Daniels J M, Leeder R G, Brien J F, Massey T E
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ont., Canada.
Can J Physiol Pharmacol. 1990 Sep;68(9):1261-8. doi: 10.1139/y90-189.
Amiodarone is a potent and efficacious antiarrhythmic agent, yet associated with its use are life-threatening pulmonary fibrosis and hepatotoxicity. We have investigated the susceptibility of the male Sprague-Dawley rat to pulmonary and hepatic toxicity after repeated exposure to amiodarone and the effects of such exposure on hepatic and extrahepatic drug metabolizing enzymes. Animals received amiodarone (200 mg.kg-1.day-1 i.p., 5 days/week) for 1 week followed by 150 mg.kg-1.day-1 (5 days/week) for 3 additional weeks. No signs of pulmonary fibrosis or hepatotoxicity were observed, based on histological examination, lung hydroxyproline content, and plasma alanine aminotransferase activity. Analysis of tissues revealed extensive accumulation of amiodarone and desethylamiodarone in lung and liver, but concentrations were significantly lower in animals treated for 4 weeks than for 1 week. In a separate experiment, rats received amiodarone 150 mg.kg-1.day-1 i.p. (5 days/week) for 1 or 4 weeks. No differences in tissue concentrations of amiodarone and desethylamiodarone were detected between animals treated for 1 or 4 weeks. This regimen did not affect hepatic or extrahepatic monooxygenase activities. These results indicate that, in the male Sprague-Dawley rat, there is no observable pulmonary or hepatic toxicity following short-term amiodarone exposure, and there is enhanced elimination of amiodarone and desethylamiodarone when the daily dose of amiodarone is decreased after 1 week from 200 to 150 mg/kg.
胺碘酮是一种强效且有效的抗心律失常药物，但使用该药物会伴有危及生命的肺纤维化和肝毒性。我们研究了雄性Sprague-Dawley大鼠反复接触胺碘酮后对肺和肝毒性的易感性，以及这种接触对肝内和肝外药物代谢酶的影响。动物接受胺碘酮（200mg·kg-1·天-1腹腔注射，每周5天），持续1周，随后为150mg·kg-1·天-1（每周5天），再持续3周。基于组织学检查、肺羟脯氨酸含量和血浆丙氨酸转氨酶活性，未观察到肺纤维化或肝毒性的迹象。组织分析显示，肺和肝中胺碘酮和去乙基胺碘酮大量蓄积，但接受4周治疗的动物体内的浓度显著低于接受1周治疗的动物。在另一项实验中，大鼠接受胺碘酮150mg·kg-1·天-1腹腔注射（每周5天），持续1周或4周。接受1周或4周治疗的动物之间，未检测到胺碘酮和去乙基胺碘酮的组织浓度存在差异。该方案未影响肝内或肝外单加氧酶活性。这些结果表明，在雄性Sprague-Dawley大鼠中，短期接触胺碘酮后未观察到明显的肺或肝毒性，并且当胺碘酮的每日剂量在1周后从200mg/kg降至150mg/kg时，胺碘酮和去乙基胺碘酮的消除增强。
