Differential effect of biliary and micronodular cirrhosis on oxidative drug metabolism. In vivo-in vitro correlations of dextromethorphan metabolism in rat models

Biochem Pharmacol. 1991 May 15;41(10):1513-9. doi: 10.1016/0006-2952(91)90569-q.


Oxidative drug metabolism is impaired in liver cirrhosis; it is unclear, however, whether this depends on the etiology of cirrhosis. Therefore, we studied the metabolism of dextromethorphan in two rat models: biliary cirrhosis induced by bile duct ligation and micronodular cirrhosis induced by chronic exposure to CCl4/phenobarbital. Results were compared with aminopyrine N-demethylation assessed by a breath test in vivo; the latter was reduced to a similar extent in biliary (-41%) and micronodular (-37%) cirrhosis compared to controls. In contrast, clearance of dextromethorphan was significantly (P less than 0.001) reduced in biliary (25.4 +/- 5.3 mL/min/kg) but not in micronodular cirrhosis (48.6 +/- 15.6) as compared to controls (62.2 +/- 16.2). Intrinsic clearance of dextromethorphan in vitro was reduced by 95% and 63% in biliary and micronodular cirrhosis, respectively (P less than 0.001 vs controls). It correlated with dextromethorphan clearance in vivo (r = 0.68, P less than 0.001) whereas correlation with aminopyrine N-demethylation was weak (r = 0.42, P less than 0.05). Our results demonstrate a differential effect of biliary and micronodular cirrhosis on isoenzymes responsible for aminopyrine and dextromethorphan demethylation.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Dextromethorphan / pharmacokinetics*
  • Dextrorphan / metabolism
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis, Biliary / metabolism*
  • Male
  • Metabolic Clearance Rate
  • Methylation
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Models, Biological
  • Organ Size / drug effects
  • Oxidoreductases, O-Demethylating / metabolism
  • Rats
  • Rats, Inbred Strains
  • Spleen / drug effects


  • Dextrorphan
  • Dextromethorphan
  • Oxidoreductases, O-Demethylating