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Xenobiotica
the fate of foreign compounds in biological systems
Volume 42, 2012 - Issue 3
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General Xenobiochemistry

Associating in vitro target binding and in vivo CNS occupancy of serotonin reuptake inhibitors in rats: The role of free drug concentrations

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Pages 256-265 | Received 12 Jul 2011, Accepted 27 Aug 2011, Published online: 21 Oct 2011
 

Abstract

  1. The present study aimed at investigating the theory that free (unbound) active site concentrations are the best predictors of target binding of compounds blocking the serotonin transporter (Sert) in the central nervous system (CNS).

  2. Thirteen serotonin reuptake inhibitors were evaluated for their Sert-binding affinities in vitro and in vivo in rats together with their unbound fractions in plasma and brain. Cortical Sert occupancy was used in vivo to acquire EC50-estimates from total plasma, free plasma, whole brain, and free brain concentrations after acute drug administration.

  3. The in vitroin vivo Sert occupancy analyses showed that the best correlation was achieved when unbound brain concentrations were employed. Unbound brain concentrations also provided a better correlation when compared with unbound plasma concentrations, which could be related to lack of equilibrium between plasma and brain at time of measurements or involvement of active brain efflux processes. In addition, brain-free fractions were shown to be directly correlated to the lipophilicity of the compounds.

  4. These data emphasize the use and impact of applying free fraction data in assessment of pharmacological in vitroin vivo correlations and demonstrates its use to validate in vivo Sert occupancy as pharmacodynamic marker for serotonin reuptake inhibitors in rats.

Acknowledgments

Department of Medicinal Chemistry, H. Lundbeck A/S is acknowledged for synthesis of test compounds (Klaus Bøgesø, Jan Kehler, and Anette Sørensen). The authors thank Helle Porsdal, Berit Merete Rasmussen, June Nathalie Byskov, Karina Gerdes, Mona Elster, and Lisbet Petri for their skillful technical assistance.

Declaration of interest

The authors are employed at H. Lundbeck A/S.

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