Characterization of imatinib metabolites in rat and human liver microsomes: differentiation of hydroxylation from N-oxidation by liquid chromatography/atmospheric pressure chemical ionization mass spectrometry

Rapid Communications in Mass Spectrometry : RCM
Shuguang MaMagang Shou

Abstract

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.

References

Dec 18, 2001·Rapid Communications in Mass Spectrometry : RCM·W TongJ E Patrick
Jul 12, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hans-Peter GschwindGerhard Gross
Aug 27, 2005·Clinical Pharmacokinetics·Bin PengHorst Schran
Sep 19, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Shuguang MaMagang Shou

Citations

Apr 16, 2011·Analytical and Bioanalytical Chemistry·Lada IvanovaSilvio Uhlig
Mar 23, 2010·Journal of Chromatography. a·Michal HolcapekMiroslav Lísa
Jul 23, 2015·Journal of Chromatography. a·David FriedeckýTomáš Adam
Aug 31, 2012·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Hoa LePeter W Fan
Dec 3, 2014·Journal of Pharmaceutical and Biomedical Analysis·Pradipbhai D KalariyaR Srinivas
Apr 11, 2017·Drug Metabolism Reviews·Ivanna HrynchakVera Marisa Costa

Related Concepts

Imatinib mesylate
Benzamides
Liquid Chromatography
Hydroxylation
Microsomes, Liver
Oxidation-Reduction
Piperazines
Pyrimidines
Mass Spectrometry
Cell Differentiation Process

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