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 after intravenous injection
In healthy male volunteers, about 82% of a 0.01 mg/kg dose of [14C] ibutilide fumarate was excreted in the urine (about 7% of the dose as unchanged ibutilide) and the remainder (about 19%) was recovered 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: six patients who had New York Heart Association (NYHA) class II or III heart failure due to left ventricular dysfunction (mean +/- SD left ventricular ejection fraction (LVEF) 30 +/- 9%); 10 patients who did not have left ventricular dysfunction (mean +/- SD LVEF 54 +/- 5% in six of these 10 patients) served as controls. All patients received a single dose of ibutilide 1.0 mg administered intravenously over 10 minutes. Blood samples were obtained through an indwelling catheter in the contralateral arm before ibutilide administration, at the end of the infusion, and at 5, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, and 48 hours after the infusion. Serum ibutilide concentrations were determined by using high-performance liquid chromatography and mass spectrometry. No significant differences were noted between the heart failure and normal left ventricular function groups 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 from time zero extrapolated to infinity (mean +/- SD 11.0 +/- 9.4 vs 13.2 +/- 10.6 ug*hr/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 hrs, p=0.99). The pharmacokinetics of ibutilide do not appear to be altered in patients with NYHA class II or III heart failure due to left ventricular systolic dysfunction.
In healthy male volunteers, about 82% of a 0.01 mg/kg dose of (14)C ibutilide fumarate was excreted in the urine (about 7% of the dose as unchanged ibutilide) and the remainder (about 19%) was recovered in the feces.
After intravenous infusion, ibutilide plasma concentrations rapidly decrease in a multiexponential fashion. The pharmacokinetics of ibutilide are highly variable among subjects. Ibutilide has a high systemic plasma clearance that approximates liver blood flow (about 29 mL/min/kg), a large steady-state volume of distribution (about 11 L/kg) in healthy volunteers, and minimal (about 40%) protein binding. Ibutilide is also cleared rapidly and highly distributed in patients being treated for atrial flutter or atrial fibrillation. The elimination half-life averages about 6 hours (range from 2 to 12 hours). The pharmacokinetics of ibutilide are linear with respect to the dose of Corvert over the dose range of 0.01 mg/kg to 0.10 mg/kg. The enantiomers of ibutilide fumarate have pharmacokinetic properties similar to each other and to ibutilide fumarate.

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Metabolism / Metabolites
Primarily hepatic. Eight metabolites of ibutilide were detected in metabolic profiling of urine. These metabolites are thought to be formed primarily by o-oxidation followed by sequential b-oxidation of the heptyl side chain of ibutilide. Of the eight metabolites, only the o-hydroxy metabolite possesses class III electrophysiologic properties similar to that of ibutilide in an in vitro isolated rabbit myocardium model.
Eight metabolites of ibutilide were detected in metabolic profiling of urine. These metabolites are thought to be formed primarily by omega-oxidation followed by sequential beta-oxidation of the heptyl side chain of ibutilide. Of the eight metabolites, only the omega-hydroxy metabolite possesses class III electrophysiologic properties similar to that of ibutilide in an in vitro isolated rabbit myocardium model. The plasma concentrations of this active metabolite, however, are less than 10% of that of ibutilide.

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Biological Half-Life
6 hours (ranges from 2-12 hours)
The elimination half-life averages about 6 hours (range from 2 to 12 hours).
Sixteen adult patients with atrial fibrillation or atrial flutter requiring conversion to normal sinus rhythm: six patients who had New York Heart Association (NYHA) class II or III heart failure due to left ventricular dysfunction (mean +/- SD left ventricular ejection fraction (LVEF) 30 +/- 9%); 10 patients who did not have left ventricular dysfunction (mean +/- SD LVEF 54 +/- 5% in six of these 10 patients) served as controls. All patients received a single dose of ibutilide 1.0 mg administered intravenously over 10 minutes. ... No significant differences were noted between the heart failure and normal left ventricular function groups in the following parameters: ... half-life (12.5 +/- 10.7 vs 12.4 +/- 8.6 hrs, p=0.99).

Protein Binding
40%

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Interactions
Supraventricular arrhythmias may mask the cardiotoxicity associated with excessive digoxin levels. Therefore, it is advisable to be particularly cautious in patients whose plasma digoxin levels are above or suspected to be above the usual therapeutic range. Coadministration of digoxin did not have effects on either the safety or efficacy of ibutilide in the clinical trials.
The potential for proarrhythmia may increase with the administration of ibutilide fumarate injection to patients who are being treated with drugs that prolong the QT interval, such as phenothiazines, tricyclic antidepressants, tetracyclic antidepressants, and certain antihistamine drugs (H1 receptor antagonists).
Class Ia antiarrhythmic drugs (Vaughan Williams Classification), such as disopyramide, quinidine, and procainamide, and other class III drugs, such as amiodarone and sotalol, should not be given concomitantly with ibutilide fumarate injection or within 4 hours postinfusion because of their potential to prolong refractoriness. In the clinical trials, class I or other class III antiarrhythmic agents were withheld for at least 5 half-lives prior to ibutilide infusion and for 4 hours after dosing, but thereafter were allowed at the physician's discretion.
Ibutilide is a class III antiarrhythmic agent 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 for the treatment of TdP, but its use as a prophylactic agent for this arrhythmia has not yet been established. The present study investigated whether high dose of magnesium would increase the safety and efficacy of ibutilide administration. A total of 476 patients with atrial fibrillation or atrial flutter who were candidates for conversion to SR were divided into 2 groups. Group A consisted of 229 patients who received ibutilide to convert atrial fibrillation or atrial flutter to SR. Group B consisted of 247 patients who received an intravenous infusion of 5 g of magnesium sulfate for 1 hour followed by the administration of ibutilide. Then, another 5 g of magnesium were infused for 2 additional hours. Of the patients in groups A and B, 154 (67.3%) and 189 (76.5%), respectively, were converted to SR (p = 0.033). Ventricular arrhythmias (sustained, nonsustained ventricular tachycardia, and TdP) occurred significantly more often in group A than in group B (7.4% vs 1.2%, respectively, p = 0.002). TdP developed in 8 patients (3.5%) in group A and in none (0%) in group B (p = 0.009). The administration of magnesium (despite the high doses used) was well tolerated. In conclusion, the administration of high doses of magnesium probably makes ibutilide a much safer agent, and magnesium increased the conversion efficacy 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
Anti-Arrhythmia Agents
Ibutilide fumarate injection is indicated for the rapid conversion of atrial fibrillation or atrial flutter of recent onset to sinus rhythm. Patients with atrial arrhythmias of longer duration are less likely to respond to ibutilide fumarate injection. The effectiveness of ibutilide has not been determined in patients with arrhythmias of more than 90 days in duration. /Included in US product label/
Ibutilide is administered as a rapid infusion (1 mg over 10 minutes) for the immediate conversion of atrial fibrillation or flutter to sinus rhythm. The drug's efficacy rate is higher in patients with atrial flutter (50-70%) than in those with atrial fibrillation (30-50%). In atrial fibrillation, the conversion rate is lower in those in whom the arrhythmia has been present for weeks or months compared with those in whom it has been present for days.

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Drug Warnings
/BOXED WARNING/ LIFE-THREATENING ARRHYTHMIAS-APPROPRIATE TREATMENT ENVIRONMENT. Covert can cause potentially fatal arrhythmias, particularly sustained polymorphic ventricular tachycardia, usually in association with QT prolongation (torsades de pointes), but sometimes without documented QT prolongation. In registration studies, these arrhythmias, which require cardioversion, occurred in 1.7% of treated patients during, or within a number of hours of, use of Covert. These arrhythmias can be reversed if treated promptly. It is essential that Covert be administered in a setting of continuous ECG monitoring and by personnel trained in identification and treatment of acute ventricular arrhythmias, particularly polymorphic ventricular tachycardia. Patients with atrial fibrillation of more than 2 to 3 days' duration must be adequately anticoagulated, generally for at least 2 weeks. CHOICE OF PATIENTS. Patients with chronic atrial fibrillation have a strong tendency to revert after conversion to sinus rhythm and treatments to maintain sinus rhythm carry risks. Patients to be treated with Covert, therefore, should be carefully selected such that the expected benefits of maintaining sinus rhythm outweigh the immediate risks of Covert, and the risks of maintenance therapy, and are likely to offer an advantage compared with alternative management.
Patients with chronic atrial fibrillation have a strong tendency to revert after conversion to sinus rhythm and treatments to maintain sinus rhythm carry risks. Patients to be treated with ibutilide fumarate injection, therefore, should be carefully selected such that the expected benefits of maintaining sinus rhythm outweigh the immediate risks of ibutilide fumarate injection, and the risks of maintenance therapy, and are likely to offer an advantage compared with alternative management.
Clinical trials with ibutilide fumarate injection in patients with atrial fibrillation and atrial flutter did not include anyone under the age of 18. Safety and effectiveness of ibutilide in pediatric patients has not been established.
FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
For more Drug Warnings (Complete) data for Ibutilide (11 total), please visit the HSDB record page.

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Pharmacodynamics
Ibutilide prolongs the action potential duration and increases both atrial and ventricular refractoriness in vivo, i.e., class III electrophysiologic effects. Voltage clamp studies indicate that ibutilide, at nanomolar concentrations, delays repolarization by activation of a slow, inward current (predominantly sodium), rather than by blocking outward potassium currents, which is the mechanism by which most other class III antiarrhythmics act.

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.)