The Impact of Liver Cirrhosis and Cholelithiasis on Phase I and II Reactions Using Antipyrine and Trimethadione as a Model Substrate

Five male patients with extrahepatic cholelithasis and ten male patients with liver cirrhosis were administered simultaneously 4mg/kg trimethadione (TMO) and 500mg/man antipyrine (AP). Changes in phase I (AP and TMO) and phase II (AP) reactions of the model substrates in liver disease were examined. The patients with liver cirrhosis exhibited prolonged half-life (t1/2) and decreased metabolic clearance (CL) of AP when compared with cholelithasis patients, while no change was found in the apparent volume of distribution (Vd). The serum dimethadione (DMO)/TMO ratio at 4hr after oral administration of TMO was apparently decreased in the cirrhotic patients. The cirrhotic patients also exhibited significant decreases in urinary excretion and clearance for production of three major AP metabolites (4-hydroxyantipyrine, 3-hydroxymethyl-3-norantipyrine, and 3-hydroxymethylantipyrine), while no significant differences between the cirrhotic patients and cholelithasis patients were noted in percentages of either total or individual glucuronidation of these metabolites. These findings suggest that AP and TMO metabolisms (phase I) are severely impaired in cirrhotic patients, whereas glucuronidation of AP is unaffected (phase II).