Metabolomics reveals the metabolic map of procainamide in humans and mice

Li, Fei; Patterson, Andrew D; Krausz, Kristopher W; Dick, Bernhard; Frey, Felix J; Gonzalez, Frank J; Idle, Jeffrey R (2012). Metabolomics reveals the metabolic map of procainamide in humans and mice. Biochemical pharmacology, 83(10), pp. 1435-44. New York, N.Y.: Elsevier 10.1016/j.bcp.2012.02.013

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology

UniBE Contributor:

Dick, Bernhard; Frey, Felix Julius and Idle, Jeffrey

ISSN:

0006-2952

Publisher:

Elsevier

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:38

Last Modified:

06 Dec 2013 13:37

Publisher DOI:

10.1016/j.bcp.2012.02.013

PubMed ID:

22387617

Web of Science ID:

000302435000012

URI:

https://boris.unibe.ch/id/eprint/15229 (FactScience: 222521)

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