Abnormal Glucuronidation of Zomepirac in Patients with Cirrhosis of the Liver

Authors

  • Felix Witassek,

    1. Department of Clinical Pharmacology, University of Berne, 3010 Berne, Switzerland
    Current affiliation:
    1. Department of Parasitology, University of Zurich, Winterthurerstrasse 266A, 8057 Zurich, Switzerland.
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    • Dr. Witassek is the recipient of a stipend of the Paul-Martini-Stiftung

  • Johannes Bircher,

    1. Department of Clinical Pharmacology, University of Berne, 3010 Berne, Switzerland
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  • Philipp Huguenin,

    1. Department of Clinical Pharmacology, University of Berne, 3010 Berne, Switzerland
    Current affiliation:
    1. National Cancer Institute, NIH, Building 37, Room GD 24, Bethesda, Maryland 20205.
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  • Rudolf Preisig

    Corresponding author
    1. Department of Clinical Pharmacology, University of Berne, 3010 Berne, Switzerland
    • Rudolf Preisig, M.D., Department of Clinical Pharmacology, University of Berne, Murtenstrasse 35, 3010 Berne, Switzerland.
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Abstract

The disposition of zomepirac was investigated in 18 patients with various liver diseases and in 10 healthy normal subjects in order to further test the hypothesis that glucuronidation of drugs may be spared in liver disease. Severity of the liver disease was assessed by the galactose elimination capacity. Following oral administration of zomepirac (200 mg), plasma and urinary drug concentrations were measured by high-pressure liquid chromatography. Urine was assayed before and after alkaline hydrolysis. The apparent oral clearance of zomepirac was 3.7 ± S.D. 1.2, 3.0 ± 0.8, and 1.8 ± 0.6 mlmin_1kg_1 in normal subjects, patients with mild liver disease, and cases with cirrhosis, respectively. In patients with liver disease, the reduction in zomepirac clearance was significantly correlated with the abnormalities in galactose elimination capacity (r = 0.83, n = 18), suggesting that the functioning liver cell mass was the major determinant of the rate of zomepirac disposition. These results are not consistent with the original hypothesis but suggest that–in contrast to ether-glucuronidation–ester-glucuronidation may be abnormal in liver disease. Dosage adjustments may, therefore, be necessary in patients with cirrhosis of the liver.

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