Ma Shuguang, Xu Yang, Shou Magang
Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
Rapid Commun Mass Spectrom. 2009 May;23(10):1446-50. doi: 10.1002/rcm.4023.
In vitro metabolism of imatinib was investigated in rat and human liver microsomes. Atmospheric pressure chemical ionization (APCI) mass spectrometry (MS) was applied in differentiating hydroxyl metabolites from N-oxides of imatinib because N-oxides are known to undergo deoxygenation during APCI. In addition, the major oxidative metabolite (M9, N-oxidation on the piperazine ring) was observed to undergo in-source fragmentation by elimination of formaldehyde. This fragment ion resulted from Meisenheimer rearrangement with migration of the N-methyl group to the corresponding N-methoxyl piperazine, followed by elimination of formaldehyde due to thermal energy activation at the vaporizer of APCI source. The presence of this fragment ion distinguished not only N-oxide from isomeric hydroxylated metabolite, but also unambiguously indicated that oxidation occurred on the N-4 of the piperazine ring where the methyl group was attached.
在大鼠和人肝微粒体中研究了伊马替尼的体外代谢。采用大气压化学电离（APCI）质谱（MS）来区分伊马替尼的羟基代谢物和N-氧化物，因为已知N-氧化物在APCI过程中会发生脱氧反应。此外，观察到主要的氧化代谢物（M9，哌嗪环上的N-氧化）在离子源中通过消除甲醛发生碎裂。该碎片离子是由于迈森海默重排，N-甲基迁移至相应的N-甲氧基哌嗪，随后在APCI源的蒸发器处因热能激活而消除甲醛产生的。该碎片离子的存在不仅区分了N-氧化物和异构羟基化代谢物，还明确表明氧化发生在连接甲基的哌嗪环的N-4位上。
