title: Quantitative LC-MS determination of liposomal encapsulated prednisolone phosphate and non-encapsulated prednisolone concentrations in murine whole blood and liver tissue.
abstract: 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.
authors: Pharmaceutical Sciences and Clinical Supply, Merck Sharp Dohme (MSD), Oss, The Netherlands. Electronic address: e.a.w.smits@gmail.com.
authors: Evelien A W
authors: EA
authors: Smits
authors: Pharmaceutical Sciences and Clinical Supply, Merck Sharp Dohme (MSD), Oss, The Netherlands.
authors: José A
authors: JA
authors: Soetekouw
authors: Specifications Development and Analytical Control, MSD, Oss, The Netherlands.
authors: Irene
authors: I
authors: van Doormalen
authors: Specifications Development and Analytical Control, MSD, Oss, The Netherlands.
authors: Bart H J
authors: BH
authors: van den Berg
authors: Specifications Development and Analytical Control, MSD, Oss, The Netherlands.
authors: Marcel P
authors: MP
authors: van der Woude
authors: Specifications Development and Analytical Control, MSD, Oss, The Netherlands.
authors: Nicolette
authors: N
authors: de Wijs-Rot
authors: Department of Pharmaceutical Sciences, Utrecht University, The Netherlands.
authors: Herman
authors: H
authors: Vromans
mesh_terms: D000818:Animals; D002138:Calibration; D002626:Chemistry, Pharmaceutical; D002853:Chromatography, Liquid / Q000592:standards; D005938:Glucocorticoids / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D057230:Limit of Detection; D008081:Liposomes; D008099:Liver / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D011239:Prednisolone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D012015:Reference Standards; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization / Q000592:standards; D013678:Technology, Pharmaceutical / Q000379:methods*; D014018:Tissue Distribution
chemical_list: D005938:Glucocorticoids; D008081:Liposomes; C009022:prednisolone phosphate; D011239:Prednisolone
keywords: Blood; Liposomal pharmacokinetics; Liver; Orbitrap; Prednisolone phosphate