Smits Evelien A W, Soetekouw José A, van Doormalen Irene, van den Berg Bart H J, van der Woude Marcel P, de Wijs-Rot Nicolette, Vromans Herman
Pharmaceutical Sciences and Clinical Supply, Merck Sharp Dohme (MSD), Oss, The Netherlands.
Pharmaceutical Sciences and Clinical Supply, Merck Sharp Dohme (MSD), Oss, The Netherlands.
J Pharm Biomed Anal. 2015 Nov 10;115:552-61. doi: 10.1016/j.jpba.2015.07.012. Epub 2015 Jul 26.
The underlying pharmacokinetic profile of liposomal drug delivery systems is not yet fully known. This is primarily due to a lack of suitable quantitative bioanalytical methodology to simultaneously determine separate liposomal-encapsulated and non-encapsulated drug tissue concentrations in complex biological samples. Here, an LC-MS method was developed which enables the simultaneous quantification of separate liposomal-encapsulated prednisolone phosphate and non-encapsulated prednisolone concentrations in whole blood and liver tissue. Liquid chromatography, negative electrospray ionization and Orbitrap-MS analysis allowed highly accurate and sensitive detection of prednisolone phosphate (PP) and prednisolone (P) in complex matrix. Using dexamethasone phosphate and dexamethasone as internal standards, the quantitative LC-MS method was optimized and validated for high selectivity, sensitivity and quantitative accuracy of PP and P from liposomes. The lower limits of quantitation were 0.99μmol/L blood and 0.53nmol/g liver for PP, and 229nmol/L blood and 0.514nmol/g liver for P. Quantitative accuracies of 84-118% were observed. The intra-run precision was ≤11%. Application of this new LC-MS method will yield the first liposomal pharmacokinetic profile showing accurate encapsulated and non-encapsulated drug tissue concentrations separately. This is also the first quantitative LC-MS method for the simultaneous quantification of the prodrug PP and its parent drug P in whole blood and liver tissue samples.
脂质体药物递送系统的潜在药代动力学特征尚未完全明确。这主要是由于缺乏合适的定量生物分析方法，无法同时测定复杂生物样品中脂质体包裹的药物和未包裹的药物的组织浓度。在此，开发了一种液相色谱-质谱（LC-MS）方法，该方法能够同时定量全血和肝组织中脂质体包裹的泼尼松龙磷酸酯和未包裹的泼尼松龙的浓度。液相色谱、负电喷雾电离和轨道阱质谱分析能够在复杂基质中对泼尼松龙磷酸酯（PP）和泼尼松龙（P）进行高精度和高灵敏度的检测。以地塞米松磷酸酯和地塞米松作为内标，对该定量LC-MS方法进行了优化和验证，以确保其对脂质体中PP和P具有高选择性、高灵敏度和定量准确性。PP的定量下限为全血0.99μmol/L和肝脏0.53nmol/g，P的定量下限为全血229nmol/L和肝脏0.514nmol/g。观察到的定量准确度为84%-118%。批内精密度≤11%。应用这种新的LC-MS方法将首次获得脂质体药代动力学特征，分别显示准确的包裹药物和未包裹药物的组织浓度。这也是第一种用于同时定量全血和肝组织样品中前药PP及其母体药物P的定量LC-MS方法。
