Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A, for the treatment of Alzheimer's disease
Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A, for the treatment of Alzheimer's disease
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DOI：
10.1038/aps.2013.7
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发表时间：
2013-07-01
影响因子：
8.2
通讯作者：
Hong, Zhen
中科院分区：
文献类型：
--
作者：
Jia, Jing-ying;Zhao, Qian-hua;Hong, Zhen
目的：从中药蛇足石杉（Thunb）Trev 中分离得到的石杉碱甲（Huperzine A）是一种新型可逆、选择性 AChE 抑制剂。本研究的目的是评估石杉碱 A 的新型类似物 ZT-1 在健康中国受试者中单剂量和多剂量的药代动力学和耐受性。 方法：这是一项双盲、安慰剂对照、随机、单剂量和多剂量研究。对于单剂量研究，根据三向拉丁方设计，9 名受试者被随机分为 3 组，接受 ZT-1（0.5、0.75 或 1 mg，口服）。对于多剂量研究，9 名受试者连续 8 天接受 ZT-1（0.75 mg/d，口服）。在耐受性研究中，40 名受试者被随机分为 5 组，接受单剂量 ZT-1（0.5、0.75、1、1.25 或 1.5 mg，口服）。使用 LC-MS/MS 测定 ZT-1 和 Hup A 的血浆和尿液浓度。计算药代动力学参数，包括C-max、AUC(0-72)(h)和AUC(0-无穷大)。整个研究过程中均进行了耐受性评估。结果：ZT-1被迅速吸收并转化为石杉碱甲，因此ZT-1的血浆和尿液浓度均低于定量限（
Aim: Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects.Methods: This was a double-blinded, placebo-controlled, randomized, single-and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including C-max, AUC(0-72) (h) and AUC(0-infinity) were calculated. Tolerance assessments were conducted throughout the study.Results: ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (