clarke, Jean Viggers, Sharon Cheetham, Phil Jeffrey, Rod Porter, and Kevin D. Read

Biology Department (J.W., K.L.C.), Medicinal Chemistry Department (R.P.), and Drug Metabolism and Pharmacokinetics Department (A.L.), Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development, Harlow, Essex, United Kingdom; Drug Metabolism and Pharmacokinetics Department, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development, Verona, Italy (K.D.R.); Drug Metabolism and Pharmacokinetics Department, Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development, Harlow, Essex, United Kingdom (P.J.); Drug Metabolism and Pharmacokinetics Department, UCB Pharma, Slough, Berkshire, United Kingdom (S.W.); and RenaSci, Biocity Nottingham, Nottingham, United Kingdom (J.V., S.C.)

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.

Address correspondence to: Kevin Read, Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, Scotland, UK. E-mail: k.read{at}dundee.ac.uk




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X. Liu, O. Vilenski, J. Kwan, S. Apparsundaram, and R. Weikert
Unbound Brain Concentration Determines Receptor Occupancy: A Correlation of Drug Concentration and Brain Serotonin and Dopamine Reuptake Transporter Occupancy for Eighteen Compounds in Rats
Drug Metab. Dispos., July 1, 2009; 37(7): 1548 - 1556.
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