LC-MS/MS法测定人血浆中氯吡格雷浓度及两种片剂的生物等效性研究  

Determination of Clopidogrel Concentration in Human Plasma by LC-MS/MS and Bioequivalence Study of 2 Kinds of Tablets

作　　者：束超[1] 徐怀友[1] 邵凤[1] 赵理杰 陶春蕾[1] 

机构地区：[1]安徽中医药大学研究生部,合肥230031

出　　处：《中国药房》2016年第11期1483-1486,共4页China Pharmacy

摘　　要：目的：建立测定人血浆中氯吡格雷浓度的方法,研究两种硫酸氢氯吡格雷片剂的生物等效性。方法：60名健康男性受试者随机分为A、B、C、D四组,采用两制剂四周期重复交叉设计,分别空腹（A、B组）和餐后（C、D组）口服受试制剂及参比制剂各75mg,采用液相色谱-串联质谱（LC-MS/MS）法测定人血浆中氯吡格雷的浓度。以地西泮为内标,色谱柱为Ultimate XB-C18,流动相为乙腈-0.05%甲酸溶液（84∶16,V/V）,以多反应监测方式进行正离子扫描,用于定量分析的离子对分别为m/z 322.00→212.00（氯吡格雷）、m/z 285.00→154.00（内标）,采用DAS 3.2.8软件计算药动学参数,以双向单侧t检验、非参数检验法考察两制剂的生物等效性。结果：氯吡格雷血药浓度在20-5 000 pg/ml范围内线性关系良好。空腹口服受试制剂或参比制剂的tmax分别为（0.850±0.356）、（0.764±0.336）h,cmax分别为（1 514.550±1 120.469）、（1 506.900±1 054.008）pg/ml,t1/2分别为（4.036±3.615）、（4.056±4.193）h,AUC0-t分别为（2 721.814±2 062.832）、（2 826.051±2 526.683）pg·h/ml;餐后口服受试制剂或参比制剂的tmax分别为（1.513±0.709）、（1.558±0.743）h,cmax分别为（5 219.509±2 711.907）、（5 520.337±3 336.664）pg/ml,t1/2分别为（5.800±4.729）、（5.513±4.206）h;AUC0-t分别为（10 890.81±4 101.357）、（11 350.653±4 174.848）pg·h/ml。两种给药条件下,受试制剂AUC0-t、AUC0-∞、cmax的90%置信区间均在参比制剂相应参数的80%-125%之内,两制剂tmax间的差异均无统计学意义（P〉0.05）。结论：该方法快速、灵敏,无杂质干扰。两种片剂生物等效。OBJECTIVE：To establish a method for the determination of clopidogrel in human plasma,and to study the bioequvivalence of 2 kinds of Clopidogrel hydrogen sulfate tablets. METHODS：60 healthy male volunteers were randomly divided into group A,B,C and D. By four cycles repeated cross-over design,they were given fasting（group A and B）and postprandial（group C and D）test or reference preparation 75 mg. The concentration of clopidogrel in human plasma was determined by LC-MS/MS. Using diazepam as internal standard,Ultimate XB-C18 column was adopted with mobile phase consisted of acetonitrile-0.05% formic acid（84 ∶ 16,V/V）. Positive ion detection was conducted in MRM mode,and monitoring transition ion-pair was m/z 322.00→212.00 for clopidogrel and m/z 285.00→154.00 for internal standard. Pharmacokinetic parameters were calculated by using DAS 3.2.8 software,and two-way and unilateral t test and non-parameters test were used to investigate the bioequivalence of two preparations. RESULTS：The linear rang of clopidogrel was 20-5 000 pg/ml. The pharmacokinetic parameters of test preparation or reference preparation after fasting oral administration were as follows：tmaxwere（0.850 ± 0.356）and（0.764 ± 0.336）h;cmaxwere（1 514.550± 1 120.469）and（1 506.900±1 054.008）pg/ml;t1/2were（4.036±3.615）and（4.056±4.193）h;AUC0-twere（2 721.814±2 062.832）and（2 826.051±2 526.683）pg·h/ml. Those of test preparation or reference preparation after postprandial oral administration were as follows：tmaxwere（1.513 ± 0.709） and（1.558 ± 0.743）h;cmaxwere（5 219.509 ± 2 711.907） and（5 520.337 ±3 336.664） pg/ml;t1/2were（5.800 ± 4.729） and（5.513 ± 4.206）h;AUC0-twere（10 890.81 ± 4 101.357）and（11 350.653 ±4 174.848）pg·h/ml. Under two kinds of condition,90%CI of AUC0-t,AUC0-∞and cmaxof test preparations were 80%-125% of corresponding parameters of reference preparations,there was no statistical significance in tmaxbetween two preparations（P〉0.05）.CON

关 键 词：硫酸氢氯吡格雷片 氯吡格雷 药动学 生物等效性 液相色谱-串联质谱法 

分 类 号：R971.4[医药卫生—药品] R969.1[医药卫生—药学]