Kodavanti U P, Mehendale H M
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505.
Am J Respir Cell Mol Biol. 1991 Apr;4(4):369-78. doi: 10.1165/ajrcmb/4.4.369.
Amiodarone (AM) pulmonary phospholipidosis in patients receiving this drug is well recognized. We investigated the in vivo phospholipidosis-inducing potency of AM and its major nonpolar metabolite, desethylamiodarone (DEA), in rats, their ability to inhibit phospholipases, and also the effects on pulmonary uptake of [14C] AM. Fisher-344 male rats (200 to 250 g) were given AM or DEA (100 mg/kg/d orally) for 2, 7, or 21 d. Food consumption and body weight gain were significantly reduced by both AM and DEA treatment. The control rats, therefore, were pair-fed. Both drugs increased the number of cells in lavage during the treatment. Lung/body weight ratio increased after 21 d of treatment in AM rats. Mortality increased to 100% by day 10 in DEA-treated rats, unlike in AM-treated rats, where 20 to 30% of the animals died during this period and thereafter. No further mortality occurred during 21 d of treatment. Levels of phospholipids increased in lavaged lung, alveolar lavage cells, and surfactant material in AM- as well as DEA-treated rats. However, there was no significant difference between the two treatment groups. Phospholipases A and C were measured in lysosomal soluble fractions of lavaged lung and sonicated lung lavage cells. Both drugs exerted inhibitory action on phospholipases in the lavage cells but, to some extent, spared phospholipases in lysosomal plus mitochondrial soluble fraction isolated from lavaged lung with reversibility in enzyme inhibition despite continuous treatment. [14C] AM uptake by perfused lung, lavage cells as well as surfactant supernatant was increased in AM- and DEA-treated rats. Again, increase in pulmonary uptake of [14C]AM was similar in AM- and DEA-treated rats. These results thus suggest: (1) DEA is more toxic to rats than is AM, at the dose level used. The ability to sequester AM and the parameters related to phospholipidosis revealed no significant differences between these two analogs. (2) Both drugs are inhibitors of lavage cell phospholipases and also are inhibitory to lung lysosomal phospholipases to a lesser extent. Recovery of lung phospholipases occurred despite continuous treatment. (3) AM- and DEA-induced phospholipidosis increased the uptake of [14C]AM by perfused lung. (4) The mechanism of AM-induced pulmonary phospholipidosis includes selective in vivo inhibition of phospholipases.
接受胺碘酮（AM）治疗的患者出现胺碘酮肺磷脂沉积症已广为人知。我们研究了AM及其主要非极性代谢产物去乙基胺碘酮（DEA）在大鼠体内诱导磷脂沉积症的效力、它们抑制磷脂酶的能力，以及对[14C]AM肺摄取的影响。给体重200至250克的雄性Fisher - 344大鼠口服AM或DEA（100毫克/千克/天），持续2、7或21天。AM和DEA治疗均显著降低了食物消耗量和体重增加。因此，对对照大鼠进行配对喂食。两种药物在治疗期间均增加了灌洗细胞数量。AM组大鼠治疗21天后肺/体重比增加。与AM组大鼠不同，DEA组大鼠在第10天时死亡率升至100%，AM组在此期间及之后有20%至30%的动物死亡。在21天的治疗期间未再出现死亡情况。AM组和DEA组大鼠灌洗肺、肺泡灌洗细胞及表面活性物质中的磷脂水平均升高。然而，两个治疗组之间无显著差异。在灌洗肺的溶酶体可溶性部分及超声处理的肺灌洗细胞中检测磷脂酶A和C。两种药物对灌洗细胞中的磷脂酶均有抑制作用，但在一定程度上对从灌洗肺中分离出的溶酶体加线粒体可溶性部分中的磷脂酶影响较小，尽管持续治疗，酶抑制仍具有可逆性。AM组和DEA组大鼠灌注肺、灌洗细胞及表面活性物质上清液对[14C]AM的摄取均增加。同样，AM组和DEA组大鼠肺对[14C]AM摄取的增加相似。因此，这些结果表明：（1）在所使用的剂量水平下，DEA对大鼠的毒性比AM更大。这两种类似物在螯合AM的能力及与磷脂沉积症相关的参数方面无显著差异。（2）两种药物均为灌洗细胞磷脂酶的抑制剂，对肺溶酶体磷脂酶的抑制作用较小。尽管持续治疗，肺磷脂酶仍可恢复。（3）AM和DEA诱导的磷脂沉积症增加了灌注肺对[14C]AM的摄取。（4）AM诱导肺磷脂沉积症的机制包括体内对磷脂酶的选择性抑制。
