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 inve stigated a group of patients with cirrhosis with or without surgical p orta-caval shunt for d-propoxyphene and its major metabolite, norpropo xyphene kinetics. A small dose of d-propoxyphene (0.7 mg/kg body weigh t) was given orally to seven normal subjects, 15 patients with cirrhos is 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-pr opoxyphene AUC ratios should reflect both the degree of portal-systemi c shunting and the severity of hepatocyte dysfunction. Norpropoxyphene /d-propoxyphene AUC ratios were significantly lower in patients with c irrhosis (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 sh unt (0.53+/-0.23) than in patients with cirrhosis but without surgical shunt (1.10+/-0.63). Moreover, there was an overall statistically sig nificant correlation between norpropoxyphene/d-propoxyphene AUC ratios and branched to aromatic amino acids ratios (r(s)=0.91) and fasting v enous NH4 (r(s)=-O.6). On the other hand, there was only a weak correl ation between norpropoxyphene/d-propoxyphene AUC ratios and the C-14-a minopyrine breath test (r(s)=0.43). These data suggest that the norpro poxyphene/d-propoxyphene AUC ratio reflects both shunting and reduced hepatocellular function. The norpropoxyphene/d-propoxyphene ratio dete rmined 2 h after d-propoxyphene administration might be a suitable cli nical parameter because of its close correlation with norpropoxyphene/ d-propoxyphene AUC ratio (r(s)=0.91). However, before more extensive c linical use can be considered, certain problems must be clarified such as the optimal dosage form of the test substance, the influence of bo dy fat deposition on d-propoxyphene AUC and the most accurate technica l methodology to assess low d-propoxyphene and norpropoxyphene plasma concentrations. The norpropoxyphene/d-propoxyphene ratio might be a us eful parameter in the future for evaluating the dose of drugs with rel atively high hepatic extraction to be given orally to patients with ci rrhosis. (C) Journal of Hepatology.