液-质联用法研究磷霉素钙在健康人体的生物等效性

Bioequivalence studies of fosfomycin calcium in healthy volunteers by liquid chromatography tandem mass spectrometry assay

目的：建立液-质联用法测定人血浆中磷霉素钙的浓度，研究磷霉素钙的人体药动学及生物等效性。方法：血浆样品中加入内标阿德福韦，经乙腈蛋白沉淀，SB-Aq C18色谱柱进行分离，流动相流速为1．0mL·min^-1,梯度洗脱方式，采用多反应监测（MRM）的负离子方式检测。结果：在100～25000μg·L^-1范围内呈良好的线性关系，日内及日间精密度（RSD）小于8％。受试制剂和参比制剂的tmax分别为（1．8±0．2）h和（2．4±0．5）h，（Cmax分别为（6034．0±1540．9）μg·L^-1和（6182．5±1221．4）μg·L^-1，AUG0-t分别为（43755．6±7198．0）μg·h·L^-1。和（43720．1±9134．2）μg·h·L^-1。结论：本法准确，灵敏无杂质干扰。两种制剂生物等效。

OBJECTIVE A simple, sensitive and rapid liquid chromatography tandem mass spectrometry assay was developed and validated for the quantification of fosfomycin calcium in human plasma. The assay was applied in a bioequivalence study of two suspension formulations of fosfomycin calcium. METHODS Adefovir was used as internal standard （I. S. ）. After protein precipitation by acetonitrile, the analyte and I. S. were separated on a Zorbax SB-Aq C18 column using gradient elution at a flow rate of 1.0 mL. min 1. Detection was by electrospray negative ionization mass spectrometry in the multiple-reaction monitoring mode. RESULTS The method was linear over the range of 100- 25 000 μg·L^-1 with inter-and intra-day precisions （as rela- tive standard deviation〈8%. The pharmacokinetics parameters of test and reference formulations were as follows： tmax were （1.8 ± 0. 2） h and （2.4 ± 0. 5） h, respectively; Cmax were （6 034. 0 ± 1 540. 9）μg·L^-1 and （6 182. 5 ± 1 221.4） μg·L^-1 respectively, AUGht were （43 755.6 ± 7 198. 0） μg·h·L^-1 and （43 720. 1 ± 9 134. 2） μg·h·L^-1respectively. CONCLUSION The method is accurate and sensitive with no endogenous interference. The two formulations are bioequivalent.