Identifying lactone hydrolysis in pharmaceuticals. A tool for metabolite structural characterization.
Methods to characterize metabolic transformations in a rapid and reliable fashion are required for facilitating the development of all new pharmaceuticals. One metabolic transformation, which is the focus of this study, is lactone hydrolysis. For pharmaceuticals containing lactones, hydrolysis occurs readily due to both enzymatic and nonenzymatic processes. Hydrolysis affects both the bioavailability and the efficacy of lactone-containing drugs and pro-drugs. To facilitate the characterization of lactones and their corresponding hydrolysis products, we have developed a mass spectrometric method that can readily discriminate between a lactone and its corresponding carboxylic acid, even when these changes are accompanied by other modifications that occur during metabolism. This method uses characteristic product ions in MS/MS experiments, and the trends described herein can be applied broadly to several types of lactones. To demonstrate the efficacy of this approach, two different lactones that had undergone multiple modifications were characterized, and in both cases, lactone hydrolysis was readily discernible, based on the MS/MS data.
Yi
Lin
L
Department of Chemistry, University of Kansas, Lawrence, Kansas 66045, USA.
Bandu
Mary L
ML
Desaire
Heather
H
D002264:Carboxylic Acids / Q000737:chemistry; D006868:Hydrolysis; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D013058:Mass Spectrometry / Q000379:methods; D015394:Molecular Structure; D008970:Molecular Weight; D012680:Sensitivity and Specificity
D002264:Carboxylic Acids; D007783:Lactones