Differential effect of biliary and micronodular cirrhosis on oxidative drug metabolism. In vivo-in vitro correlations of dextromethorphan metabolism in rat models.
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.
Roos
F J
FJ
Department of Clinical Pharmacology, Berne, Switzerland.
Zysset
T
T
Reichen
J
J
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003915:Dextromethorphan / Q000493:pharmacokinetics*; D003917:Dextrorphan / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism*; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008745:Methylation; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009929:Organ Size / Q000187:drug effects; D010090:Oxidoreductases, O-Demethylating / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013154:Spleen / Q000187:drug effects
D003917:Dextrorphan; D003915:Dextromethorphan; D010090:Oxidoreductases, O-Demethylating