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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 the determination of sulbactam plasma concentration in rat plasma and to study the pharmacokinetics of meropenem and imipenem on sulbactam in rats influences. Methods: Eighteen Sprague-Dawley rats were randomly divided into sulbactam, meropenem and sulbactam groups and imipenem + sulbactam group. The rats were administered intravenously and blood was collected at the prescribed time points. The plasma samples were treated with acetic acid Ethyl ester extraction and LC-MS / MS. The negative ion mode and multiple reaction monitoring (MRM) were used for the determination of plasma concentration. The quantitative ion pair was m / z 232.3 → m / z 139.9 (sulbactam) And m / z 423.4 → m / z 207.1 (cefuroxime, internal standard). Pharmacokinetic parameters were calculated by DAS 2.0.1 and compared statistically. Results: Sulbactam had good linearity in the range of 0.250 ~ 200μg · mL ~ (-1) and the method met the requirements. Pharmacokinetic test results show that the combination of meropenem or imipenem after sulbactam in rats the main pharmacokinetic parameters t max, C max, AUC, MRT, t 1 / 2z) , CL_z and V_z compared with the single sulbactam, no significant difference. Conclusion: Compared with the reported methods, the method proposed in this study has the characteristics of fast, efficient and small amount of biological samples, which is suitable for the study of the pharmacokinetics of sulbactam in rats. Meropenem, imipenem, Barton in rats pharmacokinetic process had no significant effect, suggesting that the evaluation of such drug interactions need to take into account pharmacodynamics and other methods.