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Research ArticleArticle

In Vitro and In Vivo Disposition of 2,2-Dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (CI-976)

Identification of a Novel Five-Carbon Cleavage Metabolite in Rats

Michael W. Sinz, Ann E. Black, Susan M. Bjorge, Ann Holmes, Bharat K. Trivedi and Thomas F. Woolf
Drug Metabolism and Disposition January 1997, 25 (1) 123-130;
Michael W. Sinz
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Ann E. Black
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Susan M. Bjorge
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Ann Holmes
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Bharat K. Trivedi
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Thomas F. Woolf
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Identification of a Novel Five-Carbon Cleavage Metabolite in Rats

Abstract

The metabolism of CI-976, a potent inhibitor of liver and intestinal acyl coenzyme A:cholesterol acyltransferase, was investigated in isolated rat hepatocytes and Wistar rats after oral administration. The major metabolite observed both in vitroand in vivo was identified as the 6-carbon, chain-shortened 5,5-dimethyl-6-oxo-[(2,4,6-trimethoxyphenyl)amino]hexanoic acid (M-4). M-4 was determined to be formed from the ω-carboxylic acid 11,11-dimethyl-12-oxo-12-[(2,4,6-trimethoxyphenyl)amino]dodecanoic acid (M-1) via the 2- and 4-carbon, chain-shortened intermediate metabolites {9,9-dimethyl-10-oxo-10-[(2,4,6-trimethoxyphenyl)amino]decanoic acid (M-2) and 7,7-dimethyl-8-oxo-8-[(2,4,6-trimethoxyphenyl)amino]octanoic acid (M-3)}, respectively. M-1 was, in turn, determined to be derived from ω-hydroxy CI-976. A minor metabolite, identified in vitro and in vivo, was a novel 5-carbon, chain-shortened derivative, 6,6-dimethyl-7-oxo-7-[(2,4,6-trimethoxyphenyl)amino]heptanoic acid (M-5). M-5 was shown not to be formed from either M-1 or the ω-hydroxy derivative. Separate incubation of CI-976 (ω-oxidation and β-oxidation pathways) and M-1 (β-oxidation only) indicated a potential gender difference in the ω-oxidation of CI-976. Both the ω-oxidation and β-oxidation pathways were enhanced by clofibrate and phenobarbital induction, and CI-976 metabolism was completely inhibited when coincubated with SKF525A pointing to cytochrome P450-mediated metabolism, presumably CYP4A. Etomoxir andl-carnitine had minor effects on the β-oxidation of M-1, indicating β-oxidation occurs predominately within peroxisomes.

Footnotes

  • Send reprint requests to: Dr. Michael W. Sinz, Parke-Davis Pharmaceutical Research, 2800 Plymouth Road, Ann Arbor, MI 48105.

  • ↵1 Present address: Bayer Research, 400 Morgan Lane, West Haven, CT.

  • Portions of this work were presented at the 1992 North American International Society for the Study of Xenobiotics, Bar Harbour, FL (Sinz et al., 1992).

  • Abbreviations used are::
    ACAT
    acyl coenzyme A:cholesterol acyltransferase
    CI-976
    2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide
    CYP
    cytochrome P450
    M-4
    5,5-dimethyl-6-oxo-6-[(2,4,6-trimethoxyphenyl)amino]hexanoic acid
    IS
    internal standard
    M-1
    11,11-dimethyl-12-oxo-12-[(2,4,6-trimethoxyphenyl)amino]dodecanoic acid
    M-5
    6,6-dimethyl-7-oxo-7-[(2,4,6-trimethoxyphenyl)amino]heptanoic acid
    BSA
    bovine serum albumin
    CMC
    carboxymethyl cellulose
    P450
    cytochrome P450
    UNK
    unknown
    M-2
    9,9-dimethyl-10-oxo-10-[(2,4,6-trimethoxyphenyl)amino]decanoic acid
    M-3
    7,7-dimethyl-8-oxo-8-[(2,4,6-trimethoxyphenyl)amino]octanoic acid
    • Received July 18, 1996.
    • Accepted October 10, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
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1 Jan 1997
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Research ArticleArticle

In Vitro and In Vivo Disposition of 2,2-Dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (CI-976)

Michael W. Sinz, Ann E. Black, Susan M. Bjorge, Ann Holmes, Bharat K. Trivedi and Thomas F. Woolf
Drug Metabolism and Disposition January 1, 1997, 25 (1) 123-130;

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Research ArticleArticle

In Vitro and In Vivo Disposition of 2,2-Dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (CI-976)

Michael W. Sinz, Ann E. Black, Susan M. Bjorge, Ann Holmes, Bharat K. Trivedi and Thomas F. Woolf
Drug Metabolism and Disposition January 1, 1997, 25 (1) 123-130;
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