Adams P C, Holt D W, Storey G C, Morley A R, Callaghan J, Campbell R W
Circulation. 1985 Nov;72(5):1064-75. doi: 10.1161/01.cir.72.5.1064.
The pharmacokinetic characteristics of amiodarone suggest extensive tissue deposition. We confirmed this by measuring tissue concentrations of the drug and of its major metabolite, desethylamiodarone, in human tissues. These were obtained at autopsy (n = 9), surgery (n = 7), or biopsy (n = 2) from 18 patients who had been treated with amiodarone for varying periods of time. High concentrations of amiodarone were found in fat (316 mg/kg wet weight in autopsy specimens, 344 mg/kg wet weight in biopsy specimens). Amiodarone and desethylamiodarone concentrations (mg/kg wet weight, autopsy samples) were also high in liver (391 and 2354), lung (198 and 952), adrenal gland (137 and 437), testis (89 and 470), and lymph node (83 and 316). We also found high concentrations of amiodarone (306 mg/kg wet weight) and desethylamiodarone (943 mg/kg wet weight) in abnormally pigmented ("blue") skin from patients with amiodarone-induced skin pigmentation. These values were 10-fold higher than those in unpigmented skin from the same patients. These high concentrations were associated with lysosomal inclusion bodies in dermal macrophages in the pigmented skin. The inclusion bodies were intrinsically electron dense and were shown to contain iodine by energy dispersive x-ray microanalysis. Lysosomal inclusion bodies shown by electron microscopy to be multilamellar were seen in other tissues. These tissues included terminal nerve fibers in pigmented skin, pulmonary macrophages, blood neutrophils, and hepatocytes and Kupffer cells. These characteristic ultrastructural findings occur in both genetic lipidoses and lipidoses induced by other drugs, e.g., perhexiline. We conclude that during therapy with amiodarone, widespread deposition of amiodarone and desethylamiodarone occurs. This leads to ultrastructural changes typical of a lipidosis. These changes are seen clearly in tissues associated with the unwanted effects of amiodarone, e.g., skin, liver and lung.
胺碘酮的药代动力学特征表明其在组织中广泛沉积。我们通过测量人体组织中该药物及其主要代谢产物去乙基胺碘酮的浓度来证实这一点。这些组织浓度数据来自18例接受不同疗程胺碘酮治疗的患者的尸检（n = 9）、手术（n = 7）或活检（n = 2）样本。在脂肪组织中发现了高浓度的胺碘酮（尸检样本中湿重为316 mg/kg，活检样本中湿重为344 mg/kg）。胺碘酮和去乙基胺碘酮的浓度（mg/kg湿重，尸检样本）在肝脏（391和2354）、肺（198和952）、肾上腺（137和437）、睾丸（89和470）以及淋巴结（83和316）中也很高。我们还在胺碘酮诱导的皮肤色素沉着患者的异常色素沉着（“蓝色”）皮肤中发现了高浓度的胺碘酮（306 mg/kg湿重）和去乙基胺碘酮（943 mg/kg湿重）。这些值比同一患者未色素沉着皮肤中的值高10倍。这些高浓度与色素沉着皮肤中真皮巨噬细胞内的溶酶体包涵体有关。这些包涵体本质上电子密度高，通过能量色散X射线微分析显示含有碘。在电子显微镜下显示为多层的溶酶体包涵体也见于其他组织。这些组织包括色素沉着皮肤中的终末神经纤维、肺巨噬细胞、血液中性粒细胞以及肝细胞和库普弗细胞。这些特征性的超微结构发现既见于遗传性脂质贮积病，也见于其他药物如哌克昔林诱导的脂质贮积病。我们得出结论，在胺碘酮治疗期间，胺碘酮和去乙基胺碘酮会广泛沉积。这会导致脂质贮积病典型的超微结构变化。这些变化在与胺碘酮不良作用相关的组织如皮肤、肝脏和肺中清晰可见。
