LC-MS/MS法测定人血浆中奥拉西坦的浓度及其两种口服制剂在健康中国人体的生物等效性(英文)  

LC-MS/MS method for quantitation of oxiracetam in human plasma:application to a bioequivalence study of its two oral formulations in healthy Chinese subjects

作　　者：张丹[1] 杨漫[1] 张娅喃[1] 韩静[1] 王振龙[1] 刘会臣[1] 

机构地区：[1]航天中心医院临床药理室,北京100049

出　　处：《中国新药与临床杂志》2014年第4期281-288,共8页Chinese Journal of New Drugs and Clinical Remedies

摘　　要：目的建立测定人血浆中奥拉西坦的LC-MS/MS法,并评价其两种口服制剂的生物等效性。方法采用随机、双周期、自身交叉试验设计,22名中国健康男性受试者于两个周期分别口服单剂量的奥拉西坦颗粒(受试制剂)和奥拉西坦胶囊(参比制剂),给药剂量均为800 mg,采集血浆样本并测定奥拉西坦的浓度。血浆样本以乙腈沉淀蛋白后,选用HC-C18色谱柱(150 mm×4.6 mm,5μm),以甲醇︰2 mmol·L-1乙酸铵5︰95(V/V)为流动相,流速为1.0 mL·min-1。选用API3200型三重四极杆串联质谱仪的多重反应监测(MRM)扫描方式进行监测,电喷雾离子化源,正离子方式。使用DAS2.1.1软件计算药动学参数,评价两种制剂的生物等效性。结果血浆中奥拉西坦的线性范围为0.250～25.0 mg·L-1(r>0.99),定量下限为0.250 mg·L-1;日内、日间相对标准差(RSD)均小于11.0%;相对误差(RE)均在±11.0%的范围以内;提取回收率较高,且可重现;奥拉西坦在各种贮存条件下均较稳定。受试制剂和参比制剂的AUC0-t分别为(78.1±15.5)和(81.8±16.1)mg·h·L-1,AUC0-∞分别为(80.4±15.5)和(83.9±16.5)mg·h·L-1,ρmax分别为(15.8±2.8)和(15.8±3.0)mg·L-1,tmax分别为(0.95±0.30)和(1.05±0.54)h,t1/2分别为(5.09±1.34)和(5.04±1.72)h。受试制剂的相对生物利用度F0-t和F0-∞分别为(98.4±28.4)%、(98.7±27.7)%。结论该方法快速、灵敏、专属性强、重现性好,适用于奥拉西坦口服制剂的人体生物等效性研究。受试制剂和参比制剂的吸收速度和吸收程度相当,具有生物等效性。AIM To develop a rapid and sensitive liquid chromatography- tandem mass spectrometric （LC-MS/MS） method for quantitative analysis of oxiracetam in human plasma, and evaluate the bioequivalence of its two oral formulations. METHODS In a randomized, 2- period, crossover bioequivalence study, 22 healthy Chinese male subjects received a single oral dose of oxiracetam granules （test formulation） or oxiracetam capsules （reference formulation）, which both contained 800 mg oxiracetam. Plasma samples were collected for oxiracetam measurement. After plasma sample was subjected to acetonitrile protein precipitation,oxiracetam and piracetam in plasma （internal standard, IS） were separated using a C18 column （150 mm× 4.6 mm, 5 μm）. The mobile phase was methanol ： 2 mmol·L^-1 ammonium acetate （5 ： 95, V/V） at a flow rate of 1.0 mL ·min^-1. Detection was performed using positive multiple reaction monitoring （MRM） mode by electrospray ionization （ESI） mass spectrometry. The main pharmacokinetic parameters were calculated and the equivalence of two formulations was evaluated by DAS 2.1.1. RESULTS The linear concentration range of oxiracetam in plasma was 0.250 - 25.0 mg·L^-1 and the lower limit of quantification was 0.250 mg·L^-1. The relative standard deviation （RSD） of intra-and inter-day precision was 〈 11.0%, and the relative error （RE） was within ± 11.0%. The extraction recoveries were high and reproducible. Oxiracetam was found to be stable under various storage conditions. The main pharmacokinetic parameters of test formulation and reference formulation were as follows： AUC0-t （78.1 ＋ 15.5） and （81.8 ＋ 16.1） mg·L^-1 AUC0-∞ （80.4 ± 15.5） and （83.9 ± 16.5）mg·L^-1, ρ_max （15.8 ± 2.8） and （15.8 ±3.0） mg·L^-1, _max （0.95 ± 0.30） and （1.05 ± 0.54） h, t1/2 （5.09± 1.34） and （5.04 ± 1.72） h, respectively. The relative bioavailability of test formulation F0-t and F0-∞ were （98.4 ± 28.4） % and （98.7 ± 27.7） %,

关 键 词：奥拉西坦 色谱法 高压液相 串联质谱法 血浆 药动学 生物等效性 

分 类 号：R917[医药卫生—药物分析学] R969.1[医药卫生—药学]