液相色谱-串联质谱法测定大鼠血浆中舒巴坦的浓度及其药动学研究

Determination of sulbactam in rat plasma by LC-MS/MS and its pharmacokinetic study

目的:建立测定大鼠血浆中舒巴坦血药浓度的液相色谱-串联质谱(LC-MS/MS)法,探讨美罗培南、亚胺培南对舒巴坦在大鼠体内的药动学影响。方法:将18只SD大鼠随机分为舒巴坦组、美罗培南+舒巴坦组和亚胺培南+舒巴坦组,分别静脉注射给药,按规定时间点采血,血浆样品经乙酸乙酯萃取,LC-MS/MS法测定血药浓度;采用负离子模式,多重反应监测(multiple reaction monitoring,MRM),定量离子对为m/z232.3→m/z139.9(舒巴坦)和m/z423.4→m/z 207.1(头孢呋辛,内标)。经DAS 2.0.1计算药动学参数,并进行统计学比较。结果:舒巴坦在0.250~200μg·mL^(-1)范围内线性关系良好,方法学符合要求。药动学试验结果表明,合用美罗培南或亚胺培南后,舒巴坦在大鼠体内的主要药动学参数t_(max)、C_(max)、AUC、MRT、t_(1/2z)、CL_z和V_z与单用舒巴坦相比,无显著性差异。结论:和已报道的方法比较,本研究所建方法具有快速、高效,生物样品用量小的特点,适用于舒巴坦在大鼠体内药动学的研究;美罗培南、亚胺培南对舒巴坦在大鼠体内的药动学过程无明显影响,提示评价此类药物相互作用还需同时考虑药效学等方法。

OBJECTIVE To establish a liquid chromatography-tandem mass spectrometry（LC-MS/MS）method for determination of sulbactam and study the effects of meropenem and imipenem on pharmacokinetics of sulbactam in rats.METHODS Eighteen rats were divided into sulbactam alone and combination groups randomly,received sulbactam or sulbactam combined with meropenem or imipenem,respectively.The concentrations of sulbactam in rat plasma were determined at different time points by the LC-MS/MS method.The compounds were quantified by multiple-reaction monitoring（MRM）mode using transition mass of m/z232.3→m/z139.9 for sulbactam and m/z 423.4→m/z 207.1 for cefuroxim（internal standard）.The main pharmacokinetic parameters were processed by the software DAS 2.0.1 and compared.RESULTS The calibration curves of sulbactam were linear in the range 0.250-200 g·mL^-1.Indicators of the method validation were in line with requirements.The results of the pharmacokinetic study indicated that there was no significant difference between the pharmacokinetic parameters of sulbactam in rats with or without meropenem or imipenem.CONCLUSION This method is rapid,efficient,only needs a smaller sample volume.It is suitable for pharmacokinetic studies of sulbactam in rats.Meropenem or imipenem has no obvious influence on pharmacokinetics of sulbactam.When evaluating the drug interaction,pharmacodynamics should also be considered.