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Research ArticleArticle

Metabolism and Pharmacokinetics, in the Rat, of (R)-N-(2-Heptyl)Methyl-Propargylamine (R-2HMP), A New Potent Monoamine Oxidase Inhibitor and Antiapoptotic Agent

David A. Durden, Lillian E. Dyck, Bruce A. Davis, Ya-Dong Liu and Alan A. Boulton
Drug Metabolism and Disposition February 2000, 28 (2) 147-154;
David A. Durden
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Lillian E. Dyck
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Bruce A. Davis
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Ya-Dong Liu
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Alan A. Boulton
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Abstract

(R)-N-(2-Heptyl)-N-methylpropargylamine (R-2HMP) is a monoamine oxidase inhibitor and putative antiapoptotic agent analogous to (R)-deprenyl. In the rat, the major amine metabolites of R-2HMP have been identified as (R)-N-2-heptylmethylamine (R-2HMA), (R)-N-2-heptylpropargylamine (R-2HPA), and (R)-2-heptylamine (R-2HA). After R-2HMP was administered s.c. to male Wistar rats, it was observed that the greatest concentration was of the original drug followed in decreasing order byR-2HMA, R-2HPA, and R-2HA in brain, liver, and plasma at all times after administration. The greatest concentrations of the three metabolites were found in brain followed by liver and plasma, and the peak concentrations occurred between 15 and 30 min after administration. After oral administration, the liver contained the greatest concentrations of drug and metabolites, and, again, the peak concentrations occurred at about 15 min. In all cases, depropargylation appears to occur at a faster rate than demethylation. After s.c. administration, R-2HMP and its metabolites exhibited biexponential redistribution and elimination losses. Half-lives of the compounds in brain for the redistribution phase were: R-2HMP, 10 min;R-2HMA, 11 min; R-2HPA, 16 min; andR-2HA, 15 min.

Footnotes

  • Send reprint requests to: D.A. Durden, Neuropsychiatry Research Unit, University of Saskatchewan, 103 Wiggins Rd., Saskatoon, SK, S7N 5E4, Canada. E-mail: david.durden{at}usask.ca

  • ↵1 Present address: Agriculture and Agri-Foods Canada, 107 Science Place, Saskatoon, SK, S7N 0X2.

  • Abbreviations used are::
    R-2HMP
    (R)-N-(2-heptyl)-N-methylpropargylamine
    R-2HMA
    (R)-N-2-heptylmethylamine
    R-2HPA
    (R)-N-2-heptylpropargylamine
    R-2HA
    (R)-2-heptylamine
    MPA
    methylpropargylamine
    TFEOH
    trifluoroethanol
    PFB
    pentafluorobenzoyl
    PFB-Cl
    pentafluorobenzoyl chloride
    RBC
    red blood cells
    GC
    gas chromatography
    MS
    mass spectrometry
    EI
    electron impact
    MOR
    method of residuals
    NLR
    nonlinear least-squares regression
    AUC
    area under the curve
    MAO
    monoamine oxidase
    2HA-D5
    1,1,1,3,3-pentadeutero-2-heptylamine
    2HMA-D3
    N-trideuteromethyl-2-heptylamine
    2HMA-D5
    N-methyl-1,1,1,3,3,-pentadeutero-2-heptylamine
    2HMA-D8
    N-trideuteromethyl-1,1,1,3,3,-pentadeutero-2-heptylamine
    2HMP-D8
    N-trideutero-methyl-[1,1,1,3,3,-pentadeutero-2-heptyl]-propargylamine
    2HPA-D5
    N-[1,1,1,3,3-pentadeutero-2-heptyl]-propargylamine
    • Received May 14, 1999.
    • Accepted October 12, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (2)
Drug Metabolism and Disposition
Vol. 28, Issue 2
1 Feb 2000
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Research ArticleArticle

Metabolism and Pharmacokinetics, in the Rat, of (R)-N-(2-Heptyl)Methyl-Propargylamine (R-2HMP), A New Potent Monoamine Oxidase Inhibitor and Antiapoptotic Agent

David A. Durden, Lillian E. Dyck, Bruce A. Davis, Ya-Dong Liu and Alan A. Boulton
Drug Metabolism and Disposition February 1, 2000, 28 (2) 147-154;

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Research ArticleArticle

Metabolism and Pharmacokinetics, in the Rat, of (R)-N-(2-Heptyl)Methyl-Propargylamine (R-2HMP), A New Potent Monoamine Oxidase Inhibitor and Antiapoptotic Agent

David A. Durden, Lillian E. Dyck, Bruce A. Davis, Ya-Dong Liu and Alan A. Boulton
Drug Metabolism and Disposition February 1, 2000, 28 (2) 147-154;
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