Effects of ioglycamide on the hepatic transport of bilirubin and its mono- and diconjugates in the rat

Authors

  • Vital A. Mesa,

    1. Laboratory of Hepatology, Department of Medical Research, University of Leuven, Campus Gasthuisberg, B-3000 Leuven, Belgium
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  • Johan Fevery M. D.,

    Corresponding author
    1. Laboratory of Hepatology, Department of Medical Research, University of Leuven, Campus Gasthuisberg, B-3000 Leuven, Belgium
    • Laboratory of Hepatology, Department of Medical Research, University of Leuven Campus Gasthuisberg, B-3000 Leuven, Belgium
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  • Karel P. M. Heirwegh,

    1. Laboratory of Hepatology, Department of Medical Research, University of Leuven, Campus Gasthuisberg, B-3000 Leuven, Belgium
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  • Jan De Groote

    1. Laboratory of Hepatology, Department of Medical Research, University of Leuven, Campus Gasthuisberg, B-3000 Leuven, Belgium
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Abstract

Bilirubin seems to share the biliary excretion pathway with other organic anions, but not with bile acids. We studied the effects of the organic anion ioglycamide, an iodinated contrast agent, on bilirubin metabolism in Wistar rats. This compound does not undergo conjugation and is characterized by a maximal biliary secretory rate (Tm). The results show that in spite of producing a 3-fold increase in bile flow, ioglycamide excretion under Tm conditions decreased the output of unconjugated bilirubin and its monoconjugate by approximately 90%. Diconjugated bilirubin decreased by only 50% and became by far the predominant pigment in bile (86.5 ± 6.0% of total pigment vs. 61.0 ± 4.0% in basal conditions, n = 12). Unconjugated and monoconjugated bilirubins changed in parallel suggesting that the former arises from the monoconjugates. In serum, dicon-jugated bilirubin augmented from trace amounts to 1.15 ± 0.17 μmole per liter. Total conjugated pigments in serum increased from 5 to 85% of total bilirubin.

Bile acid output remained unchanged. Pretreatment of rats with ioglycamide altered neither the activity of bilirubin UDP-glucuronyltransferase nor the ratio of diconjugate to monoconjugate formed at both low (25 μM) and high (164 μM) bilirubin concentrations. The observed biological effects of ioglycamide were dose-dependent and fully reversible. We suggest that ioglycamide interferes with the excretion of conjugated bilirubins (“bilirubinostasis”). The monoconjugates retained in the hepatocyte might then undergo more efficient transformation to diconjugates, the latter thus becoming the most important bile pigments in serum and bile.

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