A carrier-protein receptor is not a prerequisite for avid hepatic elimination of highly bound compounds: A study of propranolol elimination by the isolated perfused rat liver

Authors

  • D. Brian Jones,

    1. Departments of Gastroenterology and Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria 3084, Australia and Victorian College of Pharmacy, Parkville, Victoria 3052, Australia
    Current affiliation:
    1. Division of Gastroenterology, McMaster University, Hamilton, Ontario, Canada L8N 3Z5
    Search for more papers by this author
  • Michael S. Ching,

    1. Departments of Gastroenterology and Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria 3084, Australia and Victorian College of Pharmacy, Parkville, Victoria 3052, Australia
    Search for more papers by this author
  • Richard A. Smallwood,

    1. Departments of Gastroenterology and Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria 3084, Australia and Victorian College of Pharmacy, Parkville, Victoria 3052, Australia
    Search for more papers by this author
  • Denis J. Morgan Ph.D.

    Corresponding author
    1. Departments of Gastroenterology and Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria 3084, Australia and Victorian College of Pharmacy, Parkville, Victoria 3052, Australia
    • Victorian College of Pharmacy, 381 Royal Parade, Parkville, Victoria 3052, Australia
    Search for more papers by this author

Abstract

The highly efficient hepatic extraction of propranolol by the isolated perfused rat liver does not diminish when albumin binding is increased from 30 to 75%. One possible explanation of this insensitivity of propranolol uptake to changes in albumin binding is the mediation of uptake of bound ligand by an albumin receptor on the hepatocyte as postulated for oleate, taurocholic acid and rose bengal. To test this hypothesis, the hepatic extraction of propranolol was studied in the isolated perfused rat liver using α1-acid glycoprotein, which lacks a hepatocyte receptor, as the carrier protein in the perfusate rather than albumin. Livers were perfused with a medium containing propranolol (4 μM) and varying concentrations of α1-acid glycoprotein (0 to 25 μM). Hepatic extraction of propranolol was very high (0.990 ± 0.006; mean ± S.D.) and did not alter significantly despite an increase in bound fraction from 0.2 to 0.8, thus closely paralleling the findings when albumin is the carrier protein. This result indicates that bound propranolol is efficiently cleared by the liver, presumably by a “free intermediate” mechanism, in the absence of a specific carrier-protein receptor on the hepatocyte. This study does not, therefore, support the albumin receptor hypothesis.

Ancillary