Disease relevance of Deethylamiodarone

• The relationship of apparent steady-state serum concentrations of amiodarone and its metabolite, desethylamiodarone, to therapeutic and toxic effects was assessed in 127 patients who had treatment-resistant ventricular or supraventricular arrhythmias or were intolerant to other agents [1].
• Amiodarone- and desethylamiodarone-induced myelinoid inclusion bodies and toxicity in cultured rat hepatocytes [2].
• Amiodarone and desethylamiodarone plasma levels did not correlate with changes in either sinus cycle length, QTc interval, ventricular effective refractory period, AH and HV intervals or ventricular tachycardia cycle length [3].
• No significant differences in plasma or myocardial concentrations of amiodarone or desethylamiodarone were observed between animals which developed ventricular fibrillation and those which did not [4].
• We, therefore, studied the effect of the drug and its major metabolite, desethylamiodarone (DEA), on the in vitro binding of thyroid hormone (T3) to its receptor protein using the rat beta 1-thyroid hormone receptor expressed in Escherichia coli [5].

High impact information on Deethylamiodarone

• 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) [6].
• 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 [6].
• These results demonstrate that both amiodarone and its major metabolite, desethylamiodarone, induce lysosomal inclusions, which, under appropriate conditions, can be dissociated from cell death [2].
• Because thyroid hormones are known to act through nuclear receptor proteins, the binding of amiodarone and desethylamiodarone was measured to nuclear extracts derived from human lymphocytes, bovine atrium and ventricle and rat liver [7].
• Relation between amiodarone and desethylamiodarone plasma concentrations and electrophysiologic effects, efficacy and toxicity [3].

Chemical compound and disease context of Deethylamiodarone

• When analyzed in a multivariate model, conversion was related to desethylamiodarone plasma level (p = 0.0006), arrhythmia duration (p = 0.04), left atrial area (p = 0.02), and concomitant treatment with verapamil (p = 0.01) [8].
• 1. The concentrations of amiodarone/desethylamiodarone, digoxin, flecainide and sotalol were measured in serum collected immediately prior to death and in postmortem blood collected from the femoral vein and artery of an 18-year-old male with congenital heart disease who developed a fatal arrhythmia [9].

Biological context of Deethylamiodarone

• Amiodarone and desethylamiodarone, its active metabolite, were measured in the plasma, atrial tissue and pericardial fat of patients undergoing cardiac surgery [10].
• The modulating effect on drug resistance of amiodarone (AM) and its metabolite desethylamiodarone (DEA) was studied in a P-glycoprotein-positive human colon carcinoma cell line COLO 320, and a human small-cell lung carcinoma cell line GLC4 and its adriamycin (Adr)-resistant subline GLC4-Adr (both P-glycoprotein-negative) [11].
• To gain insight into the position of the binding site of desethylamiodarone on TR beta1 we investigated the naturally occurring mutants Y321C, R429Q, P453A, P453T and the artificial mutants L421R and E457A in the ligand binding domain of human TR beta1 [12].
• Desethylamiodarone markedly reduced cell number as assessed from both DNA and protein content [13].
• Amiodarone but not desethylamiodarone protects the mitochondrial energy metabolism of the perfused heart during ischemia in perfused hearts [14].

Anatomical context of Deethylamiodarone

• A linear correlation between hepatocyte drug concentration and multilamellar inclusion bodies was found for both amiodarone and desethylamiodarone [2].
• In conclusion, the equilibration of amiodarone and desethylamiodarone concentrations between myocardium and plasma appears to occur slowly in patients undergoing long-term treatment with amiodarone.(ABSTRACT TRUNCATED AT 250 WORDS)[10]
• Amiodarone and desethylamiodarone distribution in the atrium and adipose tissue of patients undergoing short- and long-term treatment with amiodarone [10].
• Additional experiments were carried out in bovine aortic endothelial cells to explore the effects of N-desethylamiodarone on the intracellular Ca2+ concentration ([Ca2+]i) [15].
• As AMD displays direct toxic effect on different cell types, we investigated the cytotoxic effect of AMD and its main metabolite, desethylamiodarone (DEA), in thyroid (TAD-2) and nonthyroid (HeLa) cell lines [16].

Associations of Deethylamiodarone with other chemical compounds

• Incubation with subtoxic concentrations of either amiodarone (7.6 microM) or desethylamiodarone (8 microM) for 24 hr resulted in the development of myelinoid inclusion bodies in the hepatocytes without any excess release of lactate dehydrogenase [2].
• In vitro, 10 micromol/L N-desethylamiodarone caused a sustained increase of the endothelial [Ca2+]i. Pretreatment of the volunteers with acetylsalicylic acid reduced the maximum N-desethylamiodarone-induced venodilation to 22% +/- 8%; L-NMMA reduced the maximum N-desethylamiodarone-induced venodilation to 18% +/- 11% [15].
• AM acts, via its major metabolite desethylamiodarone, in vitro and in vivo as a thyroid hormone receptor alpha(1) (TRalpha(1)) and TRbeta(1) antagonist [17].
• Serum mexiletine, amiodarone, and desethylamiodarone concentrations were measured by an HPLC method [18].
• Effect of amiodarone and desethylamiodarone on the pharmacokinetics of antipyrine in the rat [19].

Gene context of Deethylamiodarone

• In humans, cytochrome P450 3A (CYP3A4) is a major enzyme involved in the metabolism of amiodarone (AM) to its major metabolite, desethylamiodarone (DEA) [20].
• Amiodarone is metabolized by CYP3A to N-desethylamiodarone (N-DEA) [21].
• Desethylamiodarone interferes with the binding of co-activator GRIP-1 to the beta 1-thyroid hormone receptor [22].
• The N-deethylation of amiodarone to desethylamiodarone is known to be catalyzed by cytochrome P450 (CYP) 2C8 [23].
• Desethylamiodarone treatment resulted in a neutrophilic alveolitis, but the levels of TNF-alpha and TGF-beta were not significantly different from control animals [24].

Analytical, diagnostic and therapeutic context of Deethylamiodarone

• Myocardial amiodarone and desethylamiodarone concentrations in patients undergoing cardiac transplantation [25].
• Clinical measurement of serum amiodarone and desethylamiodarone by using solid-phase extraction followed by HPLC with a high-carbon reversed-phase column [26].
• Amiodarone or desethylamiodarone were administered intravenously either 10 min prior to ischaemia or 2 min prior to reperfusion [4].
• Microassay of amiodarone and desethylamiodarone in serum by capillary electrophoresis with head-column field-amplified sample stacking [27].
• Amiodarone (1.95 micrograms/mL) and desethylamiodarone (0.80 microgram/mL) were added together into the cell culture [28].

References