Extrahepatic metabolism of 4-methylumbelliferone and lidocaine in the anhepatic rabbit.
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.
Nyberg
S L
SL
Department of Surgery, University of Minnesota, Minneapolis 55455, USA.
Mann
H J
HJ
Hu
M Y
MY
Payne
W D
WD
Hu
W S
WS
Cerra
F B
FB
Remmel
R P
RP
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
D000779:Anesthetics, Local; D007202:Indicators and Reagents; D014468:Umbelliferones; D006923:Hymecromone; D008012:Lidocaine