title: Metabolomics reveals the metabolic map of procainamide in humans and mice.
abstract: 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.
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Patterson
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.forename: Bernhard
authors.initials: B
authors.lastname: Dick
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Frey
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Idle
mesh_terms: D000215:Acylation; D000328:Adult; D000818:Animals; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D008297:Male; D055432:Metabolomics; D051379:Mice; D010084:Oxidation-Reduction; D011342:Procainamide / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D011342:Procainamide