UPLC-MS/MS测定人血浆中咪达那新的浓度及其生物等效性研究

Determination of imidafenacin in human plasma by UPLC-MS/MS and its bioequivalence

用UPLC-MS/MS测定人血浆中咪达那新的浓度,并应用于咪达那新片在中国健康受试者中的药代动力学及生物等效性研究。采用Acquity UPLC BEH C8(2.1 mm×50 mm,1.7μm)色谱柱,流动相A为2 mmol/L乙酸铵溶液(含0.2%乙酸),B为乙腈,梯度洗脱。采用液液萃取的前处理方法减小血浆样品的基质效应。质谱条件为正离子模式,咪达那新和咪达那新-d10的检测离子分别为m/z 320.2→238.1和m/z 330.2→248.2。临床试验采用单剂量双周期自身交叉试验设计,24例健康受试者空腹条件下口服咪达那新片参比制剂或受试制剂。使用上述检测方法检测生物样品中咪达那新的含量,后用DAS3.2.8软件进行药代动力学及生物等效研究。咪达那新在10.0~1 000 pg/mL范围内线性良好,低、中、高浓度的样品提取回收率分别为84.0%、88.0%、90.0%,基质效应分别为105%、100%、101%。参比及受试制剂的药代动力学参数cmax分别为524.8和612.6 pg/mL,tmax分别为1.250和1.063 h,AUC0-∞分别为2 229和2 466 pg/mL·h,参比制剂及受试制剂生物等效。

A sensitive and selective method for the determination of imidafenacin in human plasma using liquid chromatography combined with mass spectrometry was established,and was applied to the pharmacokinetic and bioequivalence studies of imidafenacin in healthy Chinese volunteers.After the liquid-liquid extraction pretreatment,samples were separated by UPLC on BEH C8(2.1 mm×50 mm,1.7 μm) column with mobile phase 2 mmol/L ammonium acetate solution with 0.2% acetic acid and acetonitrile using gradient elution.The mass instrument was operated in the positive ion mode,and the monitored transition was set at m/z 320.2→238.1 and m/z 330.2→248.2 for imidafenacin and IS(imidafenacin-d10),respectively.In the single-dose,double cycle,self-crossover clinical trial,24 healthy Chinese volunteers received 0.1 mg reference or test imidafenacin tablet orally under fasting condition.Drug concentration in plasma was determined by this method and the pharmacokinetic parameters were calculated by DAS 3.2.8 software.The linear range of the analysis method is 10.0 pg/mL to 1 000 pg/mL.The extraction recoveries of the low medium and high concentration samples were 84.0%,88.0% and 90.0%,respectively.The matrix effects of low medium and high concentration samples were 105%,100% and 101%,respectively.The pharmacokinetic parameters of imidafenacin for the reference and test tablets were as follows:cmax 524.8 pg/mL vs 612.6 pg/mL,tmax 1.250 h vs 1.063 h,AUC0-∞ 2 229 pg ·h/mL vs 2 466 pg ·h/mL.The reference and test tablets of imidafenacin were bioequivalent.This method proved to be rapid and accurate for the pharmacokinetic and bioequivalence studies of imidafenacin.