PT  - JOURNAL ARTICLE
AU  - S L Nyberg
AU  - H J Mann
AU  - M Y Hu
AU  - W D Payne
AU  - W S Hu
AU  - F B Cerra
AU  - R P Remmel
TI  - Extrahepatic metabolism of 4-methylumbelliferone and lidocaine in the anhepatic rabbit.
DP  - 1996 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 643--648
VI  - 24
IP  - 6
4099  - http://dmd.aspetjournals.org/content/24/6/643.short
4100  - http://dmd.aspetjournals.org/content/24/6/643.full
SO  - Drug Metab Dispos1996 Jun 01; 24
AB  - Extrahepatic drug metabolism was studied in an anhepatic rabbit model. Plasma concentrations of 4-methylumbelliferone (4-MU) and its major metabolites, 4-methylumbelliferyl-O-glucuronide and 4-methyumbelliferyl sulfate, along with lidocaine and its major metabolites, monoethylglycinexylidide and 3-hydroxylidocaine, were measured in sham rabbits (n = 4) and anhepatic rabbits (n = 4) following bolus intravenous administration of each drug. Along with concentration profiles of the drugs and metabolites, pharmacokinetic analyses of 4-MU metabolism and lidocaine metabolism were used to assess the extrahepatic metabolism of these classical substrates. Total body clearance of 4-MU in the anhepatic rabbits was about 50% that of the sham animals. Extensive extrahepatic glucuronidation of 4-MU was revealed by comparing the AUC ratios of 4-methylumbelliferyl-O-glucuronide and 4-MU in anhepatic and sham rabbit groups. Sulfation of 4-MU was reduced significantly in the anhepatic group, although some extrahepatic sulfation was observed. Total body clearance of lidocaine was reduced 3-fold in anhepatic animals. 3-Hydroxylidocaine was only detected in plasma samples from sham animals. These results emphasize the importance of extrahepatic sites in drug metabolism, especially glucuronidation of phenolic compounds such as 4-MU.