一种用于定量测定人血浆和大鼠血浆中磷霉素的液相色谱-串联质谱法的开发与应用。

Development and application of an LC-MS/MS method for quantification of fosmidomycin in human and rat plasma.

作者信息

Pfaffendorf Christoph, Sackmann Keanu D, Mischlinger Johannes, Dejon-Agobé Jean Claude, Maïga-Ascofaré Oumou, Ahenkan Ebenezer, Adegnika Ayôla Akim, Ramharter Michael, Uhl Philipp, Fricker Gert, Wicha Sebastian G

机构信息

Institute of Pharmacy, Dept. of Clinical Pharmacy, University of Hamburg, Bundesstrasse 45, 20146, Hamburg, Germany.

Centre for Tropical Medicine, Department of Medicine, Bernhard Nocht Institute for Tropical Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

出版信息

Malar J. 2025 Jul 25;24(1):243. doi: 10.1186/s12936-025-05489-1.

DOI:10.1186/s12936-025-05489-1

PMID:40713723

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12297723/

Abstract

BACKGROUND

Malaria still poses a significant burden on global health, with millions of cases reported annually and rising resistance to current treatments, emphasizing the need for new therapeutic strategies. Fosmidomycin, initially recognized for its antibacterial properties, has emerged as a promising candidate in the fight against malaria.

METHODS

In this study, a sensitive and robust LC-MS/MS method for quantifying fosmidomycin in human and rat plasma was developed and validated. Plasma samples were prepared using a simple protein precipitation method with 10% trichloroacetic acid (TCA). The assay featured a rapid run time of 5 min, and validation was performed according to the European Medicines Agency's guidelines.

RESULTS

The method validation confirmed its selectivity, linearity, accuracy, precision, and stability. Notably, the calibration range was established from 0.25 to 15 mg/L, demonstrating improvements over previous methodologies with lower limits of quantification of 0.5-1.0 mg/L. Using the developed LC-MS/MS method, plasma samples were analysed from a clinical trial conducted in Gabon, as well as from a pharmacokinetic study involving male Wistar rats, revealing viable pharmacokinetic profiles for fosmidomycin.

CONCLUSIONS

These findings confirm the utility of the developed analytical method for supporting the clinical development of fosmidomycin as a potential therapy for malaria.

摘要

背景

疟疾仍然给全球健康带来重大负担，每年报告数百万病例，且对当前治疗方法的耐药性不断上升，这凸显了新治疗策略的必要性。磷霉素最初因其抗菌特性而被认可，现已成为抗击疟疾的一个有前景的候选药物。

方法

在本研究中，开发并验证了一种灵敏且稳健的用于定量人血浆和大鼠血浆中磷霉素的液相色谱 - 串联质谱（LC - MS/MS）方法。血浆样本采用含10%三氯乙酸（TCA）的简单蛋白沉淀法制备。该测定法的运行时间为5分钟，且根据欧洲药品管理局的指南进行了验证。

结果

方法验证证实了其选择性、线性、准确性、精密度和稳定性。值得注意的是，校准范围设定为0.25至15毫克/升，相较于之前定量下限为0.5 - 1.0毫克/升的方法有了改进。使用所开发的LC - MS/MS方法，对在加蓬进行的一项临床试验以及一项涉及雄性Wistar大鼠的药代动力学研究中的血浆样本进行了分析，揭示了磷霉素可行的药代动力学特征。