超高效液相-串联质谱法测定人血浆中塞来昔布浓度及两种塞来昔布胶囊在中国健康人体内的生物等效性  

Determination of concentration of celecoxib by UHPLC-MS/MS in human plasma and bioequivalence of two celecoxib capsules in Chinese healthy volunteers

作　　者：许浩云[1] 陈月[2] 冯岩 伊金玲 谢黎崖[1] XU Hao-yun;CHEN Yue;FENG Yan;YI Jin-ling;XIE Li-ya(Drug Clinical Trial Institution,the First Affiliated Hospital of Xiamen University,Xiamen FUJIAN 361003,China;Department of Pharmacy,the First Affiliated Hospital of Xiamen University,Xiamen FUJIAN 361003,China;AccuBE PharmaTech(Xiamen)Co.,Ltd,Xiamen FUJIAN 361026,China)

机构地区：[1]厦门大学附属第一医院药物临床试验机构,福建厦门361003 [2]厦门大学附属第一医院药剂科,福建厦门361003 [3]莱必宜科技(厦门)有限公司,福建厦门361026

出　　处：《中国新药与临床杂志》2020年第12期741-746,共6页Chinese Journal of New Drugs and Clinical Remedies

基　　金：重大新药创制科技重大专项十三五基金资助项目(2020ZX09201005)。

摘　　要：目的建立超高效液相色谱-串联质谱(UHPLC-MS/MS)法测定人血浆中塞来昔布的浓度,研究两种塞来昔布胶囊的药动学及在中国健康人体内的生物等效性。方法采用随机、开放、两周期、两序列、双交叉设计,空腹试验和餐后试验各36例健康受试者,单剂量口服塞来昔布胶囊受试制剂和参比制剂0.2 g。采用UHPLC-MS/MS法测定血浆中塞来昔布浓度,色谱柱Kinetex C18 100A (50 mm×2.1 mm,2.6μm);0.2%甲酸的水溶液(A)-含0.2%甲酸的乙腈溶液(B)为流动相,梯度洗脱,流速0.3 m L·min^-1;电喷雾电离源,负离子多反应离子监测(MRM),塞来昔布与内标(塞来昔布-d7)的离子对m/z分别为380.0/315.9和387.2/323.0。经Win Non Lin 8.0软件统计,非房室模型法计算药动学参数,并判定两制剂是否等效。结果空腹试验中受试制剂和参比制剂的主要药动学参数cmax分别为(552±251)、(571±324)μg·L^-1,tmax分别为3.00(1.00,5.00)、2.50 (1.00,5.00) h;t1/2分别为(11.40±4.71)、(15.78±18.17) h;AUC0-t分别为(6 096.45±3 529.51)(5 718.79±3 227.17)μg·h·L^-1;AUC0-∞分别为(6 350.34±3 765.24)、(6 223.45±3 455.96)μg·h·L^-1。餐后试验中受试制剂和参比制剂的主要药动学参数cmax分别为(1 610±554)、(1 460±476)μg·L^-1;tmax分别为5.00 (1.50,5.50)、5.00 (1.50,5.50)h;t1/2分别为(5.61±1.80)、(5.54±1.74) h;AUC0-t分别为(9 816.87±3 094.32)、(9 518.57±2 983.02)μg·h·L^-1;AUC0-∞分别为(9 870.43±3 104.96)μg·h·L^-1、(9 574.63±2 998.23)μg·h·L^-1。受试制剂与参比制剂的AUC0-t、AUC0-∞和cmax几何均值比值的90%置信区间均在80%-125%之间。结论本研究建立的UHPLC-MS/MS法能快速、准确测定人血浆中塞来昔布的浓度,两种塞来昔布胶囊生物等效。AIM To establish a UHPLC-MS/MS method for the determination of the concentration of celecoxib in human plasma,and evaluate the pharmacokinetics and the bioequivalence of two celecoxib capsules in Chinese healthy volunteers.METHODS In a random,open,2 periods,2 sequence,self-crossover study,thirty-six healthy volunteers in fasting test and thirty-six healthy volunteers in fed test were given single oral dose of celecoxib capsule 0.2 g.The concentrations of celecoxibin plasma were determined by a UHPLC-MS/MS method.The column was Kinetex C18 100A(50mm×2.1 mm,2.6μm) and the mobile phase consisted of 0.2%formic acid in water (A) and 0.2%formic acid in acetonitrile(B) with gradient elution;the flow rate was set as 0.3 m L·min^-1.Electrospray ionization source with negative ion multiple reactive ion monitoring (MRM) were used,and ion pair m/z of celecoxib and internal standard (celecoxib-d7) were 380.0/315.9 and 387.2/323.0,respectively.The pharmacokinetic parameters of celecoxib were calculated with non-compartmental analysis method using Win Non Lin 8.0,and the bioequivalence was assessed.RESULTS In fasting test,the pharmacokinetic parameters of celecoxib of the test(T) and reference(R) preparation were as follow:the cmax were (552±251)μg·L^-1and (571±324)μg·L^-1,the tmax were 3.00 (1.00,5.00) h and 2.50 (1.00,5.00) h,the t1/2 were (11.40±4.71) h and(15.78±18.17) h,the AUC0-t were (6 096.45±3 529.51)μg·h·L^-1 and (5 718.79±3 227.17)μg·h·L^-1,the AUC0-∞were (6 350.34±3 765.24)μg·h·L^-1 and (6 223.45±3 455.96)μg·h·L^-1.In fed test,the pharmacokinetic parameters of celecoxib of T and R were as follow:the cmax were (1 610±554)μg·L^-1 and (1 460±476)μg·L^-1,the tmax were 5.00(1.50,5.50) h and 5.00 (1.50,5.50) h,the t1/2 were (5.61±1.80) h and (5.54±1.74) h,the AUC0-t were (9 816.87±3 094.32)μg·h·L^-1 and (9 518.57±2 983.02)μg·h·L^-1,AUC0-∞were (9 870.43±3 104.96)μg·h·L^-1 and(9 574.63±2 998.23)μg·h·L^-1.The 90%confidence intervals of geometric mean ratio for AUC0-t,AUC

关 键 词：塞来昔布 超高效液相色谱 串联质谱法 血药浓度 药动学 生物等效性 

分 类 号：R969.1[医药卫生—药理学]