Disposition and fate of polyoxyethylene glycerol ricinoleate as determined by LC-Q-TOF MS coupled with MS^(ALL),SWATH and HR MS/MS techniques  

作　　者：Ruifeng Bai Dong Sun Yuqin Shan Zhiqiong Guo Dafeng Chu John Paul Fawcett Jingkai Gu 

机构地区：[1]Center for Drug Metabolism Research,School of Life Sciences,Jilin University,Changchun 130012,China

出　　处：《Chinese Chemical Letters》2021年第10期3237-3240,共4页中国化学快报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China (Nos.81872831 and 82030107);the National Science and Technology Major Projects for “significant new drugs creation” of the 13th five-year plan (Nos.2017ZX09101001 and 2018ZX09721002007, China)。

摘　　要：Polyoxyethylene glycerol ricinoleate(PGR) serves as a solubilizer/emulsifier that is commonly used in pharmaceutical formulations despite being associated with severe anaphylactoid hypersensitivity reactions.Cremophor EL?(CrEL) is the most representative PGR produced from reacting ethylene oxide with castor oil.To help clarify the cause of side effects and potentially improve the safety of PGR-based drug delivery vehicle,we have developed separate but related analytical methods for the quantitation of CrEL and its main metabolites,glycerol ethoxylate(GE) and ricinoleic acid(RA).Since CrEL and GE are highly disperse mixtures of polymers that are not amenable to analysis by conventional liquid chromatographytandem mass spectrometry(LC-MS/MS),we used liquid chromatography-triple-quadrupole-time-of-flight mass spectrometry(LC-Q-TOF MS) combined with product ion data acquisition by MSALLand sequential window acquisition of all theoretical fragments mass spectrometry(SWATH MS),respectively to perform the analysis.In contrast,RA is a single molecular entity that could be readily analyzed using conventional LC-HR MS/MS.Selection of specific fragment ions for CrEL,GE,RA and their internal standards enabled a precise quantitation of such a complex analytes system in rat plasma after a single and simple sample preparation method.Assay validation indicated linearity for CrEL,GE and RA over the concentration ranges 0.2~20.0 μg/mL,0.1~10.0 μg/mL and 0.1~20.0 μg/m L,respectively with satisfactory results for other validation parameters.A subsequent pharmacokinetic study involving single intravenous 200 mg/kg injections of CrEL to rats showed the methods enable comprehensive and high throughput quantitation of CrEL and its metabolites in a biological matrix.Our combination of assays provides effective application in investigating the cause of the hypersensitivity reaction of PGR and potentially to improve its safety for using as a vehicle in drug formulations.

关 键 词：Polyoxyethylene glycerol ricinoleate Cremophor EL LC-Q-TOF MS Glycerol ethoxylate Ricinoleic acid 

分 类 号：TQ460.4[化学工程—制药化工] O657.63[理学—分析化学]