Identifying Lactone Hydrolysis in Pharmaceuticals. A Tool for Metabolite Structural Characterization

Abstract

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.

Identification and characterization of supercritical fluid extracts of Rhizoma Chuanxiong by high performance liquid chromatography ion trap mass spectrometry

“…In this study, the LC-MS/MS method could not distinguish stereoscopic isomers, senkyunolide H and I, and those phthalide dimers, either naturally occurring riligustilide and levistolide A or those formed when high concentration of extracts were stored for a long period of time and induced by heat or light. MS, MS 2 , and have investigated a group of lactones related to pharmaceuticals and their corresponding hydrolysis products, carboxylic acids and discovered that they underwent different CID fragmentation pathways [11]. They have demonstrated that, under positive ESI mode, lactones had neutral losses of CO but not H 2 O and few could loose H 2 O and CO together, while acids behaved just the opposite, loosing H 2 O, H 2 O and CO together, but not CO alone.…”

Analytical Tools and Approaches for Metabolite Identification in Early Drug Discovery

“…But up to now the interpretation of this data has been highly manual, requiring the intervention of an expert. An increasing emphasis on computer assisted spectral interpretation (67,68) can now be seen. The software products Mass Frontier (38) and ACD (61) are bringing some of these tools to the market.…”

Second-order calibration method applied to process three-way excitation–emission-kinetic fluorescence data: A novel tool for real-time quantitative analysis of the lactone hydrolysis of irinotecan in human plasma

“…Many drug candidates, including camptothecin (CPT), its analogues, and statins, contain lactone functional groups, and their efficacy is directly affected by lactone hydrolysis [3][4][5]. CPT and its derivatives are pentacyclic alkaloids containing quinoline (rings A and B), indolizinone (rings C and D), and an α-hydroxy δ-lactone moiety (ring E; Fig.…”

“…To date, several reports have described the hydrolysis and lactonization reactions of CPTs measured by ultraviolet spectrometry (UV-vis) and spectrofluorimetry [11][12][13], capillary zone electrophoresis [14], high-performance liquid chromatography (HPLC) with ultraviolet [15], fluorescence detection [16,17], and mass spectrometry [5]. The above methods are indeed useful for measuring the rates of hydrolysis and lactonization.…”