Roos F J, Zysset T, Reichen J
Department of Clinical Pharmacology, Berne, Switzerland.
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.
在肝硬化患者中，氧化药物代谢受损；然而，尚不清楚这是否取决于肝硬化的病因。因此，我们在两种大鼠模型中研究了右美沙芬的代谢：胆管结扎诱导的胆汁性肝硬化和长期接触四氯化碳/苯巴比妥诱导的小结节性肝硬化。将结果与通过体内呼气试验评估的氨基比林N-去甲基化进行比较；与对照组相比，胆汁性肝硬化（-41%）和小结节性肝硬化（-37%）中后者的降低程度相似。相比之下，与对照组（62.2±16.2）相比，胆汁性肝硬化（25.4±5.3 mL/min/kg）中右美沙芬的清除率显著降低（P<0.001），而小结节性肝硬化中则未降低（48.6±15.6）。在体外，胆汁性肝硬化和小结节性肝硬化中右美沙芬的内在清除率分别降低了95%和63%（与对照组相比，P<0.001）。它与体内右美沙芬清除率相关（r = 0.68，P<0.001），而与氨基比林N-去甲基化的相关性较弱（r = 0.42，P<0.05）。我们的结果表明，胆汁性肝硬化和小结节性肝硬化对负责氨基比林和右美沙芬去甲基化的同工酶有不同的影响。
