D-propoxyphene and norpropoxyphene kinetics after the oral administration of D-propoxyphene: a new approach to liver function?

In an attempt to design a liver function test which takes into account both portal-systemic shunting and hepatocellular dysfunction, we investigated a group of patients with cirrhosis with or without surgical porta-caval shunt for d-propoxyphene and its major metabolite, norpropoxyphene kinetics. A small dose of d-propoxyphene (0.7 mg/kg body weight) was given orally to seven normal subjects, 15 patients with cirrhosis and seven patients with cirrhosis and surgical portacaval shunt. D-propoxyphene and norpropoxyphene areas under the plasma concentration-time from 0 to 4-h (AUC) were determined by the trapezoidal method. As d-propoxyphene is a high extraction drug and since the production of norpropoxyphene should reflect the amount of d-propoxyphene available to the hepatocytes, we tested the hypothesis that norpropoxyphene/d-propoxyphene AUC ratios should reflect both the degree of portal-systemic shunting and the severity of hepatocyte dysfunction. Norpropoxyphene/d-propoxyphene AUC ratios were significantly lower in patients with cirrhosis (mean+/-S.D.: 0.92+/-0.59) than in controls (2.51+/-0.45) and also significantly lower in patients with cirrhosis and a surgical shunt (0.53+/-0.23) than in patients with cirrhosis but without surgical shunt (1.10+/-0.63). Moreover, there was an overall statistically significant correlation between norpropoxyphene/d-propoxyphene AUC ratios and branched to aromatic amino acids ratios (r(s)=0.91) and fasting venous NH4 (r(s)=-O.6). On the other hand, there was only a weak correlation between norpropoxyphene/d-propoxyphene AUC ratios and the C-14-aminopyrine breath test (r(s)=0.43). These data suggest that the norpropoxyphene/d-propoxyphene AUC ratio reflects both shunting and reduced hepatocellular function. The norpropoxyphene/d-propoxyphene ratio determined 2 h after d-propoxyphene administration might be a suitable clinical parameter because of its close correlation with norpropoxyphene/d-propoxyphene AUC ratio (r(s)=0.91). However, before more extensive clinical use can be considered, certain problems must be clarified such as the optimal dosage form of the test substance, the influence of body fat deposition on d-propoxyphene AUC and the most accurate technical methodology to assess low d-propoxyphene and norpropoxyphene plasma concentrations. The norpropoxyphene/d-propoxyphene ratio might be a useful parameter in the future for evaluating the dose of drugs with relatively high hepatic extraction to be given orally to patients with cirrhosis. (C) Journal of Hepatology.