Ibutilide is a strong inhibitor of IKr, with an EC50 value of 20 nM at +20 mV in atrial tumor myocytes (AT-1) cells [1]. It blocked IKr in cells expressing HERG+MDR1*1 to the same degree as it did in cells expressing HERG alone (IC50: 22.5 nM vs 27.4 nM). MDR1*7-expressing cells, on the other hand, demonstrated substantial resistance to ibutilide (IC50: 105.3 nM vs 27.4 nM) [2].

Both in vivo and in vitro, ibutilide lengthens the cardiac repolarization time [1]. Ibutilide infusion can result in both monomorphic and polymorphic nonsustained ventricular tachycardia [3]. The three cumulative dosages of 0.01, 0.02, and 0.05 mg/kg iv are administered over a period of 10 minutes.

Animal/Disease Models: 15 adult mongrel dogs, both male and female [1]
Doses: 0.01, 0.02 and 0.05 mg/kg
Route of Administration: intravenous (iv) (iv)injection; injection administration. Results for each 10-minute infusion: Action potential duration (APD90) at 90% prolongation was Dramatically longer in patients with congestive heart failure (CHF) treated with ibutilide (0.01 mg/kg) compared with controls. An increase in left and right ventricular APD90 dispersion was observed in CHF at 0.01 mg/kg but not in the control group.

Absorption, Distribution and Excretion
Rapid absorption after intravenous injection. In healthy male volunteers, approximately 82% of the 0.01 mg/kg dose of ibutilide [14C]fumarate was excreted in the urine (approximately 7% was excreted unchanged), and the remainder (approximately 19%) was excreted in the feces. 11 L/kg 29 mL/min/kg Sixteen adult patients with atrial fibrillation or atrial flutter requiring conversion to normal sinus rhythm were included: 6 patients with NYHA class II or III heart failure due to left ventricular dysfunction (mean ± standard deviation of left ventricular ejection fraction (LVEF) 30 ± 9%); and 10 patients without left ventricular dysfunction (6 of whom had a mean ± standard deviation of LVEF 54 ± 5%) served as a control group. All patients received a single intravenous injection of 1.0 mg ibutilide over 10 minutes. Blood samples were collected via an indwelling catheter in the contralateral arm before administration of ibutilide, at the end of infusion, and at 5, 15, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, and 48 hours after infusion. Serum ibutilide concentrations were determined using high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS). No significant differences were observed between the heart failure group and the normal left ventricular function group in the following parameters: maximum serum ibutilide concentration (median (interquartile range) 3.8 (2.3–5.7) vs 5.8 (3.1–14.4) ug/L, p=0.31), area under the serum concentration-time curve extrapolated from time zero to infinity (mean ± standard deviation 11.0 ± 9.4 vs 13.2 ± 10.6 ughr/L, p=0.88), steady-state volume of distribution (1380 ± 334 vs 1390 ± 964 L, p=0.99), systemic clearance (129 ± 60 vs 125 ± 81 L/hr, p=0.92), or half-life (12.5 ± 10.7 vs 12.4 ± 8.6 hr, p=0.99). The pharmacokinetics of ibutilide appear unchanged in patients with NYHA class II or III heart failure due to left ventricular systolic dysfunction. In healthy male volunteers, approximately 82% of a 0.01 mg/kg dose of ibutilide labeled with 14C fumarate is excreted in the urine (approximately 7% is excreted unchanged), with the remainder (approximately 19%) excreted in the feces. Following intravenous infusion, plasma concentrations of ibutilide decrease rapidly in a multi-exponential manner. The pharmacokinetics of ibutilide vary considerably among individuals. Ibutilide has a high systemic plasma clearance, approaching hepatic blood flow (approximately 29 mL/min/kg), a large steady-state volume of distribution in healthy volunteers (approximately 11 L/kg), and very low protein binding (approximately 40%). Ibutilide is rapidly cleared and widely distributed in patients receiving treatment for atrial flutter or atrial fibrillation. Its elimination half-life is approximately 6 hours on average (range 2 to 12 hours). Within a dose range of 0.01 mg/kg to 0.10 mg/kg, the pharmacokinetics of ibutilide are linear with respect to the dose of Corvert. Ibutilide fumarate enantiomers have similar pharmacokinetic properties to each other and to ibutilide fumarate. Metabolism/Metabolites: Primarily metabolized in the liver. Eight metabolites of ibutilide were detected in urinary metabolic profiling. These metabolites are believed to be formed primarily by ortho-oxidation of the heptyl side chain of ibutilide followed by β-oxidation. In an in vitro isolated rabbit myocardial model, only the ω-hydroxy metabolite exhibited class III electrophysiological properties similar to ibutilide. However, the plasma concentration of this active metabolite was less than 10% of that of ibutilide.

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Biological Half-Life
6 hours (range 2–12 hours)
Elimination half-life was approximately 6 hours (range 2–12 hours).
16 adult patients with atrial fibrillation or atrial flutter requiring conversion to normal sinus rhythm: 6 with New York Heart Association (NYHA) NYHA class II or III heart failure due to left ventricular dysfunction (mean ± standard deviation of left ventricular ejection fraction (LVEF) 30 ± 9%); 10 patients without left ventricular dysfunction (6 of whom had a mean ± standard deviation of LVEF 54 ± 5%) served as the control group. All patients received a single intravenous injection of 1.0 mg ibutilide over 10 minutes. ...No significant differences were observed between the heart failure group and the normal left ventricular function group in the following parameters: ...half-life (12.5 +/- 10.7 vs 12.4 +/- 8.6 hours, p = 0.99).

Protein Binding
40% interaction Supraventricular arrhythmias may mask cardiotoxicity caused by digoxin overdose. Therefore, extra caution is advised in patients with plasma digoxin levels higher than or suspected to be higher than the usual treatment range. In clinical trials, co-administration of digoxin with ibutilide did not affect its safety and efficacy. In patients receiving QT interval prolonging medications, such as phenothiazines, tricyclic antidepressants, tetracyclic antidepressants, and certain antihistamines (H1 receptor antagonists), injection of ibutilide fumarate may increase the risk of arrhythmias. Due to the potential for prolonged refractory period, class Ia antiarrhythmic drugs (Vaughan Williams classification), such as disopyramide, quinidine, and procainamide, and other class III antiarrhythmic drugs, such as amiodarone and sotalol, should not be used concurrently with ibutilide fumarate injection or within 4 hours after infusion. In clinical trials, Class I or other Class III antiarrhythmic drugs were discontinued at least 5 half-lives before ibutilide infusion and within 4 hours after administration, after which they could be used as appropriate by the physician. Ibutilide is a Class III antiarrhythmic drug indicated for cardioversion of atrial fibrillation and atrial flutter to sinus rhythm (SR). The most serious complication of ibutilide is torsades de pointes (TdP). Magnesium has been successfully used to treat TdP, but its efficacy as a preventative agent for this arrhythmia has not been established. This study aimed to investigate whether high-dose magnesium could improve the safety and efficacy of ibutilide administration. A total of 476 patients with atrial fibrillation or atrial flutter who met the cardioversion criteria were included and divided into two groups. Group A consisted of 229 patients who received ibutilide to convert atrial fibrillation or atrial flutter to sinus rhythm. Group B consisted of 247 patients who received 5 g magnesium sulfate intravenously for 1 hour followed by ibutilide, and then another 5 g magnesium sulfate infusion for 2 hours. In groups A and B, 154 (67.3%) and 189 (76.5%) patients, respectively, converted to sinus rhythm (p = 0.033). The incidence of ventricular arrhythmias (sustained ventricular tachycardia, non-sustained ventricular tachycardia, and torsades de pointes) was significantly higher in group A than in group B (7.4% and 1.2%, respectively, p = 0.002). Torsades de pointes occurred in 8 patients (3.5%) in group A, while none (0%) occurred in group B (p = 0.009). Despite the use of high-dose magnesium, patients tolerated it well. In conclusion, high-dose magnesium administration may make ibutilide a safer drug, and magnesium improves the conversion efficiency of ibutilide.

[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]. B F McBride, et al. 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]. S S Chugh, et al. Altered response to Ibutilide in a heart failure model. Cardiovasc Res. 2001 Jan;49(1):94-102.

Therapeutic Uses

Antiarrhythmic Drug
Ibutilide fumarate injection is indicated for the rapid conversion of recent atrial fibrillation or atrial flutter to sinus rhythm. Patients with longer-term atrial arrhythmias may respond poorly to ibutilide fumarate injection. The efficacy of ibutilide in patients with arrhythmias lasting more than 90 days has not been established. /US Product Label Content/
Ibutilide is administered via rapid intravenous infusion (1 mg, administered over 10 minutes) for the immediate conversion of atrial fibrillation or atrial flutter to sinus rhythm. The efficacy rate is higher in patients with atrial flutter (50-70%) than in patients with atrial fibrillation (30-50%). In atrial fibrillation, the cardioversion rate is lower in patients with atrial flutter lasting for weeks or months than in patients with atrial fibrillation lasting for days.
Drug Warnings
/Black Box Warning/ Life-threatening arrhythmias - Appropriate treatment environment. Covert can cause potentially fatal arrhythmias, particularly sustained polymorphic ventricular tachycardia, often accompanied by QT prolongation (torsades de pointes), although QT prolongation may sometimes be absent. In the registry study, 1.7% of patients treated with Covert experienced arrhythmias requiring cardioversion during or within hours of use. These arrhythmias are reversible with timely treatment. Covert must be used under continuous ECG monitoring and by personnel trained to identify and treat acute ventricular arrhythmias, especially polymorphic ventricular tachycardia. Patients with atrial fibrillation lasting more than 2 to 3 days must receive adequate anticoagulation therapy, typically for at least 2 weeks. Patient selection: Patients with chronic atrial fibrillation are highly susceptible to relapse after conversion to sinus rhythm, and there are risks associated with maintaining sinus rhythm. Therefore, patients receiving Covert should be carefully selected to ensure that the expected benefit of maintaining sinus rhythm outweighs the short-term risks of Covert and the risks of maintenance therapy, and that it offers an advantage over alternative treatment options. Patients receiving ibutilide fumarate injections should also be carefully screened to ensure that the expected benefit of maintaining sinus rhythm outweighs the short-term risks of ibutilide fumarate injections and the risks of maintenance therapy, and that it may offer an advantage over alternative treatment options. Clinical trials of ibutilide fumarate injections in patients with atrial fibrillation and atrial flutter did not include patients under 18 years of age. The safety and efficacy of ibutilide in pediatric patients have not been established. FDA Pregnancy Risk Category: C/Risk cannot be ruled out. Adequate, well-controlled human studies are lacking, and animal studies have not shown any risk to the fetus or lack relevant data. Use of this drug during pregnancy may cause harm to the fetus; however, the potential benefits may outweigh the potential risks. / For more complete data on drug warnings for ibutilide (11 in total), please visit the HSDB records page.

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Pharmacodynamics
Ibutilide prolongs the action potential duration in vivo and increases the atrial and ventricular refractory periods, i.e., a Class III electrophysiological effect. Voltage clamp studies have shown that nanomolar concentrations of ibutilide delay repolarization by activating slow inward currents (primarily sodium currents), rather than by blocking outward potassium currents as most other Class III antiarrhythmic drugs do.

C20H36N2O3S

384.57644

384.245

122647-31-8

Ibutilide fumarate;122647-32-9

60753

Colorless to light yellow oil

1.099g/cm3

522.4ºC at 760mmHg

269.7ºC

9.71E-12mmHg at 25°C

5.317

2

5

14

26

443

0

ALOBUEHUHMBRLE-UHFFFAOYSA-N

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

N-[4-[4-[ethyl(heptyl)amino]-1-hydroxybutyl]phenyl]methanesulfonamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)