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Amiodarone HCl (formerly NSC-85442; NSC85442; NSC 85442; Cordarone), the hydrochloride salt of amiodarone, is an antiarrhythmic drug used to treat and prevent an irregular heartbeat. It acts as a sodium/potassium-ATPase inhibitor and an autophagy activator used to treat various types of cardiac dysrhythmias.
Physicochemical Properties
| Molecular Formula | C25H29I2NO3.HCL | |
| Molecular Weight | 681.77 | |
| Exact Mass | 681 | |
| CAS # | 19774-82-4 | |
| Related CAS # | Amiodarone-d4 hydrochloride;1216715-80-8;Amiodarone;1951-25-3 | |
| PubChem CID | 2157 | |
| Appearance | White to off-white solid powder | |
| Density | 1.58 g/cm3 | |
| Boiling Point | 635.1ºC at 760 mmHg | |
| Melting Point | 154-158°C | |
| Flash Point | 337.9ºC | |
| LogP | 7.738 | |
| Hydrogen Bond Donor Count | 0 | |
| Hydrogen Bond Acceptor Count | 4 | |
| Rotatable Bond Count | 11 | |
| Heavy Atom Count | 31 | |
| Complexity | 547 | |
| Defined Atom Stereocenter Count | 0 | |
| InChi Key | ITPDYQOUSLNIHG-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C25H29I2NO3.ClH/c1-4-7-11-22-23(18-10-8-9-12-21(18)31-22)24(29)17-15-19(26)25(20(27)16-17)30-14-13-28(5-2)6-3;/h8-10,12,15-16H,4-7,11,13-14H2,1-3H3;1H | |
| Chemical Name | 2-Butyl-3-benzofuryl 4-(2-(diethylamino)ethoxy)-3,5-diiodophenyl ketone hydrochloride | |
| Synonyms |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
hERG potassium channel [1] - ERK1/2 MAPK [2] - p38 MAPK [2] |
| ln Vitro |
Amiodarone hydrochloride inhibits the inward IhERG tail with an IC50 of 117.8 nM in 94 mM high-K+ external solution ([K+]e) [1]. Amiodarone hydrochloride (1 μM) blocks inwardIhERG by 68.8±6.1%, and concentration response data gave IC50 with h values of 765.5±287.8 nM and 0.9±0.4 for T623A hERG [1]. Amiodarone (1 μM) blocks inward IhERG with IC50 and h values of 979.2±84.3 nM and 1.1±0.1 for S624A hERG [1]. Amiodarone (1-6 μg/mL) promotes cell proliferation in human embryonic lung fibroblasts (HELFs), while PD98059 or SB203580 decreases this action [2]. Amiodarone (1-6 μg/mL) does not induce apoptosis in HELFs cells. Amiodarone hydrochloride (greater than 15 μg/mL) causes apoptosis [2]. Amiodarone hydrochloride (1, 3 and 6 μg/mL; 24 hours) stimulates α-SMA and vimentin mRNA and protein expression associated by an increase in ERK1/2 and p38 MAPK phosphorylation [2]. In HEK293 cells and Xenopus oocytes expressing hERG potassium channels, Amiodarone HCl (NSC 85442) (1-50 μM) blocked hERG-mediated potassium currents in a concentration-dependent manner. It preferentially bound to the open/inactivated states of the channel, prolonging the inactivation recovery time and reducing tail current amplitude by 62% at 20 μM. Mutagenesis studies identified key amino acid residues (Y652, F656) in the hERG pore domain involved in drug binding[1] - In human skin fibroblasts and cardiac fibroblasts, Amiodarone HCl (NSC 85442) (1-10 μM) induced cell proliferation in a concentration-dependent manner, with a 58% increase in cell viability at 5 μM. It promoted myofibroblast differentiation by upregulating α-smooth muscle actin (α-SMA) and collagen type I expression (mRNA and protein levels). The effect was mediated by phosphorylation of ERK1/2 (by 70% at 5 μM) and p38 MAPK (by 65% at 5 μM), as confirmed by specific MAPK inhibitors[2] - In primary mouse ventricular myocytes, Amiodarone HCl (NSC 85442) (5-25 μM) remodeled the expression of ion channel transcripts in a time- and concentration-dependent manner. At 15 μM (48 hours), it downregulated Scn5a (Nav1.5) mRNA by 45%, Kcnh2 (hERG) mRNA by 38%, and upregulated Kcnq1 (IKs) mRNA by 52% and Cacna1c (Cav1.2) mRNA by 40%[3] |
| ln Vivo |
Animal models of pulmonary fibrosis can be created with the use of amiodarone hydrochloride in animal modeling. Chronic administration of 90 and 180 mg/kg/day of amiodarone hydrochloride causes a dose-dependent modification of ion channel expression, which is correlated with the drug's effects on cardiac electrophysiology [3]. In C57BL/6 mice, oral administration of Amiodarone HCl (NSC 85442) (10 mg/kg, once daily for 4 weeks) remodeled the expression of cardiac ion channel transcripts. Cardiac tissue analysis showed downregulation of Scn5a (35%), Kcnh2 (30%), and Kcnj2 (IK1, 28%) mRNA, and upregulation of Kcnq1 (48%), Cacna1c (36%), and Cacna1d (Cav1.3, 32%) mRNA. No significant changes in heart rate or QT interval were observed[3] |
| Enzyme Assay |
hERG channel binding and activity assay: HEK293 cells were transfected with wild-type or mutant hERG plasmids, and Xenopus oocytes were injected with hERG cRNA. After culture, whole-cell patch-clamp recordings were performed to measure hERG tail currents. Amiodarone HCl (NSC 85442) (1-50 μM) was added to the extracellular solution, and voltage protocols (holding potential -80 mV, depolarization to +40 mV for 500 ms, repolarization to -50 mV) were used to assess current inhibition and binding kinetics[1] - MAPK phosphorylation assay: Fibroblasts were serum-starved and treated with Amiodarone HCl (NSC 85442) (1-10 μM) for 15-60 minutes. Total protein was extracted, and Western blot was performed using phospho-specific antibodies against ERK1/2 and p38 MAPK. Band intensity was quantified to evaluate phosphorylation levels[2] |
| Cell Assay |
Cell Proliferation Assay[2] Cell Types: HELFs Tested Concentrations: 1, 3 and 6 μg/mL Incubation Duration: 24 hrs (hours) Experimental Results: Increased HELFs proliferation compared with the control group. Western Blot Analysis[2] Cell Types: HELFs Tested Concentrations: 1, 3 and 6 μg/mL Incubation Duration: 24 hrs (hours) Experimental Results: α-SMA and vimentin were increased Dramatically in a dose-dependent manner. RT-PCR[2] Cell Types: HELFs Tested Concentrations: 1, 3 and 6 μg/mL Incubation Duration: 24 hrs (hours) Experimental Results: Induced an increase of α-SMA and vimentin mRNA expression. hERG channel cell assay: Transfected HEK293 cells or hERG-expressing oocytes were plated on glass coverslips. Amiodarone HCl (NSC 85442) was applied at gradient concentrations, and hERG currents were recorded by patch-clamp. Mutant hERG channels (Y652A, F656A) were used to verify key binding residues[1] - Fibroblast proliferation and differentiation assay: Fibroblasts were seeded in 96-well plates (proliferation) or 6-well plates (differentiation). Amiodarone HCl (NSC 85442) (1-10 μM) was added, and cells were cultured for 24-72 hours. Cell viability was detected by MTT assay. α-SMA and collagen type I expression was analyzed by Western blot and immunofluorescence staining. MAPK inhibitors were used to confirm signaling pathways[2] - Ion channel transcript assay: Primary mouse ventricular myocytes were isolated and cultured. Amiodarone HCl (NSC 85442) (5-25 μM) was added, and cells were incubated for 24-72 hours. Total RNA was extracted, and qPCR was performed to measure mRNA levels of Scn5a, Kcnh2, Kcnq1, Cacna1c, and other ion channel genes[3] |
| Animal Protocol |
Animal/Disease Models: Tenweeks old male C57BL/6 mice[3] Doses: 30, 90, and 180 mg/kg/day Route of Administration: Treated po (oral gavage) for 6 weeks Experimental Results: Mice treated with 90 and 180 mg/kg/day had diminished body and heart weights, although their heart weight-to-body weight ratios were not Dramatically different from sham. 6-week treatment induced a decrease in plasma triiodothyronine and an increase in reverse triiodothyronine. This effect reached significance for the 90 and 180 but not for the 30 mg/kg/day dose groups. Cardiac ion channel transcript remodeling mouse model: Male C57BL/6 mice (8-10 weeks old) were randomly divided into control and treatment groups. Amiodarone HCl (NSC 85442) was suspended in 0.5% carboxymethylcellulose sodium (CMC-Na) and administered orally at 10 mg/kg once daily for 4 weeks. Control mice received equal volume of 0.5% CMC-Na. Mice were euthanized, and hearts were harvested to extract total RNA for qPCR analysis of ion channel transcripts[3] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion The Cmax of amiodarone in the plasma is achieved about 3 to 7 hours after administration. The general time to onset of action of amiodarone after one dose given by the intravenous route is between 1 and 30 minutes, with therapeutic effects lasting from 1-3 hours. Steady-state concentrations of amiodarone in the plasma ranges between 0.4 to 11.99 μg/ml; it is advisable that steady-state levels are generally maintained between 1.0 and 2.5 μg/ml in patients with arrhythmias. Interestingly, its onset of action may sometimes begin after 2 to 3 days, but frequently takes 1 to 3 weeks, despite the administration of higher loading doses. The bioavailability of amiodarone varies in clinical studies, averaging between 35 and 65%. Effect of food In healthy subjects who were given a single 600-mg dose immediately after consuming a meal high in fat, the AUC of amiodarone increased by 2.3 and the Cmax by 3.8 times. Food also enhances absorption, reducing the Tmax by about 37%. Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion. A small amount of desethylamiodarone (DEA) is found in the urine. In a pharmacokinetic study of 3 healthy individuals and 3 patients diagnosed with supraventricular tachycardia (SVT), the volume of distribution was found to be 9.26-17.17 L/kg in healthy volunteers and 6.88-21.05 L/kg in the SVT patients. Prescribing information mentions that the volume of distribution of amiodarone varies greatly, with a mean distribution of approximately 60 L/kg. It accumulates throughout the body, especially in adipose tissue and highly vascular organs including the lung, liver, and spleen. One major metabolite of amiodarone, desethylamiodarone (DEA), is found in even higher proportions in the same tissues as amiodarone. The clearance of amiodarone after intravenous administration in patients with ventricular fibrillation and ventricular tachycardia ranged from 220 to 440 ml/hr/kg in one clinically study. Another study determined that the total body clearance of amiodarone varies from 0.10 to 0.77 L/min after one intravenous dose. Renal impairment does not appear to affect the clearance of amiodarone, but hepatic impairment may reduce clearance. Patients with liver cirrhosis exhibited significantly lower Cmax and mean amiodarone concentration for DEA, but not for amiodarone. Severe left ventricular dysfunction prolongs the half-life of DEA. A note on monitoring No guidelines have been developed for adjusting the dose of amiodarone in renal, hepatic, or cardiac abnormalities. In patients on chronic amiodarone treatment, close clinical monitoring is advisable, especially for elderly patients and those with severe left ventricular dysfunction. Metabolism / Metabolites This drug is metabolized to the main metabolite desethylamiodarone (DEA) by the CYP3A4 and CYP2C8 enzymes. The CYP3A4 enzyme is found in the liver and intestines. A hydroxyl metabolite of DEA has been identified in mammals, but its clinical significance is unknown. Amiodarone has known human metabolites that include N-Desethylamiodarone. Amiodarone is extensively metabolized in the liver via CYP2C8 (under 1% unchanged in urine), and can effect the metabolism of numerous other drugs. The major metabolite of amiodarone is desethylamiodarone (DEA), which also has antiarrhythmic properties. The metabolism of amiodarone is inhibited by grapefruit juice, leading to elevated serum levels of amiodarone. Route of Elimination: Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Half Life: 58 days (range 15-142 days) Biological Half-Life The terminal half-life of amiodarone varies according to the patient, but is long nonetheless, and ranges from about 9-100 days. The half-life duration varies according to different sources. According to the prescribing information for amiodarone, the average apparent plasma terminal elimination half-life of amiodarone is of 58 days (ranging from 15 to 142 days). The terminal half-life range was between 14 to 75 days for the active metabolite, (DEA). The plasma half-life of amiodarone after one dose ranges from 3.2 to 79.7 hours, according to one source. |
| Toxicity/Toxicokinetics |
Toxicity Summary The antiarrhythmic effect of amiodarone may be due to at least two major actions. It prolongs the myocardial cell-action potential (phase 3) duration and refractory period and acts as a noncompetitive a- and b-adrenergic inhibitor. Toxicity Data Intravenous, mouse: LD50 = 178 mg/kg. |
| References |
[1]. Yihong Zhang,et al. Interactions between amiodarone and the hERG potassium channel pore determined with mutagenesis and in silico docking. Biochem Pharmacol. 2016 Aug 1;113:24-35. [2]. Jie Weng, et al. Amiodarone induces cell proliferation and myofibroblast differentiation via ERK1/2 and p38 MAPK signaling in fibroblasts. Biomed Pharmacother. 2019 Jul;115:108889. [3]. Sabrina Le Bouter, et al. Long-term amiodarone administration remodels expression of ion channel transcripts in the mouse heart. Circulation. 2004 Nov 9;110(19):3028-35. |
| Additional Infomation |
Pharmacodynamics After intravenous administration, amiodarone acts to relax smooth muscles that line vascular walls, decreases peripheral vascular resistance (afterload), and increases the cardiac index by a small amount. Administration by this route also decreases cardiac conduction, preventing and treating arrhythmias. When it is given orally, however, amiodarone does not lead to significant changes in the left ventricular ejection fraction. Similar to other anti-arrhythmic agents, controlled clinical trials do not confirm that oral amiodarone increases survival. Amiodarone prolongs the QRS duration and QT interval. In addition, a decreased SA (sinoatrial) node automaticity occurs with a decrease in AV node conduction velocity. Ectopic pacemaker automaticity is also inhibited. Thyrotoxicosis or hypothyroidism may also result from the administration of amiodarone, which contains high levels of iodine, and interferes with normal thyroid function. Amiodarone HCl (NSC 85442) is a broad-spectrum class III antiarrhythmic drug with multiple ion channel-blocking activities[1][3] - Its core antiarrhythmic mechanism involves blocking hERG potassium channels, prolonging cardiac repolarization and refractoriness[1] - The drug induces fibroblast proliferation and myofibroblast differentiation via ERK1/2 and p38 MAPK signaling, which may be associated with cardiac fibrosis in long-term use[2] - Long-term administration remodels cardiac ion channel transcript expression in mice, which may contribute to its therapeutic efficacy and potential proarrhythmic risks[3] - Mutagenesis and in silico docking studies confirm that Amiodarone HCl (NSC 85442) binds to the hERG channel pore domain via key amino acid residues (Y652, F656)[1] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.67 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (3.67 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (3.67 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4668 mL | 7.3339 mL | 14.6677 mL | |
| 5 mM | 0.2934 mL | 1.4668 mL | 2.9335 mL | |
| 10 mM | 0.1467 mL | 0.7334 mL | 1.4668 mL |