【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 reac-tions.Cremophor EL(R) (CrEL) is the most representa
【机 构】
：
Center for Drug Metabolism Research,School of Life Sciences,Jilin University,Changchun 130012,China
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Polyoxyethylene glycerol ricinoleate (PGR) serves as a solubilizer/emulsifier that is commonly used in pharmaceutical formulations despite being associated with severe anaphylactoid hypersensitivity reac-tions.Cremophor EL(R) (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 chromatography-tandem 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 MSALL and 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 conven-tional 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 concentra-tion ranges 0.2～20.0 μg/mL,0.1～10.0 μg/mL and 0.1～20.0 μg/mL,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.
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