LC-MS方法研究氢溴酸高乌甲素在小鼠体内的药代动力学(英文)

本文建立了一种快速、灵敏的LC-MS法用于检测小鼠血浆中的高乌甲素浓度。采用ESI源和多反应监测(MRM)的方式进行检测,所选用的高乌甲素和内标延胡索乙素的反应离子对分别为m/z 585→535和m/z 356→m/z 192。该方法在3.0～2 000.0 ng·mL-1浓度内线性关系良好,定量下限为3.0 ng·mL-1,日内和日间精密度(RSD)均小于9.9%,准确度(RE)在±4.8%之内。氢溴酸高乌甲素分别以1.0、2.0和4.0 mg·kg-1单剂量静脉注射给予小鼠后,t1/2分别为0.47、0.48和0.49 h,AUC0-t分别为55.5、110.5和402.9 ng·h·mL-1。实验结果表明,氢溴酸高乌甲素单剂量静脉注射给予小鼠后,在低剂量(1.0～2.0 mg·kg-1)范围内其药动学行为符合线性动力学特征,当给药剂量(2.0 mg·kg-1)增大至4.0 mg·kg-1时,AUC增加至约4倍,而Vz和CL却显著降低,呈现非线性动力学特征,可能与高浓度下药物血浆蛋白结合率的降低有关。

Pharmacokinetic study of lappaconitine hydrobromide in mice by LC-MS

A high sensitive and rapid method was developed for the analysis of lappaconitine in mouse plasma using liquid chromatography coupled to mass spectrometry (LC-MS). Detection was performed by positive ion electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode, monitoring the transitions m/z 585 --> m/z 535 and m/z 356 --> m/z 192, for the quantification of lappaconitine and tetrahydropalmatine (internal standard, IS), respectively. The method was linear over the concentration range of 3.0-2000.0 ng x mL(-1). The lower limit of quantification was 3.0 ng x mL(-1). Intra- and inter-run precisions (RSD) were both less than 9.9% and accuracy (RE) within +/- 4.8%. After single intravenous injections of lappaconitine hydrobromide at 1.0, 2.0 and 4.0 mg x kg(-1), the elimination half-lives (t(1/2)) were 0.47, 0.48 and 0.49 h, and the areas under the curve (AUC(0-t)) were 55.5, 110.5 and 402.9 ng x h x mL(-1), separately. The pharmacokinetic profile of lappaconitine was linear at relatively lower dose levels (1.0-2.0 mg x kg(-1)). When the dose increased farther to 4.0 mg x kg(-1), the Vz and CL decreased, and the increase fold of the AUC was much larger than that of the dose.