Differential effect of biliary and micronodular cirrhosis on oxidative drug metabolism

Abstract

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<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<0.001 vs controls). It correlated with dextromethorphan clearance in vivo (r = 0.68, P<0.001) whereas correlation with aminopyrine N-demethylation was weak (r=0.42, P<0.05). Our results demonstrate a differential effect of biliary and micronodular cirrhosis on isoenzymes responsible for aminopyrine and dextromethorphan demethylation.