Naylor S, Kajbaf M, Lamb J H, Jahanshahi M, Gorrod J W
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905.
Biol Mass Spectrom. 1993 Jul;22(7):388-94. doi: 10.1002/bms.1200220705.
The use of precursor ion and constant neutral loss scanning as a means of rapidly detecting drug metabolites is evaluated. Four clinically useful drugs, namely (i) cyclophosphamide, (ii) mifentidine, (iii) cimetropium bromide and (iv) haloperidol, were subjected to microsomal incubations to afford phase I metabolites. Aside from a minor clean-up procedure involving zinc sulfate precipitation of microsomal proteins and solid-phase extraction of metabolites using a Sep-pak C-18 cartridge, the mixtures were analysed directly by fast atom bombardment tandem mass spectrometry. It is demonstrated that such screening strategies are important in detecting novel metabolites. However, there are some problems associated with only using such methods, including (i) the possibility of not detecting metabolites that undergo unusual collision-induced dissociation fragmentation pathways, (ii) the non-detection of metabolites that have undergone metabolic change at unusual sites of reactivity, and (iii) production of artifacts derived from the parent drug by the primary ionization process. Examples are discussed that highlight both the strengths and weaknesses of such an approach.
对使用前体离子和恒定中性丢失扫描作为快速检测药物代谢物的手段进行了评估。四种临床常用药物，即（i）环磷酰胺、（ii）米芬替丁、（iii）溴化西托溴铵和（iv）氟哌啶醇，进行微粒体孵育以生成I相代谢物。除了涉及用硫酸锌沉淀微粒体蛋白以及使用Sep-pak C-18柱对代谢物进行固相萃取的少量净化步骤外，混合物直接通过快原子轰击串联质谱进行分析。结果表明，此类筛选策略对于检测新型代谢物很重要。然而，仅使用此类方法存在一些问题，包括（i）可能无法检测到经历异常碰撞诱导解离碎裂途径的代谢物，（ii）无法检测到在异常反应位点发生代谢变化的代谢物，以及（iii）初级电离过程产生源自母体药物的假象。讨论了突出这种方法优缺点的实例。
