N-Desethylamiodarone (hydrochloride) is a major metabolite of amiodarone that inhibits the activity of cytochrome P4502D6 (CYP2D6) in rats [1]. N-Desethylamiodarone inhibits N-methyl-D-aspartic acid (NMDA)-receptor binding in synaptic membranes and enhances intrasynaptosomal free calcium [2]. N-Desethylamiodarone has been widely used to increase the ventricular defibrillation threshold and slow down the conduction speed of Purkinje fibers and ventricular muscle fibers [3].
In vitro, N-Desethylamiodarone treatment for 4 days significantly induced cell death in SGHTL-34 cells, with an EC50 value of 6.8μg/ml [4]. Treatment with 10µM N-Desethylamiodarone for 2 hours significantly enhanced nitric oxide synthase-mediated NO production in human umbilical vein endothelial cells (HUVECs)[5].
In vivo, N-Desethylamiodarone treatment via intravenous injection at a dose of 10mg/kg for 30 minutes, significantly enhanced the ventricular fibrillation threshold in pigs[6]. Intraperitoneal injection of N-Desethylamiodarone at a dose of 25mg/kg every three days for 16 days significantly inhibited melanoma metastasis in mice[7].
References:
[1] Jaruratanasirikul S, Hortiwakul R. The inhibitory effect of amiodarone and desethylamiodarone on dextromethorphan O‐demethylation in human and rat liver microsomes[J]. Journal of pharmacy and pharmacology, 1994, 46(11): 933-935.
[2] Kodavanti P R S, Pentyala S N, Yallapragada P R, et al. Amiodarone and desethylamiodarone increase intrasynaptosomal free calcium through receptor mediated channel[J]. Naunyn-Schmiedeberg's archives of pharmacology, 1992, 345(2): 213-221.
[3] Zhou L, Chen B P, Kluger J, et al. Effects of amiodarone and its active metabolite desethylamiodarone on the ventricular defibrillation threshold[J]. Journal of the American College of Cardiology, 1998, 31(7): 1672-1678.
[4] Beddows S A, Page S R, Taylor A H, et al. Cytotoxic effects of amiodarone and desethylamiodarone on human thyrocytes[J]. Biochemical pharmacology, 1989, 38(24): 4397-4403.
[5] Kishida S, Nakajima T, Ma J, et al. Amiodarone and N-desethylamiodarone enhance endothelial nitric oxide production in human endothelial cells[J]. International Heart Journal, 2006, 47(1): 85-93.
[6] Zhou L, White C M, Chen B P, et al. A comparison of the antifibrillatory effects of desethylamiodarone to amiodarone in a swine model[J]. Journal of cardiovascular pharmacology, 1999, 34(3): 440-445.
[7] Bognar Z, Cseh A M, Fekete K, et al. Amiodarone’s major metabolite, desethylamiodarone inhibits proliferation of B16-F10 melanoma cells and limits lung metastasis formation in an in vivo experimental model[J]. PLoS One, 2020, 15(9): e0239088.
N-Desethylamiodarone (hydrochloride)是amiodarone的主要代谢产物，可抑制大鼠中细胞色素P4502D6 (CYP2D6)的活性[1]。N-Desethylamiodarone可抑制突触膜中N-methyl-D-aspartic acid (NMDA)受体的结合，并提高突触小体内的游离钙含量[2]。N-Desethylamiodarone已被广泛用于提高心室除颤阈值，并减慢浦肯野纤维和心室肌纤维的传导速度[3]。
在体外，N-Desethylamiodarone处理SGHTL-34细胞4天，显著诱导了细胞死亡，EC50值为6.8µg/ml[4]。10µM的N-Desethylamiodarone处理人脐静脉内皮细胞(HUVECs)2小时，显著增强了一氧化氮合酶介导的一氧化氮（NO）产生[5]。
在体内，静脉注射10mg/kg剂量的N-Desethylamiodarone 30分钟，显著提高了猪的心室颤动阈值[6]。每三天腹腔注射25mg/kg剂量的N-Desethylamiodarone，持续16天，显著抑制了小鼠体内黑色素瘤的转移[7]。