UPLC-MS/MS法测定类风湿关节炎患者血浆中艾瑞昔布及其羟基/羧基代谢物浓度

Determination of imrecoxib and Its Hydroxyl/carboxyl Metabolites in Plasma of Patients with Rheumatoid Arthritis by UPLC-MS/MS

目的:建立血浆中艾瑞昔布及其羟基代谢物(M1)、羧基代谢物(M2)超高效液相色谱-串联质谱法测定方法,并用于服用艾瑞昔布片的类风湿关节炎(RA)患者稳态血药谷浓度测定。方法:以Waters ACQUITY UPLC BEH C18(50 mm×2.1 mm,1.7μm)色谱柱,以甲醇-0.1%甲酸水溶液为流动相进行梯度洗脱。采用电喷雾离子源(ESI),正离子模式检测,内标为塞来昔布,多反应监测参数设置如下:m/z 370.10→236.10(艾瑞昔布),m/z 386.10→236.00(M1),m/z 400.20→236.00(M2),m/z 382.09→281.31(内标);使用该方法检测服用艾瑞昔布片的RA患者艾瑞昔布谷浓度及M1、M2血浓度。结果:血浆中艾瑞昔布、M1及M2的线性范围分别为1~100 ng·ml^(-1)(r=0.9985),2~200 ng·ml^(-1)(r=0.9996),20~2000 ng·ml^(-1)(r=0.9993)。3种化合物的回收率为87.07%~106.07%。共测定67例服用艾瑞昔布片患者,艾瑞昔布谷浓度为1.02~98.35 ng·ml^(-1),M1及M2血浓度分别为2.15~57.27 ng·ml^(-1),20.65~335.30 ng·ml^(-1)。结论:该方法简便可靠,适用于口服艾瑞昔布片RA患者的监测。

Objective:To establish an ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)method for the quantitative determination of imrecoxib and its hydroxyl metabolites(M1)and carboxyl metabolites(M2)in plasma,and apply the method in the determination of steady state plasma drug valley concentration in patients with rheumatoid arthritis(RA)treated with imrecoxib tablets.Methods:A chromatographic column Waters ACQUITY UPLC BEH C18(50 mm×2.1 mm,1.7μm)column was used and gradient elution was carried out with a mixture of 0.1%formic acid and methanol in water as the mobile phase.Electrospray ionization(ESI)was used for positive ion mode detection.The internal standard(IS)was celecoxib and the multi-reaction monitoring parameters were set as follows:m/z 370.10→236.10(imrecoxib),m/z 386.10→236.00(M1),m/z 400.20→236.00(M2)and m/z 382.09→281.37(IS).The plasma concentrations of imrecoxib,M1 and M2 in RA patients treated with imrecoxib tablets from June to December 2020 were determined by using this method.Results:The linear ranges were 1-100 ng·ml^(-1)(imrecoxib,r=0.9985),2-200 ng·ml^(-1)(M1,r=0.9996)and 20-2000 ng·ml^(-1)(M2,r=0.9993),respectively.The recoveries of the three compounds were 87.07%-106.07%.A total of 67 patients taking imrecoxib tablets were determined.The plasma concentrations of imrecoxib,M1 and M2 were significantly different among individuals with the valley concentrations ranging from 1.02 to 98.35 ng·ml^(-1),2.15 to 57.27 ng·ml^(-1)and 20.65 to 335.30 ng·ml^(-1),respectively.Conclusion:The method is simple and reliable,and suitable for the monitoring of therapeutic drugs in RA patients after oral administration of imrecoxib.