LC-MS/MS法测定人血浆中的非索非那定及其药动学研究

Studies on Determination and Pharmacokinetics of Fexofenadine in Human Plasma by LC-MS/MS

目的:建立人血浆中非索非那定的LC-MS/MS测定方法,并研究其在健康人体内的药动学特征。方法:以格列吡嗪为内标,血样经甲醇沉淀法提取,采用Agilent ZORBAX SB-C_(18)(100 mm×2.1 mm,3.5μm),以甲醇-10 mmol·L^(-1)醋酸铵水溶液(70:30)为流动相,流速0.20 ml·min^(-1);质谱选择性检测非索非那定和内标格列吡嗪离子对分别为m/z 502.1→466.2,446.0→321.1。20名健康受试者分成两组,分别进行低、中单剂量和多剂量给药的药物动力学试验。结果:非索非那定的线性范围为1.0～600.0 ng·ml^(-1)(r=0.997 6,n=5),定量下限为1.0 ng·ml^(-1),提取回收率>87.6%,日内和日间RSD≤8.5%。非索非那定的t_(1/2)为(9.29～11.14)h,MRT为(7.95～8.24)h;多剂量给药后C_(ss,max)为(206.89±123.23)ng·ml^(-1),AUC_(ss)为(1122.98±646.60)ng·h·ml^(-1),DF为(1.81±0.36)。结论:该法灵敏、简便、快捷、准确、重现性好,适用于非索非那定血药浓度测定及人体药动学研究。

Objective ： To establish an LC-MS/MS method for determination of fexofenadine in human plasma and to investigate its phammcokinetic characteristics in healthy subjects. Method： Fexofenadine and glipizide were extracted from plasma with methanol and then separated on a reversed-phase Cls column with a mobile phase of methanol-water containing 10 mmol. L-1 ammonium acetate （70 ： 30） at a flow rate of 0. 20 ml. min-1. MS was performed in the selected reaction monitoring mode using target ions at m/z 502. 1 466. 2 for fexofenadine and m/z 446.0±321.1 for internal standard. Twenty subjects were divided into two groups, taking single-dose and muhiple-dose pharmacokinetic experiment, respectively. Result ： The linear range was （ 1.0 - 600. 0 ） ng· ml - 1 （ r = 0. 997 6, n = 5 ） with a lower quantitative limit of 1.0 ng·ml-1. The extraction recovery was above 87.6% and the intra-day and inter-day precision were both less than 8.5% , respectively. Elimination half-life and mean residence time of fexofenadine were （ 9. 29 -11.14 ） h and （7.95 -8.24 ） h, respectively in the subjects after a single oral administration of fexofenadine （60 mg and 120 mg）. Main pharmacokinetic parameters of multiple-dose were as follow ： C （ 206. 89 ± 123.23 ） ng. ml -1 ,AUC （ 1 122. 98 ± 646.60 ） ng. h.ml -1, and DF （ 1. 81 ± 0. 36）. Conclusion ： The method is sensitive, simple, rapid, accurate and reproducible for plasma concentration monitoring and clinical pharmacokinetic study of fexofenadine.