Shin Kwang-Hee, Kim Kyu-Pyo, Lim Kyoung Soo, Kim Ji Who, Lee Yun-Sang, Yang Bo Yeun, Lee Jae Sung, Jung Jae-Min, Yoon Seo-Hyun, Jang In-Jin, Yu Kyung-Sang
Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Korea.
Int J Clin Pharmacol Ther. 2012 Mar;50(3):224-32. doi: 10.5414/cp201644.
This study explored microdosing methods for evaluating the distribution and pharmacokinetics (PK) of a central nervous system (CNS) drug candidate.
We used sertraline as a model drug. In this open-label, one-arm, three-period, multiple-dosing study, 10 healthy male volunteers received 6-day administrations of sertraline at doses of 5, 25 or 50 mg/d in three different periods. Before the first dose of Period 1, and 24 h after the last dose of each period, an intravenous bolus of [11C]sertraline was injected for positron emission tomography (PET) scanning. After the sixth dose in each period, serial blood samples were collected at scheduled intervals over 48 h; then serum sertraline concentrations were determined with liquid chromatography-tandem mass spectrometry (LC-MS/MS).
Sertraline was distributed in the brain within 20 min, and it was highly distributed in the putamen, cingulate, and thalamus. Linearity in steady-state Cmax and AUClast were observed in the 5 - 50 mg dose range. The results suggested that microdosing with PET was a useful method for exploring the bloodbrain- barrier penetration and distribution of a candidate CNS drug.
This study described a microdosing method that combined PET with LC-MS/MS for determining the brain distribution and PK characteristics of a CNS drug candidate.
本研究探索了用于评估一种中枢神经系统（CNS）候选药物分布和药代动力学（PK）的微剂量给药方法。
我们使用舍曲林作为模型药物。在这项开放标签、单臂、三周期、多次给药研究中，10名健康男性志愿者在三个不同周期接受了为期6天的舍曲林给药，剂量分别为5、25或50mg/d。在第1周期的首次给药前，以及每个周期的最后一剂给药后24小时，静脉推注[11C]舍曲林用于正电子发射断层扫描（PET）。在每个周期的第六剂给药后，在48小时内按预定间隔采集系列血样；然后用液相色谱-串联质谱法（LC-MS/MS）测定血清舍曲林浓度。
舍曲林在20分钟内分布于脑内，且在壳核、扣带回和丘脑高度分布。在5-50mg剂量范围内观察到稳态Cmax和AUClast的线性关系。结果表明，PET微剂量给药是探索候选CNS药物血脑屏障通透性和分布的有用方法。
本研究描述了一种将PET与LC-MS/MS相结合的微剂量给药方法，用于确定CNS候选药物的脑分布和PK特征。
