Metabolomics reveals the metabolic map of procainamide in humans and mice

详细信息	查看全文 | 推荐本文 |

• 作者：Fei Li^a ; ^{lif3@mail.nih.gov} ; Andrew D. Patterson^a ; ^b ; ^{adp117@psu.edu} ; Kristopher W. Krausz^a ; ^{krauszk@intra.nci.nih.gov} ; Bernhard Dick^c ; ^{bernhard.dick@insel.ch} ; Felix J. Frey^c ; ^{felix.frey@insel.ch} ; Frank J. Gonzalez^a ; ^{fjgonz@helix.nih.gov} ; Jeffrey R. Idle^a ; ^d ; ^{jeff.idle@ikp.unibe.ch} ; ^{jeffidle@gmail.com}
• 关键词：Procainamide ; Systemic lupus erythematosus ; Metabolomics ; N-Oxidation ; Ultra-performance liquid chromatography ; Time-of-flight mass spectrometry
• 刊名：Biochemical Pharmacology
• 出版年：2012
• 期刊代码：2_00062952
• 类别：pha
• 出版时间：15 May, 2012
• 卷：83
• 期：10
• 页码：1435-1444
• 文件大小：1418 K

摘要

Procainamide, a type I antiarrhythmic agent, is used to treat a variety of atrial and ventricular dysrhythmias. It was reported that long-term therapy with procainamide may cause lupus erythematosus in 25-30%of patients. Interestingly, procainamide does not induce lupus erythematosus in mouse models. To explore the differences in this side-effect of procainamide between humans and mouse models, metabolomic analysis using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) was conducted on urine samples from procainamide-treated humans, CYP2D6-humanized mice, and wild-type mice. Thirteen urinary procainamide metabolites, including nine novel metabolites, derived from P450-dependent, FMO-dependent oxidations and acylation reactions, were identified and structurally elucidated. In vivo metabolism of procainamide in CYP2D6-humanized mice as well as in vitro incubations with microsomes and recombinant P450s suggested that human CYP2D6 plays a major role in procainamide metabolism. Significant differences in N-acylation and N-oxidation of the drug between humans and mice largely account for the interspecies differences in procainamide metabolism. Significant levels of the novel N-oxide metabolites produced by FMO1 and FMO3 in humans might be associated with the development of procainamide-induced systemic lupus erythematosus. Observations based on this metabolomic study offer clues to understanding procainamide-induced lupus in humans and the effect of P450s and FMOs on procainamide N-oxidation.