Bundgaard Christoffer, Sveigaard Christina, Brennum Lise T, Stensbøl Tine B
Discovery DMPK , H. Lundbeck A/S, DK-2500 Valby, Denmark.
Xenobiotica. 2012 Mar;42(3):256-65. doi: 10.3109/00498254.2011.618953. Epub 2011 Oct 21.
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). 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. The in vitro-in 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. These data emphasize the use and impact of applying free fraction data in assessment of pharmacological in vitro-in vivo correlations and demonstrates its use to validate in vivo Sert occupancy as pharmacodynamic marker for serotonin reuptake inhibitors in rats.
本研究旨在探究一种理论，即游离（未结合）活性位点浓度是中枢神经系统（CNS）中阻断5-羟色胺转运体（Sert）的化合物的靶点结合的最佳预测指标。评估了13种5-羟色胺再摄取抑制剂在大鼠体内和体外的Sert结合亲和力，以及它们在血浆和脑中的未结合分数。在急性给药后，利用体内皮质Sert占有率从总血浆、游离血浆、全脑和游离脑浓度中获取EC₅₀估计值。体外-体内Sert占有率分析表明，使用未结合脑浓度时相关性最佳。与未结合血浆浓度相比，未结合脑浓度也具有更好的相关性，这可能与测量时血浆和脑之间缺乏平衡或活跃的脑外排过程有关。此外，脑游离分数与化合物的亲脂性直接相关。这些数据强调了应用游离分数数据在评估药理体外-体内相关性中的作用和影响，并证明了其用于验证体内Sert占有率作为大鼠5-羟色胺再摄取抑制剂药效学标志物的用途。
