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Research ArticleArticle

Orally Active Inhibitors Of Human Leukocyte Elastase. III. Identification and Characterization of Metabolites of l-694,458 by Liquid Chromatography-Tandem Mass Spectrometry

Debra Luffer-Atlas, Styliani H. Vincent, Susan K. Painter, Byron H. Arison, Ralph A. Stearns and Shuet-Hing Lee Chiu
Drug Metabolism and Disposition August 1997, 25 (8) 940-952;
Debra Luffer-Atlas
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Styliani H. Vincent
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Susan K. Painter
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Byron H. Arison
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Ralph A. Stearns
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Shuet-Hing Lee Chiu
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Abstract

The in vitro and in vivo metabolism ofN-[1(R)-(1,3-benzodioxol-5-yl)butyl]-3,3-diethyl-2(S)-[4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy]-4-oxo-1-azetidinecarboxamide (L-694,458) was studied in male Sprague-Dawley rats and rhesus monkeys. Analysis by LC-MS/MS and NMR revealed that the major metabolite generated in incubations with rat liver microsomes resulted fromN-oxidation of the piperazine group, while the major metabolite generated in monkey liver microsomes was the catechol that resulted from O-dealkylation of the methylenedioxyphenyl group. Other metabolites observed in these incubations include the piperazine N-desmethyl, several monohydroxylated derivatives of the parent compound, and three products that resulted from cleavage of the β-lactam ring. Incubations of parent compound with rat hepatocytes in culture generated two major metabolites that resulted from cleavage of the piperazine ring with the loss of an ethylene group from one side of the ring; one of these metabolites retained the piperazine N-methyl group, while the other did not. The metabolite profiles in vivo were similar to those observed in vitro, but they were much more complex owing to secondary and, in some cases, tertiary biotransformations of many of the primary metabolites. Bile obtained from orally dosed rats contained more than 40 parent-related components, and many of these metabolites had arisen from piperazine ring cleavage.

Footnotes

  • Send reprint requests to: Dr. Debra Luffer-Atlas, Department of Drug Metabolism, Merck Research Laboratories, P.O. Box 2000, RY80-L109, Rahway, NJ 07065.

  • ↵2 L-694,458 has been licensed to DuPont Merck and is also known as DMP 777.

  • Abbreviations used are::
    HLE
    human leukocyte elastase
    TFA
    trifluoroacetic acid
    DMSO
    dimethyl sulfoxide
    LC-MS
    liquid chromatography-mass spectrometry
    API
    atmospheric pressure ionization
    TIC
    total ion current
    EIC
    extracted ion current
    TIS
    turbo-ionspray
    CID
    collisionally induced dissociation
    SIF
    source-induced fragmentation
    CYP
    cytochrome P450
    • Received December 23, 1996.
    • Accepted April 29, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 8
1 Aug 1997
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Research ArticleArticle

Orally Active Inhibitors Of Human Leukocyte Elastase. III. Identification and Characterization of Metabolites of l-694,458 by Liquid Chromatography-Tandem Mass Spectrometry

Debra Luffer-Atlas, Styliani H. Vincent, Susan K. Painter, Byron H. Arison, Ralph A. Stearns and Shuet-Hing Lee Chiu
Drug Metabolism and Disposition August 1, 1997, 25 (8) 940-952;

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Research ArticleArticle

Orally Active Inhibitors Of Human Leukocyte Elastase. III. Identification and Characterization of Metabolites of l-694,458 by Liquid Chromatography-Tandem Mass Spectrometry

Debra Luffer-Atlas, Styliani H. Vincent, Susan K. Painter, Byron H. Arison, Ralph A. Stearns and Shuet-Hing Lee Chiu
Drug Metabolism and Disposition August 1, 1997, 25 (8) 940-952;
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