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Nonlinear formation of propranolol metabolites in dogs after portacaval transpositions

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Abstract

The formation of four major metabolites of propranolol by the liver was examined at steady state in three dogs that had undergone surgical portacaval transposition, following which injection of drug into the hindlimb delivers the total dose to the liver. Propranolol was infused directly into the liver via a hindlimb vein at dose rates ranging from 1.01 to 6.3 mg/min. In all dogs the formation of 4-hydroxypropranolol, α-naphthoxylactic acid, and propranolol glycol was saturable. Vmax and Km values were determined at steady state by relating the rate of excretion of each metabolite into bile and urine to the blood concentration of propranolol. The formation of propranolol glucuronide was a first order process. The use of a dog with a portacaval transposition has permitted development of a method to estimate, in vivo,the kinetic properties of enzymes responsible for hepatic first-pass metabolism of drugs.

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Author notes

  1. Man-Wai Lo

    Present address: Stine Laboratory, Du Pont Pharmaceuticals, P.O. Box 30, 19714, Newark, Delaware

  2. Bernie M. Silber

    Present address: Department of Pharmacodynamics, Medical Research Division, American Cyanamid Co., 10965, Pearl River, New York

Authors and Affiliations

  1. Departments of Pharmaceutical Chemistry and Pharmacy, School of Pharmacy, S-926, University of California, 94143, San Francisco, CA

    Man-Wai Lo, Susan M. Pond, Bernie M. Silber, Sidney Riegelman & Thomas N. Tozer

  2. Departments of Medicine and Surgery, School of Medicine, University of California, 94143, San Francisco, CA

    David J. Effeney

Authors
  1. Man-Wai Lo
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  2. Susan M. Pond
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  3. David J. Effeney
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  4. Bernie M. Silber
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  5. Sidney Riegelman
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  6. Thomas N. Tozer
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Additional information

Supported in part by Grants GM 16496 and 26556 from the National Institutes of General Medical Sciences, National Institute of Health.

Deceased.

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Lo, MW., Pond, S.M., Effeney, D.J. et al. Nonlinear formation of propranolol metabolites in dogs after portacaval transpositions. Journal of Pharmacokinetics and Biopharmaceutics 12, 401–412 (1984). https://doi.org/10.1007/BF01062665

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  • DOI: https://doi.org/10.1007/BF01062665

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