EXTRAHEPATIC METABOLISM OF 4-METHYLUMBELLIFERONE AND LIDOCAINE IN THEANHEPATIC RABBIT

Extrahepatic drug metabolism was studied in an anhepatic rabbit model. Plasma concentrations of 4-methylumbelliferone (4-MU) and its major m etabolites, 4-methylumbelliferyl-O-glucuronide and 4-methyumbelliferyl sulfate, along with lidocaifie and its major metabolites, monoethylgl ycinexylidide and 3-hydroxylidocaine, were measured in sham rabbits (n = 4) acid anhepatic rabbits (n = 4) following bolus intravenous admin istration of each drug. Along with concentration profiles of the drugs and metabolites, pharmacokinetic analyses of 4-MU metabolism and lido caine metabolism were used to assess the extrahepatic metabolism of th ese classical substrates. Total body clearance of 4-MU in the anhepati c rabbits was about 50% that of the sham animals. Extensive extrahepat ic glucuronidation of 4-MU was revealed by comparing the AUC ratios of 4-methylumbelliferyl-O-glucuronide and 4-MU in anhepatic and sham rab bit groups. Sulfation of 4-MU was reduced significantly in the anhepat ic group, although some extrahepatic sulfation was observed. Total bod y clearance of lidocaine was reduced 3-fold in anhepatic animals. 3-Hy droxylidocaine was only detected in plasma samples from sham animals. These results emphasize the importance of extrahepatic sites in drug m etabolism, especially glucuronidation of phenolic compounds such as 4- MU.