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Unbound Brain Concentration Determines Receptor Occupancy: A Correlation of Drug Concentration and Brain Serotonin and Dopamine Reuptake Transporter Occupancy for Eighteen Compounds in Rats

Roche Palo Alto, LLC, Palo Alto, California

It is a commonly accepted hypothesis that central nervous system (CNS) activity is determined by the unbound brain drug concentration. However, limited experimental data are available in the literature to support this hypothesis. The objective of this study was to test this hypothesis by examining the relationship between in vitro binding affinity (K_I) and in vivo activity quantified as the drug concentration occupying 50% of the transporters (OC₅₀) for 18 serotonin (SERT) and dopamine transporter (DAT) inhibitors. In vivo rat OC₅₀ was determined by autoradiography using [³H]N,N-dimethyl-2,2-amino-4-cyanophenylthiobenzylamine and [³H](–)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane-1,5-napthalenedisulfonate (WIN35,428) as the ligands to assess SERT and DAT occupancy, respectively. The unbound brain concentrations were calculated from total brain concentrations and the unbound brain fraction, which was determined by the brain homogenate method. The in vivo total brain SERT and DAT OC₅₀ values (mean ± S.D.) were 408 ± 368- and 410 ± 395-fold greater than the K_I values, respectively. In contrast, the in vivo unbound brain SERT and DAT OC₅₀ values were only 3.3 ± 2.1- and 4.1 ± 4.0-fold different from the K_I values. Therefore, prediction of the biophase drug concentration by using the unbound brain concentration rather than the total brain concentration results in an approximately 100-fold improvement for the accuracy. In the present study, a 10-fold improvement was also observed by using the unbound plasma concentration rather than the total plasma concentration to predict the biophase concentration in the brain. This study supports the hypothesis that CNS activity is more accurately determined by the unbound brain drug concentration and not by the total brain drug concentration.