Park M K, Shin K-H, Kim K-P, Kim T-E, Yoon S H, Cho J-Y, Shin S-G, Jang I-J, Yu K-S
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
Int J Clin Pharmacol Ther. 2011 Nov;49(11):672-8. doi: 10.5414/cp201578.
Sertraline is a naphthalenamine derivative which has the effect of selective serotonin reuptake inhibition. It has been used for major depression, and obsessive compulsive disorder. This study was performed to evaluate the pharmacokinetic (PK) characteristics after the administration of low dose sertraline for the purpose of exploring an application of microdosing methods in PK studies.
An open-label, three-period, single-sequence, dose-escalation study was performed in 6 healthy Korean male volunteers. Subjects were administered a single dose of 5 mg, 25 mg and 50 mg sertraline orally in each period, with 1 week washouts between periods. Blood samples were obtained up to 96 h after drug administration. Plasma concentrations were determined using high performance liquid chromatography-tandem mass spectrometry. PK parameters of sertraline were analyzed using non-compartmental methods.
A total of 6 subjects completed the study. After the administration of sertraline at 5 mg, 25 mg and 50 mg, the median tmax were 6.0, 6.0 and 4.0 h and the mean (SD) elimination half-lives were 31.9 (6.5), 27.2 (6.7) and 28.0 (6.6) h, respectively. The AUC and Cmax increased dose-dependently. The dose-normalized mean (SD) AUC and Cmax were different in each dosing group (p < 0.01) with 2.0 (0.8), 5.3 (1.2) and 6.0 (1.9) mg × hr/l/mg in the 5 mg, 25 mg and 50 mg groups for dose-normalized AUC, and 0.07 (0.01), 0.18 (0.05) and 0.21 (0.08) mg/l/mg in the 5 mg, 25 mg and 50 mg groups for dose-normalized Cmax, respectively, which indicates a lack of dose proportionality.
A lack of dose proportional properties was shown in the 5 mg dose relative to the 25 mg and 50 mg doses of sertraline. This shows that the PK parameters for low-dose sertraline could be different from those in clinical concentrations.
舍曲林是一种萘乙胺衍生物，具有选择性5-羟色胺再摄取抑制作用。它已被用于治疗重度抑郁症和强迫症。本研究旨在评估低剂量舍曲林给药后的药代动力学（PK）特征，以探索微剂量法在PK研究中的应用。
对6名健康韩国男性志愿者进行了一项开放标签、三周期、单序列、剂量递增研究。在每个周期中，受试者口服单剂量5mg、25mg和50mg舍曲林，周期之间有1周的洗脱期。给药后96小时内采集血样。使用高效液相色谱-串联质谱法测定血浆浓度。采用非房室模型方法分析舍曲林的PK参数。
共有6名受试者完成了研究。给予5mg、25mg和50mg舍曲林后，中位达峰时间分别为6.0、6.0和4.0小时，平均（标准差）消除半衰期分别为31.9（6.5）、27.2（6.7）和28.0（6.6）小时。曲线下面积（AUC）和峰浓度（Cmax）呈剂量依赖性增加。各给药组的剂量标准化平均（标准差）AUC和Cmax不同（p<0.01），5mg、25mg和50mg组的剂量标准化AUC分别为2.0（0.8）、5.3（1.2）和6.0（1.9）mg×hr/l/mg，剂量标准化Cmax分别为0.07（0.01）、0.18（0.05）和0.21（0.08）mg/l/mg，这表明缺乏剂量比例性。
相对于25mg和50mg剂量的舍曲林，5mg剂量显示出缺乏剂量比例特性。这表明低剂量舍曲林的PK参数可能与临床浓度下的参数不同。
