Metabolism of antipyrine in vivo in two rat models of liver cirrhosis. Its relationship to intrinsic clearance in vitro and microsomal membrane lipid composition.

Buters, J T; Zysset, T; Reichen, J

doi:10.1016/0006-2952(93)90662-g

1993

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Titel:: Metabolism of antipyrine in vivo in two rat models of liver cirrhosis. Its relationship to intrinsic clearance in vitro and microsomal membrane lipid composition.
Dokumenttyp:: Journal Article; Research Support, Non-U.S. Gov't
Autor(en):: Buters, J T; Zysset, T; Reichen, J
Abstract:: Antipyrine metabolism depends on at least three isoenzymes of cytochrome P450 forming the main metabolites 3-OH-, 4-OH- and norantipyrine. We investigated to what extent antipyrine clearance and metabolite formation are impaired in two models of liver cirrhosis in the rat, namely micronodular cirrhosis induced by chronic exposure to phenobarbital/CCl4 and biliary cirrhosis induced by bile duct ligation. Salivary antipyrine clearance was decreased to a similar extent in cirrhosis induced by CCl4 and bile duct ligation (-35%). Clearance for production of 3-OH-antipyrine was decreased in both models, while 4-hydroxylation was maintained. Metabolic clearance of both 3-OH-antipyrine and 4-OH-antipyrine in vivo correlated with their clearance in vitro (r = 0.658 and r = 0.583) but not with that of norantipyrine. The microsomal cholesterol content was increased by 16% and 90% in CCl4 and bile duct-ligated cirrhotic rats (P < 0.001), respectively. Membrane fluidity, expressed as the ratio of phospholipids to cholesterol, correlated with the in vivo clearance for production of norantipyrine (r = 0.841) but not of 3-OH- or 4-OH-antipyrine, while clearance in vitro was not related to altered lipid composition. Our results demonstrate that the cytochrome P450 isoenzymes responsible for the different pathways of antipyrine metabolism are affected to different extents by cirrhosis. Alterations in intrinsic clearance explain only part of the loss of hepatocellular function. Altered lipid composition contributes to this loss of function but other factors, among them loss of hepatocytes and changes in microcirculation, could be more important determinants of the decrease in xenobiotic metabolism in cirrhosis.
Zeitschriftentitel:: Biochem Pharmacol
Jahr:: 1993
Band / Volume:: 46
Heft / Issue:: 6
Seitenangaben Beitrag:: 983-91
Volltext / DOI:: doi:10.1016/0006-2952(93)90662-g
PubMed:: http://view.ncbi.nlm.nih.gov/pubmed/8216358
Print-ISSN:: 0006-2952
TUM Einrichtung:: Molekulare Allergologie (Prof. Schmidt-Weber)
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mediaTUM Gesamtbestand Einrichtungen Schools TUM School of Medicine and Health Departments Clinical Medicine Institut für Molekulare Allergologie (Prof. Schmidt-Weber)Lehrstuhl für Molekulare Allergologie und Umweltforschung (Prof. Schmidt-Weber)1993