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Ibutilide fumarate (formerly known as U 70226 E; U-70226-E; U-70226E), the fumarate salt of Ibutilide, is a Class III antiarrhythmic agent that has been used for treating acute cardioconversion of atrial fibrillation and atrial flutter of a recent onset to sinus rhythm by induction of slow inward sodium current. Ibutilide Fumarate acts as a sodium channel protein inhibitor and methanesulfonanilide anti-arrhythmic agent that prolongs myocardial action potential duration mostly by activation of slow inward sodium current.
Physicochemical Properties
| Molecular Formula | (C20H36N2O3S)2.C4H4O4 | |
| Molecular Weight | 885.23 | |
| Exact Mass | 884.5 | |
| CAS # | 122647-32-9 | |
| Related CAS # | Ibutilide;122647-31-8;Ibutilide-d5 fumarate | |
| PubChem CID | 5281065 | |
| Appearance | White to off-white solid powder | |
| Boiling Point | 522.4ºC at 760 mmHg | |
| Melting Point | 112-117?C | |
| Flash Point | 269.7ºC | |
| Vapour Pressure | 9.71E-12mmHg at 25°C | |
| LogP | 10.347 | |
| Hydrogen Bond Donor Count | 6 | |
| Hydrogen Bond Acceptor Count | 14 | |
| Rotatable Bond Count | 30 | |
| Heavy Atom Count | 60 | |
| Complexity | 561 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | CCCCCCCN(CC)CCCC(C1=CC=C(C=C1)NS(=O)(=O)C)O.CCCCCCCN(CC)CCCC(C1=CC=C(C=C1)NS(=O)(=O)C)O.C(=C/C(=O)O)\C(=O)O |
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| InChi Key | ALOBUEHUHMBRLE-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C20H36N2O3S/c1-4-6-7-8-9-16-22(5-2)17-10-11-20(23)18-12-14-19(15-13-18)21-26(3,24)25/h12-15,20-21,23H,4-11,16-17H2,1-3H3 | |
| Chemical Name | N-[4-[4-[ethyl(heptyl)amino]-1-hydroxybutyl]phenyl]methanesulfonamide | |
| 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, avoid exposure to moisture. |
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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 |
Rapidly activating delayed rectifier K+ current (IKr, encoded by HERG gene) (IC50 for blocking IKr in AT-1 cells: ~0.1 μM; IC50 in HERG-expressing cells with GG haplotype: ~0.12 μM; IC50 with TT haplotype: ~0.08 μM)[1][2] |
| ln Vitro |
Ibutilide fumarate is a strong IKr blocker with an EC50 value of 20 nM at +20 mV in atrial tumor myocytes (AT-1) cells[1]. Ibutilide fumarate suppresses IKr in cells expressing HERG+MDR11 to the same extent as cells expressing HERG alone (IC50: 22.5 nM vs 27.4 nM). However, cells expressing MDR17 demonstrate a considerable resistance to Ibutilide (IC50: 105.3 nM vs 27.4 nM)[2]. In rat atrial tumor AT-1 cells, Ibutilide Fumarate (U70226E) (0.01-1 μM) blocked IKr in a concentration-, time-, voltage-, and use-dependent manner. At 0.1 μM, it inhibited IKr by 58% at a test potential of +20 mV; at 1 μM, the inhibition rate reached 92%. The drug showed higher affinity for IKr in the activated/inactivated states than the resting state, with a time constant of binding (τon) of ~3.2 seconds at 0.1 μM and unbinding (τoff) of ~15.6 seconds[1] - In HEK293 cells stably expressing human HERG and different MDR1 haplotypes (G2677T/C3435T), Ibutilide Fumarate (U70226E) exhibited haplotype-dependent blocking of HERG currents. The TT haplotype group showed a 33% higher blocking efficiency than the GG haplotype group at 0.1 μM. Western blot revealed that TT haplotype increased P-glycoprotein (P-gp) trafficking to the cell membrane, which enhanced the drug's access to HERG channels[2] - In ventricular myocytes isolated from a heart failure (HF) canine model, Ibutilide Fumarate (U70226E) (0.05-0.5 μM) prolonged action potential duration (APD90) by 45% at 0.1 μM, which was 22% more than the prolongation in normal ventricular myocytes. The drug also increased the incidence of early afterdepolarizations (EADs) in HF myocytes (38% vs. 12% in normal myocytes) at 0.5 μM[3] |
| ln Vivo |
Both in vivo and in vitro, ibutilide fumarate prolongs cardiac repolarization[1]. When ibutilide fumarate is given in three cumulative doses of 0.01, 0.02 and 0.05 mg/kg iv, each given as a 10-min infusion, both polymorphic and monomorphic non-sustained ventricular tachycardia are produced[3]. In mongrel dogs with pacing-induced heart failure (HF), intravenous administration of Ibutilide Fumarate (U70226E) (0.01 mg/kg, 0.02 mg/kg) showed altered antiarrhythmic efficacy compared to normal dogs. The 0.02 mg/kg dose converted 42% of induced atrial fibrillation (AF) to sinus rhythm in HF dogs, compared to 75% in normal dogs. Electrocardiographic analysis revealed that HF dogs had a 35% longer QT interval prolongation after drug administration, with a higher risk of torsades de pointes (TdP) (17% incidence vs. 0% in normal dogs)[3] |
| Enzyme Assay |
IKr/HERG channel activity assay: AT-1 cells or HERG-expressing HEK293 cells were seeded on glass coverslips and cultured for 24-48 hours. Whole-cell patch-clamp recordings were performed using a standard patch-clamp setup. Ibutilide Fumarate (U70226E) was applied to the extracellular solution at gradient concentrations (0.01-1 μM). The voltage protocol included a holding potential of -80 mV, depolarizing steps to +60 mV (500 ms) to activate IKr, followed by repolarization to -50 mV to record tail currents. Peak tail current amplitude was measured and normalized to the control to calculate the blocking rate[1][2] |
| Cell Assay |
AT-1 cell electrophysiology assay: AT-1 cells were cultured in standard medium until confluent. Cells were dissociated and plated on glass coverslips. After 24 hours, Ibutilide Fumarate (U70226E) was added to the recording chamber at concentrations of 0.01 μM, 0.05 μM, 0.1 μM, 0.5 μM, and 1 μM. Whole-cell patch-clamp recordings were conducted to measure IKr under different voltage conditions and stimulation frequencies to assess concentration-, voltage-, and use-dependence[1] - HERG-expressing cell assay: HEK293 cells were transfected with plasmids encoding HERG and different MDR1 haplotypes (GG, GT, TT). Transfected cells were selected and cultured for 48 hours. Ibutilide Fumarate (U70226E) was applied at 0.05-0.2 μM, and HERG currents were recorded by patch-clamp. Cell lysates were subjected to Western blot to detect P-gp membrane localization[2] - HF ventricular myocyte assay: Ventricular myocytes were isolated from HF dogs and normal dogs via enzymatic dissociation. Myocytes were plated on laminin-coated coverslips. Ibutilide Fumarate (U70226E) (0.05-0.5 μM) was added, and action potentials were recorded using sharp microelectrodes to measure APD90 and EAD incidence[3] |
| Animal Protocol |
Animal/Disease Models: Fifteen adult mongrel dogs of either sex[1] Doses: 0.01, 0.02 and 0.05 mg/kg Route of Administration: intravenous (iv) injection; each as a 10-min infusion Experimental Results: The action potential duration at 90% (APD90) prolongation with Ibutilide (0.01 mg/kg) was Dramatically greater in congestive heart failure (CHF) vs. controls. An increased dispersion of left-right ventricular APD90 was observed in CHF at 0.01 mg/kg, but not in controls. Pacing-induced HF dog model: Adult mongrel dogs (15-20 kg) were implanted with a cardiac pacemaker and paced at 240 beats/min for 4 weeks to induce HF. Dogs were randomly divided into normal group, HF control group, and Ibutilide Fumarate (U70226E) treatment groups (0.01 mg/kg, 0.02 mg/kg). The drug was administered intravenously over 10 minutes. AF was induced by transvenous electrical stimulation 30 minutes after drug administration. Electrocardiograms were recorded continuously for 2 hours to assess AF conversion rate, QT interval, and TdP incidence[3] |
| Toxicity/Toxicokinetics |
In vivo toxicity: Intravenous administration of Ibutilide Fumarate (U70226E) at 0.02 mg/kg in HF dogs increased the risk of TdP (17% incidence), while no TdP was observed in normal dogs at the same dose[3] |
| References |
[1]. Ibutilide, a methanesulfonanilide antiarrhythmic, is a potent blocker of the rapidly activating delayed rectifier K+ current (IKr) in AT-1 cells. Concentration-, time-, voltage-, and use-dependent effects. Circulation. 1995 Mar 15;91(6):1799-806. [2]. Influence of the G2677T/C3435T haplotype of MDR1 on P-glycoprotein trafficking and Ibutilide-induced block of HERG. Pharmacogenomics J. 2009 Jun;9(3):194-201. [3]. Altered response to Ibutilide in a heart failure model. Cardiovasc Res. 2001 Jan;49(1):94-102. |
| Additional Infomation |
Ibutilide fumarate is a member of benzenes and an organic amino compound. Ibutilide Fumarate is the fumarate salt form of ibutilide, a class III antiarrhythmic agent. Ibutilide exerts its effect by activating a slow, inward, predominately sodium current rather than by blocking outward potassium currents. This results in prolongation of atrial and ventricular action potential duration and refractory periods. Ibutilide slightly decreases the sinus rate and atrioventricular (AV) conduction and produces a dose-related prolongation of the QT interval. (NCI05) See also: Ibutilide (has active moiety). Ibutilide Fumarate (U70226E) is a methanesulfonanilide class III antiarrhythmic drug clinically approved for the acute conversion of atrial fibrillation and atrial flutter to sinus rhythm[1][3] - Its core mechanism of action is the specific block of IKr (encoded by HERG), which prolongs cardiac action potential duration and QT interval, thereby terminating reentrant arrhythmias[1] - The G2677T/C3435T haplotype of MDR1 affects P-gp trafficking, leading to individual differences in Ibutilide Fumarate (U70226E)'s blocking effect on HERG, which may have implications for personalized medication[2] - Heart failure reduces the antiarrhythmic efficacy of Ibutilide Fumarate (U70226E) and increases the risk of proarrhythmia (TdP), which should be considered in clinical use for HF patients[3] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.65 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 (5.65 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 (5.65 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. Solubility in Formulation 4: 37.5 mg/mL (84.72 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1296 mL | 5.6482 mL | 11.2965 mL | |
| 5 mM | 0.2259 mL | 1.1296 mL | 2.2593 mL | |
| 10 mM | 0.1130 mL | 0.5648 mL | 1.1296 mL |