title: Extrahepatic metabolism of 4-methylumbelliferone and lidocaine in the anhepatic rabbit.
abstract: 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.
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis 55455, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Nyberg
authors.forename: H J
authors.initials: HJ
authors.lastname: Mann
authors.forename: M Y
authors.initials: MY
authors.lastname: Hu
authors.forename: W D
authors.initials: WD
authors.lastname: Payne
authors.forename: W S
authors.initials: WS
authors.lastname: Hu
authors.forename: F B
authors.initials: FB
authors.lastname: Cerra
authors.forename: R P
authors.initials: RP
authors.lastname: Remmel
mesh_terms: D000779:Anesthetics, Local / Q000097:blood / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D006498:Hepatectomy; D006923:Hymecromone / Q000097:blood / Q000378:metabolism*; D007202:Indicators and Reagents / Q000378:metabolism*; D008012:Lidocaine / Q000097:blood / Q000378:metabolism*; D011817:Rabbits; D014468:Umbelliferones / Q000097:blood / Q000378:metabolism
chemical_list: D000779:Anesthetics, Local; D007202:Indicators and Reagents; D014468:Umbelliferones; D006923:Hymecromone; D008012:Lidocaine