Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, CA 94080, USA.
J Am Soc Mass Spectrom. 2012 May;23(5):880-8. doi: 10.1007/s13361-012-0351-9. Epub 2012 Feb 14.
Identification of drug metabolites can often yield important information regarding clearance mechanism, pharmacologic activity, or toxicity for drug candidate molecules. Additionally, the identification of metabolites can provide beneficial structure-activity insight to help guide lead optimization efforts towards molecules with optimal metabolic profiles. There are challenges associated with detecting and identifying metabolites in the presence of complex biological matrices, and new LC-MS technologies have been developed to meet these challenges. In this report, we describe the development of an experimental approach that applies unique features of the hybrid linear ion trap Orbitrap mass spectrometer to streamline in vitro and in vivo metabolite identification experiments. The approach, referred to as MS(M), utilizes multiple collision cells, dissociation methods, mass analyzers, and detectors. With multiple scan types and different dissociation modes built into one experimental method, along with flexible post-acquisition analysis options, the MS(M) workflow offers an attractive option to fast and reliable identification of metabolites in different kinds of in vitro and in vivo samples. The MS(M) workflow was successfully applied to metabolite identification analysis of verapamil in both in vitro rat hepatocyte incubations and in vivo rat bile samples.
药物代谢物的鉴定通常可以提供关于候选药物分子的清除机制、药理活性或毒性的重要信息。此外，代谢物的鉴定可以提供有益的结构-活性见解，有助于指导先导化合物的优化工作，以获得具有最佳代谢特征的分子。在复杂的生物基质中检测和鉴定代谢物存在挑战，已经开发了新的 LC-MS 技术来应对这些挑战。在本报告中，我们描述了一种应用混合线性离子阱轨道阱质谱仪独特功能的实验方法，以简化体外和体内代谢物鉴定实验。该方法称为 MS（M），利用多个碰撞池、解离方法、质量分析器和检测器。由于多种扫描类型和不同的解离模式都集成在一个实验方法中，并且具有灵活的采集后分析选项，因此 MS（M）工作流程为快速可靠地鉴定不同类型的体外和体内样品中的代谢物提供了一个有吸引力的选择。MS（M）工作流程成功应用于维拉帕米在体外大鼠肝细胞孵育和体内大鼠胆汁样品中的代谢物鉴定分析。
