C-14 PROPOXYPHENE DEMETHYLATION IN THE RAT - AN EXAMPLE OF DIFFERENCES BETWEEN LIVER AND INTESTINAL DRUG-PRESYSTEMIC METABOLISM

Presystemic metabolism is believed to occur mainly in the liver with s ome minor intestinal participation, The aim of this study was to inves tigate the respective part of each of these two organs in the metaboli sm of the analgesic d-propoxyphene (DP), Pharmacological doses of DP w ere given in the duodenum (ID), the portal vein (IF), and the femoral vein (IV) of male Wistar rats, A tracer dose of C-14-DP was also admin istered either in IV, IP, or ID as well as in hepatectomized rats or r ats with bile duct diversion, In vitro demethylation occurring in live r and intestinal microsomes was also studied, Absolute DP bioavailabil ity obtained after oral administration was two times higher than that observed after portal administration (48.9% vs. 23.2%, respectively), an result opposite (i.e. a lower bioavailability) of that expected on the basis of the existence of a liver enzyme saturation phenomenon, Th e (CO2)-C-14 cumulative excretion after C-14-DP administration was sig nificantly lower after IV or ID administration than after injection in the portal vein as a bolus or within 20 min, The biliary excretion of the labeled compound varied in the opposite direction, being greater after IV or ID than after IP administration, suggesting that the metab olism of DP in the liver is influenced by an extrahepatic transformati on, This most likely occurs in the gut since the production of (CO2)-C -14 after IV administration was similar to that after ID administratio n. This transformation did not prohibit DP detection in the systemic b lood but was sufficient to increase the part eliminated with bile and to decrease the part demethylated into NP, Demethylation mainly occurs in the liver since the production of (CO2)-C-14 was nearly abolished in hepatectomized rats, Furthermore, microsomes of hepatic but not of intestinal origin were able to demethylate DP, Our data suggest that t he transformation of DP occurring in gut after oral administration is responsible for changes in the hepatic metabolism of the drug.