Amiodarone Increases the Accumulation of DEA in a Human Alveolar Epithelium-Derived Cell Line

Abstract

Amiodarone (AMD) is a highly effective drug for the treatment of cardiac dysrhythmias.1) Clinical evidence suggests that this drug has a role in reducing the relative risk for arrhythmic or sudden death and overall mortality in survivors of myocardial infarction and in heart failure patients. 2)Among the various antiarrhythmic agents, AMD has electrophysiological effects that most closely approximate those of an ideal antiarrhythmic agent.3) Although AMD is used widely, 4) AMD-induced pulmonary toxicity (AIPT) limits the clinical use of AMD.5-7) AIPT has been clinically diagnosed in 5 to 10% of patients receiving high doses of AMD and in 1.6% of patients receiving AMD at a dose of 400 mg/d or less.8) Because of its high potential for mortality, AIPT is the adverse event of greatest concern for patients receiving AMD therapy.In humans, AMD is metabolized to N-monodesethylamiodarone (DEA), an active metabolite of AMD, by P450 (CYP) 3A.9-12) The blood concentration of DEA has been shown to be comparable with that of AMD. [13][14][15] The mechanisms of AMD-or DEA-induced cytotoxicity, including altered inflammatory mediator release, 16) phosopholipidosis promotion, 17) mitochondrial dysfunction 18) and free radical production, 19) have been extensively studied. On the other hand, the tendencies of AMD and DEA to accumulate in the lung 20) are also considered factors responsible for the initiation of AIPT, and it is possible that some mechanisms contribute to the accumulation of both compounds. The accumulation of DEA in the lung is greater than that of AMD. Adams et al. reported that the DEA concentration in lung tissue of long-term AMD-treated patients was approximately 5-hold higher than that of AMD.21) Furthermore, DEA is more cytotoxic than AMD in lung cells 16) and in non-pulmonary cell types. 22)Thus, it is important to elucidate the transport mechanisms of DEA in the lung. However, the transport mechanisms of DEA as well as those of AMD have not been investigated in detail. It has been reported that DEA and AMD inhibited the transport of digoxin by human MDR1 cDNA-transfected LLC-PK 1 cells, 23) but it is unclear whether P-glycoprotein (Pgp) recognizes DEA and AMD as a substrate.Previously, we demonstrated that DEA accumulation was increased under an ATP-depleted condition in Caco-2 cells and that triiodothyronine (T 3 ) also increased the accumulation of DEA by Caco-2 cells. 24) In this study, to clarify the mechanism of high accumulation of DEA in the lung, we investigated the mechanism of AMD or DEA accumulation in A549 cells, a human alveolar epithelium-derived cell line. MATERIALS AND METHODSChemicals AMD and DEA were kindly supplied by Taisho Pharmaceutical (Tokyo, Japan). All other reagents were of the highest grade available and used without further purification. AMD and DEA were dissolved in methanol (1% w/v final concentration) due to their hydrophobic properties and poor solubility in water.Cell Culture A549 cells obtained from American Type Culture Collection (Rockville, MD, U.S.A.) were maintaine...

A Review on Amiodarone as an Antiarrhythmic Drug

“…In addition, reactive type II pneumocytes tended to occur more frequently in ventilator associated drug induced pulmonary disorders and they were associated mainly with the condition of acute lung injury [39,44]. Microscopic observations showed diffused interstitial pneumonitis with widening of alveolar septa and interstitial fibrosis in lung tissues from patients [47,48]. Organizing pneumonia, acute respiratory distress syndrome (ARDS), diffused alveolar hemorrhage (DAH) are the other adverse effects from Amiodarone administration [44,47].…”

“…Other pulmonary side effects from Amiodarone treatment include fibrosis that is the result of chronic inflammation which in turn is due to cellular damage, reduced forced vital capacity, total lung capacity and reduced diffusing capacity. Other Amiodarone side effect on lung is organizing pneumonia which is accompanied with the proliferation of granulation tissue which consists of fibroblasts, myofibroblast and collagen fibers [35,45,48]. Acute respiratory distress syndrome (ARDS) is characterized by diffuse alveolar hemorrhage which includes pulmonary edema, systemic lupus vasculitis and hemorrhage [35].…”

Amiodarone-induced Acute Respiratory Distress Syndrome Masquerading as Acute Heart Failure

“…As discussed above, a higher number of amiodarone-induced ARDS cases have been seen in patients after cardiopulmonary surgery or pulmonary angiography. Although the exact pathophysiology of amiodarone-induced ARDS is unclear, it is postulated that high inspired oxygen synergizes with amiodarone-induced free radicals to increase the lung damage (13,14). Another postulated mechanism is the development of hypersensitivity reaction similar to that seen with other organic antigen exposure such as farmer's lung characterized by influx of inflammatory cells to the lungs (15).…”

Amiodarone-induced diffuse alveolar haemorrhage: a rare but potentially life-threatening complication of a commonly prescribed medication

“…It is suspected to cause diffuse alveolar damage which can lead to alveolar haemorrhage. The DAH is characterised by oedema in the alveolar septa which increase capillary permeability 1 2. Amiodarone is thought to alter the phospholipid bilayer.…”

“…This, in turn, disrupts membrane function of cellular and organelle membranes and interferes with the normal cellular metabolic pathways. This can lead to direct cellular injury and death 2 3. Toxic oxygen species are also thought to be generated resulting in tissue injury.…”