Department of Drug Metabolism, Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
J Pharmacol Exp Ther. 2012 Apr;341(1):137-45. doi: 10.1124/jpet.111.188417. Epub 2012 Jan 10.
Translation of central nervous system occupancy and clinical effect from animal models to humans has remained elusive for many pharmacological targets. The current studies evaluate the ability of a rodent pharmacokinetic/pharmacodynamic (PK/PD) modeling approach to translate ex vivo occupancy determined in rats to that observed after positron emission tomography (PET) imaging in humans for the dual serotonin transporter (SERT) and norepinephrine transporter (NET) inhibitor duloxetine. Ex vivo transporter occupancy in rat spinal cord was evaluated after single oral doses of 0.3 to 60 mg/kg. A novel methodology, based on the initial rates of association of transporter selective radioligands to tissue homogenates, was developed and validated for the assessment of ex vivo transporter occupancy. Duloxetine exhibited selectivity for occupancy of SERT over NET in rat spinal cord with ED(50) values of 1 and 9 mg/kg, respectively. Corresponding EC(50) values for the inhibition of SERT and NET based on unbound duloxetine spinal cord concentrations were 0.5 and 8 nM. An effect compartment PK/PD modeling approach was used to analyze the relationship between the time course of duloxetine plasma concentration and SERT and NET occupancy. Duloxetine inhibited SERT and NET in rat spinal cord with a plasma EC(50) of 2.95 and 59.0 ng/ml, respectively. Similar plasma EC(50) values for the inhibition of SERT (2.29-3.7 ng/ml) have been reported from human PET studies. This study illustrates the value of translational PK/PD modeling approaches and suggests that the preclinical modeling approach used in the current study is capable of predicting plasma concentrations associated with 50% occupancy of SERT in the human central nervous system.
许多药理学靶点的中枢神经系统占有率和临床效果从动物模型到人体的转化仍然难以捉摸。本研究评估了啮齿动物药代动力学/药效学（PK/PD）建模方法的能力，该方法将大鼠离体占有率与人类正电子发射断层扫描（PET）成像后观察到的占有率进行转化，用于双 5-羟色胺转运体（SERT）和去甲肾上腺素转运体（NET）抑制剂度洛西汀。在大鼠脊髓中评估了单次口服 0.3 至 60mg/kg 后 0.3 至 60mg/kg 后的离体转运体占有率。开发并验证了一种基于组织匀浆中转运体选择性放射性配体初始结合速率的新型方法，用于评估离体转运体占有率。度洛西汀对 SERT 的占有率表现出对 NET 的选择性，在大鼠脊髓中的 ED（50）值分别为 1mg/kg 和 9mg/kg。基于未结合度洛西汀脊髓浓度，SERT 和 NET 抑制的相应 EC（50）值分别为 0.5nM 和 8nM。采用效应室 PK/PD 建模方法分析了度洛西汀血浆浓度与 SERT 和 NET 占有率之间的时间关系。度洛西汀抑制 SERT 和 NET 的大鼠脊髓，血浆 EC（50）分别为 2.95ng/ml 和 59.0ng/ml。来自人类 PET 研究的 SERT 抑制的类似血浆 EC（50）值（2.29-3.7ng/ml）。本研究说明了转化 PK/PD 建模方法的价值，并表明当前研究中使用的临床前建模方法能够预测与人类中枢神经系统中 SERT 占有率 50%相关的血浆浓度。
