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Research ArticleArticle

Contribution of Artifacts to N-Methylated Piperazine Cyanide Adduct Formation In Vitro from N-Alkyl Piperazine Analogs

Minli Zhang, Christina M. Resuello, Jian Guo, Mark E. Powell, Charles S. Elmore, Jun Hu and Karthick Vishwanathan
Drug Metabolism and Disposition May 2013, 41 (5) 1023-1034; DOI: https://doi.org/10.1124/dmd.112.050450
Minli Zhang
Drug Metabolism and Pharmacokinetics (M.Z., J.G., K.V.) and Medicinal Chemistry (J.H.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; and CNS Discovery, AstraZeneca Pharmaceuticals, Wilmington, Delaware (C.M. R., M. E. P., C.S.E.)
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Christina M. Resuello
Drug Metabolism and Pharmacokinetics (M.Z., J.G., K.V.) and Medicinal Chemistry (J.H.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; and CNS Discovery, AstraZeneca Pharmaceuticals, Wilmington, Delaware (C.M. R., M. E. P., C.S.E.)
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Jian Guo
Drug Metabolism and Pharmacokinetics (M.Z., J.G., K.V.) and Medicinal Chemistry (J.H.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; and CNS Discovery, AstraZeneca Pharmaceuticals, Wilmington, Delaware (C.M. R., M. E. P., C.S.E.)
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Mark E. Powell
Drug Metabolism and Pharmacokinetics (M.Z., J.G., K.V.) and Medicinal Chemistry (J.H.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; and CNS Discovery, AstraZeneca Pharmaceuticals, Wilmington, Delaware (C.M. R., M. E. P., C.S.E.)
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Charles S. Elmore
Drug Metabolism and Pharmacokinetics (M.Z., J.G., K.V.) and Medicinal Chemistry (J.H.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; and CNS Discovery, AstraZeneca Pharmaceuticals, Wilmington, Delaware (C.M. R., M. E. P., C.S.E.)
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Jun Hu
Drug Metabolism and Pharmacokinetics (M.Z., J.G., K.V.) and Medicinal Chemistry (J.H.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; and CNS Discovery, AstraZeneca Pharmaceuticals, Wilmington, Delaware (C.M. R., M. E. P., C.S.E.)
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Karthick Vishwanathan
Drug Metabolism and Pharmacokinetics (M.Z., J.G., K.V.) and Medicinal Chemistry (J.H.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; and CNS Discovery, AstraZeneca Pharmaceuticals, Wilmington, Delaware (C.M. R., M. E. P., C.S.E.)
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Abstract

In the liver microsome cyanide (CN)-trapping assays, piperazine-containing compounds formed significant N-methyl piperazine CN adducts. Two pathways for the N-methyl piperazine CN adduct formation were proposed: 1) The α-carbon in the N-methyl piperazine is oxidized to form a reactive iminium ion that can react with cyanide ion; 2) N-dealkylation occurs followed by condensation with formaldehyde and dehydration to produce N-methylenepiperazine iminium ion, which then reacts with cyanide ion to form the N-methyl CN adduct. The CN adduct from the second pathway was believed to be an artifact or metabonate. In the present study, a group of 4′-N-alkyl piperazines and 4′-N-[13C]methyl–labeled piperazines were used to determine which pathway was predominant. Following microsomal incubations in the presence of cyanide ions, a significant percentage of 4′-N-[13C]methyl group in the CN adduct was replaced by an unlabeled natural methyl group, suggesting that the second pathway was predominant. For 4′-N-alkyl piperazine, the level of 4′-N-methyl piperazine CN adduct formation was limited by the extent of prior 4′-N-dealkylation. In a separate study, when 4′-NH-piperaziens were incubated with potassium cyanide and [13C]-labeled formaldehyde, 4′-N-[13C]methyl piperazine CN-adduct was formed without NADPH or liver microsome suggesting a direct Mannich reaction is involved. However, when [13C]-labeled methanol or potassium carbonate was used as the one-carbon donor, 4′-N-[13C]methyl piperazine CN adduct was not detected without liver microsome or NADPH present. The biologic and toxicological implications of bioactivation via the second pathway necessitate further investigation because these one-carbon donors for the formation of reactive iminium ions could be endogenous and readily available in vivo.

Footnotes

    • Received December 3, 2012.
    • Accepted February 19, 2013.
  • dx.doi.org/10.1124/dmd.112.050450.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (5)
Drug Metabolism and Disposition
Vol. 41, Issue 5
1 May 2013
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Research ArticleArticle

Artifacts in N-Methyl Piperazine Cyanide Adduct Formation

Minli Zhang, Christina M. Resuello, Jian Guo, Mark E. Powell, Charles S. Elmore, Jun Hu and Karthick Vishwanathan
Drug Metabolism and Disposition May 1, 2013, 41 (5) 1023-1034; DOI: https://doi.org/10.1124/dmd.112.050450

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Research ArticleArticle

Artifacts in N-Methyl Piperazine Cyanide Adduct Formation

Minli Zhang, Christina M. Resuello, Jian Guo, Mark E. Powell, Charles S. Elmore, Jun Hu and Karthick Vishwanathan
Drug Metabolism and Disposition May 1, 2013, 41 (5) 1023-1034; DOI: https://doi.org/10.1124/dmd.112.050450
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