Yang Nan, Sun Qiushi, Xu Zihua, Wang Xiuyun, Zhao Xin, Cao Yuqing, Chen Li, Fan Guorong
School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China.
Molecules. 2015 Mar 6;20(3):4319-36. doi: 10.3390/molecules20034319.
A high-throughput, sensitive and specific LC-ESI-MS/MS method was established for the quantitative determination of GP205, a potent inhibitor of hepatitis C virus NS3/4A protease, in rat. The analyte was isolated from 25 μL plasma sample by 96-well LLE. Good linearity was achieved within the concentration range of 2-5000 ng/mL (r2 > 0.996). The intra- and inter-day precision was less than 10%. The accuracy ranged from 0.8% to 5.5% for GP205 in quality control samples at three levels. GP205 was stable during the analysis and the storage period. The method was successfully applied to pharmacokinetic studies of GP205 in Sprague-Dawley rats. The pharmacokinetic profiles of GP205 at three dose levels with oral administration and one dose level with intravenous administration were successfully studied for the first time in SD rats, respectively. After single oral administration of GP205 at the doses of 2.5, 5, 10 mg/kg, respectively, Cmax and AUC0-τ were proportional to the doses given. The absolute bioavailability was estimated as 34% based on the AUCs of oral administration at the dose of 5 mg/kg and intravenous administration at the dose of 1 mg/kg. The data presented in this study provides useful information for further study for GP205.
建立了一种高通量、灵敏且特异的液相色谱-电喷雾串联质谱（LC-ESI-MS/MS）方法，用于定量测定大鼠体内丙肝病毒NS3/4A蛋白酶强效抑制剂GP205。通过96孔液液萃取从25μL血浆样品中分离分析物。在2-5000 ng/mL浓度范围内实现了良好的线性关系（r2>0.996）。日内和日间精密度均小于10%。三个水平质量控制样品中GP205的准确度在0.8%至5.5%之间。GP205在分析和储存期间均稳定。该方法成功应用于GP205在Sprague-Dawley大鼠体内的药代动力学研究。首次分别成功研究了SD大鼠口服三个剂量水平和静脉注射一个剂量水平的GP205的药代动力学特征。分别单次口服2.5、5、10 mg/kg剂量的GP205后，Cmax和AUC0-τ与给药剂量成正比。基于5 mg/kg口服给药和1 mg/kg静脉给药的AUCs，绝对生物利用度估计为34%。本研究提供的数据为GP205的进一步研究提供了有用信息。
