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首页> 外文期刊>Rapid Communications in Mass Spectrometry: RCM >Comparison of triple quadrupole, hybrid linear ion trap triple quadrupole, time-of-flight and LTQ-Orbitrap mass spectrometers in drug discovery phase metabolite screening and identification in vitro — amitriptyline and verapamil as model compounds
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Comparison of triple quadrupole, hybrid linear ion trap triple quadrupole, time-of-flight and LTQ-Orbitrap mass spectrometers in drug discovery phase metabolite screening and identification in vitro — amitriptyline and verapamil as model compounds

机译：三重四极杆，混合线性离子阱三重四极杆，飞行时间和LTQ-Orbitrap质谱仪在体外药物发现阶段代谢物筛选和鉴定中的比较-阿米替林和维拉帕米为模型化合物

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摘要

Liquid chromatography in combination with mass spectrometry (LC/MS) is a superior analyticaltechnique for metabolite profiling and identification studies performed in drug discovery anddevelopment laboratories. In the early phase of drug discovery the analytical approach should beboth time- and cost-effective, thus providing as much data as possible with only one visit to thelaboratory, without the need for further experiments. Recent developments in mass spectrometershave created a situation where many different mass spectrometers are available for the task, each withtheir specific strengths and drawbacks. We compared the metabolite screening properties of fourmain types of mass spectrometers used in analytical laboratories, considering both the ability todetect the metabolites and provide structural information, as well as the issues related to timeconsumption in laboratory and thereafter in data processing. Human liver microsomal incubationswith amitriptyline and verapamil were used as test samples, and early-phase 'one lab visit only'approaches were used with all instruments. In total, 28 amitriptyline and 69 verapamil metaboliteswere found and tentatively identified. Time-of-flight mass spectrometry (TOFMS) was the onlyapproach detecting all of them, shown to be the most suitable instrument for elucidating ascomprehensive metabolite profile as possible leading also to lowest overall time consumptiontogether with the LTQ-Orbitrap approach. The latter however suffered from lower detectionsensitivity and false negatives, and due to slow data acquisition rate required slower chromatog-raphy. Approaches with triple quadrupole mass spectrometry (QqQ) and hybrid linear ion trap triplequadrupole mass spectrometry (Q-Trap) provided the highest amount of fragment ion data forstructural elucidation, but, in addition to being unable to produce very high-important accurate massdata, they suffered from many false negatives, and especially with the QqQ, from very high overalltime consumption.
机译：液相色谱与质谱联用（LC / MS）是在药物发现和开发实验室中进行的代谢物分析和鉴定研究的一项卓越分析技术。在药物开发的早期阶段，分析方法应该既节省时间又具有成本效益，因此只需一次访问实验室就可以提供尽可能多的数据，而无需进行进一步的实验。质谱仪的最新发展已经创造了一种情况，其中许多不同的质谱仪可用于该任务，每种质谱仪都有其特定的优点和缺点。我们比较了分析实验室使用的四种主要类型质谱仪的代谢物筛查特性，同时考虑了检测代谢物和提供结构信息的能力，以及实验室以及随后数据处理中与时间消耗有关的问题。用阿米替林和维拉帕米孵育人肝微粒体作为测试样品，所有仪器均采用早期的“仅一次实验室访问”方法。总共发现并初步鉴定出28种阿米替林和69种维拉帕米代谢产物。飞行时间质谱仪（TOFMS）是检测所有质谱仪的唯一方法，它被证明是尽可能阐明综合代谢物谱的最合适的仪器，与LTQ-Orbitrap方法一起，也使最低的总时间消耗。然而，后者具有较低的检测灵敏度和假阴性，并且由于缓慢的数据采集速率需要较慢的层析。使用三重四极杆质谱（QqQ）和混合线性离子阱三重四极杆质谱（Q-Trap）的方法可提供最大量的碎片离子数据以进行结构解析，但是，除了无法产生非常重要的精确质量数据外，它们还遭受许多误报，尤其是在QqQ中，由于整体时间消耗很高。

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