METABOLISM OF ANTIPYRINE IN-VIVO IN 2 RAT MODELS OF LIVER-CIRRHOSIS -ITS RELATIONSHIP TO INTRINSIC CLEARANCE IN-VITRO AND MICROSOMAL MEMBRANE LIPID-COMPOSITION

Antipyrine metabolism depends on at least three isoenzymes of cytochro me P450 forming the main metabolites 3-OH-, 4-OH- and norantipyrine. W e investigated to what extent antipyrine clearance and metabolite form ation are impaired in two models of liver cirrhosis in the rat, namely micronodular cirrhosis induced by chronic exposure to phenobarbital/C Cl4 and biliary cirrhosis induced by bile duct ligation. Salivary anti pyrine clearance was decreased to a similar extent in cirrhosis induce d 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-anti pyrine in vivo correlated with their clearance in vitro (r = 0.658 and r = 0.583) but not with that of norantipyrine. The microsomal cholest erol content was increased by 16% and 90% in CCl4 and bile duct-ligate d cirrhotic rats (P < 0.001), respectively. Membrane fluidity, express ed as the ratio of phospholipids to cholesterol, correlated with the i n vivo clearance for production of norantipyrine (r = 0.841) but not o f 3-OH- or 4-OH-antipyrine, while clearance in vitro was not related t o altered lipid composition. Our results demonstrate that the cytochro me P450 isoenzymes responsible for the different pathways of antipyrin e metabolism are affected to different extents by cirrhosis. Alteratio ns in intrinsic clearance explain only part of the loss of hepatocellu lar function. Altered lipid composition contributes to this loss of fu nction but other factors, among them loss of hepatocytes and changes i n microcirculation, could be more important determinants of the decrea se in xenobiotic metabolism in cirrhosis.