红外离子光谱法鉴定药物代谢产物——在咪唑安定中的应用 体外代谢**

IF 6.1 Q1 CHEMISTRY, MULTIDISCIPLINARY
Dr. Rianne E. van Outersterp, Dr. Jonathan Martens, Dr. Giel Berden, Arnaud Lubin, Dr. Filip Cuyckens, Prof. Dr. Jos Oomens
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引用次数: 2

摘要

药物化合物生物转化产物的鉴定是药物开发的关键步骤。在过去的几十年里,液相色谱-质谱(LC-MS)因其高灵敏度和选择性而成为代谢物谱分析的首选方法。然而,仅基于质谱,确定检测到的代谢物的完整分子结构,包括确切的生物转化位点,仍然具有挑战性。本文探讨了红外离子光谱(IRIS)作为一种新的基于质谱的方法来阐明药物代谢研究中的代谢途径。以药物咪达唑仑为例,我们直接从体外药物培养样品中鉴定出几种生物转化产物。我们发现葡萄糖醛酸代谢物的苷元MS/MS片段离子的红外光谱在检测到的I相和II相代谢物之间建立了直接联系。此外,使用量子化学计算的候选结构的红外光谱,我们能够在没有参考标准的情况下分配生物转化的确切位置。此外,我们通过识别在酸性环境中形成的几个开环咪达唑仑衍生物,证明了IRIS在结构解析中的效用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Identification of Drug Metabolites with Infrared Ion Spectroscopy – Application to Midazolam in vitro Metabolism**

Identification of Drug Metabolites with Infrared Ion Spectroscopy – Application to Midazolam in vitro Metabolism**

The identification of biotransformation products of drug compounds is a crucial step in drug development. Over the last decades, liquid chromatography-mass spectrometry (LC-MS) has become the method of choice for metabolite profiling because of its high sensitivity and selectivity. However, determining the full molecular structure of the detected metabolites, including the exact biotransformation site, remains challenging on the basis of MS alone. Here we explore infrared ion spectroscopy (IRIS) as a novel MS-based method for the elucidation of metabolic pathways in drug metabolism research. Using the drug midazolam as an example, we identify several biotransformation products directly from an in vitro drug incubation sample. We show that IR spectra of the aglycone MS/MS fragment ions of glucuronide metabolites establish a direct link between detected phase I and phase II metabolites. Moreover, using quantum-chemically computed IR spectra of candidate structures, we are able to assign the exact sites of biotransformation in absence of reference standards. Additionally, we demonstrate the utility of IRIS for structural elucidation by identifying several ring-opened midazolam derivatives formed in an acidic environment.

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CiteScore
7.30
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