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
Full text not available from this repository. (Request a copy)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 (B), Idle, Jeffrey |
ISSN: |
0006-2952 |
Publisher: |
Elsevier |
Language: |
English |
Submitter: |
Factscience Import |
Date Deposited: |
04 Oct 2013 14:38 |
Last Modified: |
29 Mar 2023 23:32 |
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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