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Research ArticleArticle

Metabolism of Carvedilol in Dogs, Rats, and Mice

William H. Schaefer, James Politowski, Bruce Hwang, Frank Dixon Jr., Anne Goalwin, Louis Gutzait, Kathleen Anderson, Charles DeBrosse, Mark Bean and Gerald R. Rhodes
Drug Metabolism and Disposition October 1998, 26 (10) 958-969;
William H. Schaefer
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James Politowski
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Bruce Hwang
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Frank Dixon Jr.
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Anne Goalwin
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Louis Gutzait
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Kathleen Anderson
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Charles DeBrosse
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Mark Bean
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Gerald R. Rhodes
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Abstract

The excretion and biotransformation of carvedilol [1-[carbazolyl-(4)-oxy]-3-[(2-methoxyphenoxyethyl)amino]-2-propanol], a new, multiple-action, neurohormonal antagonist that exhibits the combined pharmacological activities of β-adrenoreceptor antagonism, vasodilation, and antioxidation, were investigated in dogs, rats, and mice. Carvedilol was absorbed well, and biliary secretion was predominant in each species. Carvedilol was metabolized extensively in each species, and elimination of unchanged compound was minor in bile duct-catheterized rats and dogs. In dogs, glucuronidation of the parent compound and hydroxylation of the carbazolyl ring, with subsequent glucuronidation, were the major metabolic pathways. Rats showed the simplest metabolite profile; the primary metabolites were formed by hydroxylation of the carbazolyl ring, with subsequent glucuronidation. Mice displayed the most complicated metabolite profile; glucuronidation of the parent compound and hydroxylation of either the carbazolyl or phenyl ring, with subsequent glucuronidation, were the major metabolic routes. O-Dealkylation was a minor pathway in all species examined.

Footnotes

  • Send reprint requests to: William H. Schaefer, Merck and Co., WP45-325, West Point, PA 19486.

  • ↵1 Current address: ThermoQuest Finnigan Corp., San Jose, CA 95134.

  • ↵2 Current address: Rhône Poulenc Rorer, Department of Drug Disposition, Collegeville, PA 19426.

  • Abbreviations used are::
    FAB
    fast atom bombardment
    CID
    collisionally induced dissociation
    NOE
    nuclear Overhauser enhancement
    DMSO
    dimethylsulfoxide
    COSY
    correlated spectroscopy
    UDPGA
    UDP-glucuronic acid
    • Received December 8, 1997.
    • Accepted May 25, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 26, Issue 10
1 Oct 1998
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Research ArticleArticle

Metabolism of Carvedilol in Dogs, Rats, and Mice

William H. Schaefer, James Politowski, Bruce Hwang, Frank Dixon, Anne Goalwin, Louis Gutzait, Kathleen Anderson, Charles DeBrosse, Mark Bean and Gerald R. Rhodes
Drug Metabolism and Disposition October 1, 1998, 26 (10) 958-969;

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Research ArticleArticle

Metabolism of Carvedilol in Dogs, Rats, and Mice

William H. Schaefer, James Politowski, Bruce Hwang, Frank Dixon, Anne Goalwin, Louis Gutzait, Kathleen Anderson, Charles DeBrosse, Mark Bean and Gerald R. Rhodes
Drug Metabolism and Disposition October 1, 1998, 26 (10) 958-969;
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