Predicting the dopamine D2 receptor occupancy of ropinirole in rats using positron emission tomography and pharmacokinetic-pharmacodynamic modeling
Predicting the dopamine D2 receptor occupancy of ropinirole in rats using positron emission tomography and pharmacokinetic-pharmacodynamic modeling
复制标题
使用正电子发射断层扫描和药代动力学-药效学模型预测大鼠中罗匹尼罗的多巴胺 D2 受体占用率
DOI：
10.1080/00498254.2018.1428383
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发表时间：
2019-02-01
期刊：
影响因子：
1.8
通讯作者：
Miao, Liyan
中科院分区：
文献类型：
--
作者：
Huang, Chenrong;Wang, Ziteng;Miao, Liyan
1.本研究的目的是使用F-18-fallypride作为放射性示踪剂，通过正电子发射断层扫描（PET）测量多巴胺D-2/3受体占有率（RO）作为罗匹尼罗在大鼠中临床疗效的标志物，并通过药代动力学-药效学模型探索多巴胺RO与罗匹尼罗血浆浓度之间的关系。2.从用四种剂量的罗匹尼罗之一处理的16只大鼠中收集血浆。对于时间依赖性研究，取15 mg/kg剂量组16只大鼠4个时间点数据的平均值，将另外24只大鼠分为3个剂量组（5 mg/kg、30 mg/kg和60 mg/kg）进行剂量依赖性研究;通过F-18-fallypride PET扫描对动物进行评估。用WinNonlin 6.3软件建立药代动力学-药效学（PK-PD）模型，并对罗匹尼罗血药浓度与多巴胺RO进行相关性分析。血浆浓度和结合电位均以时间和剂量依赖性方式变化，通过PK-PD模型计算的诱导50% RO的血浆浓度（EC 50）为1391 ng/mL。3.F-18-fallypride是罗匹尼罗显像的合适示踪剂，其与多巴胺D-2受体的结合具有时间和浓度依赖性。建立了一个基于理论的PK-PD模型，用于描述罗匹尼罗血浆浓度与RO之间的关系，为罗匹尼罗治疗的无创和体内临床评价提供了方法学基础。
1.The purpose of this study was to measure dopamine D-2/3 receptor occupancy (RO) as a marker of the clinical efficacy of ropinirole in rats via positron emission tomography (PET) using F-18-fallypride as the radiotracer and to explore the relationship between dopamine RO and the plasma concentration of ropinirole via pharmacokinetic-pharmacodynamic modeling. 2.Plasma was collected from 16 rats treated with one of four doses of ropinirole. For the time-dependent study, the data of 16 rats in the 15 mg/kg dose group at four time points were averaged, and another 24 rats were divided into three dose groups (5 mg/kg, 30 mg/kg and 60 mg/kg) for the dose-dependent study; the animals were assessed via F-18-fallypride PET scans. The correlation between dopamine RO and the ropinirole plasma concentration was investigated, and a pharmacokinetic-pharmacodynamic (PK-PD) model was established with WinNonlin 6.3 software. Both the plasma concentration and the binding potential changed in a time- and dose-dependent manner, and the plasma concentration that induces 50% RO (EC50) as calculated by the PK-PD model was 1391 ng/mL. 3.F-18-fallypride appeared to be a suitable radiotracer for ropinirole imaging, and its binding to the dopamine D-2 receptor has time- and concentration-dependent characteristics. A theory-based PK-PD model was developed to describe the relationship between the plasma ropinirole concentration and RO, providing a methodological foundation for noninvasive and in vivo clinical evaluations of ropinirole treatment.