Metabolomics reveals the metabolic map of procainamide in humans and mice

Fei Li, Andrew D. Patterson, Kristopher W. Krausz, Bernhard Dick, Felix J. Frey, Frank J. Gonzalez, Jeffrey R. Idle

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1435-1444
Number of pages10
JournalBiochemical Pharmacology
Volume83
Issue number10
DOIs
StatePublished - May 15 2012

Fingerprint

Procainamide
Metabolomics
dimethylaniline monooxygenase (N-oxide forming)
Cytochrome P-450 CYP2D6
Metabolites
Metabolism
Acylation
Oxidation
Electrospray ionization
Liquid chromatography
Microsomes
Liquid Chromatography
Systemic Lupus Erythematosus
Oxides
Mass spectrometry
Mass Spectrometry

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Cite this

Li, F., Patterson, A. D., Krausz, K. W., Dick, B., Frey, F. J., Gonzalez, F. J., & Idle, J. R. (2012). Metabolomics reveals the metabolic map of procainamide in humans and mice. Biochemical Pharmacology, 83(10), 1435-1444. https://doi.org/10.1016/j.bcp.2012.02.013
Li, Fei ; Patterson, Andrew D. ; Krausz, Kristopher W. ; Dick, Bernhard ; Frey, Felix J. ; Gonzalez, Frank J. ; Idle, Jeffrey R. / Metabolomics reveals the metabolic map of procainamide in humans and mice. In: Biochemical Pharmacology. 2012 ; Vol. 83, No. 10. pp. 1435-1444.
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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.",
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Li, F, Patterson, AD, Krausz, KW, Dick, B, Frey, FJ, Gonzalez, FJ & Idle, JR 2012, 'Metabolomics reveals the metabolic map of procainamide in humans and mice', Biochemical Pharmacology, vol. 83, no. 10, pp. 1435-1444. https://doi.org/10.1016/j.bcp.2012.02.013

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.

In: Biochemical Pharmacology, Vol. 83, No. 10, 15.05.2012, p. 1435-1444.

Research output: Contribution to journalArticle

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AU - Li, Fei

AU - Patterson, Andrew D.

AU - Krausz, Kristopher W.

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