Extrahepatic metabolism of 4-methylumbelliferone and lidocaine in the anhepatic rabbit

Scott L. Nyberg, Henry J. Mann, Michael Y. Hu, William D. Payne, Wei Shou Hu, Frank B. Cerra, Rory P. Remmel

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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-mothyumbelliferyl 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.

Original languageEnglish (US)
Pages (from-to)643-648
Number of pages6
JournalDrug Metabolism and Disposition
Volume24
Issue number6
StatePublished - Jun 1 1996

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Nyberg, S. L., Mann, H. J., Hu, M. Y., Payne, W. D., Hu, W. S., Cerra, F. B., & Remmel, R. P. (1996). Extrahepatic metabolism of 4-methylumbelliferone and lidocaine in the anhepatic rabbit. Drug Metabolism and Disposition, 24(6), 643-648.