Drone successfully inhibited peak sodium currents in patch-clamp studies with human atrial myocytes, attaining 97% blockage at 3 μM [1]. Drone suppresses the delayed rectifier potassium current in guinea pig ventricular myocytes: the inward rectifier potassium current (IC50>30 μM), the slowly activated delayed rectifier potassium current (IC50=10 μM), and the fast activated delayed rectifier potassium current (IC50<3 μM). L-type calcium current (IC50=0.18 μM) [1] as well. In rabbit atrial node cells (IC50=63 nM) and guinea pig atrial cells (IC50=10 nM), dronedarone demonstrates potent inhibitory effects on acetylcholine-activated potassium current (IK-Ach). IK-Ach blockade by dronedarone is 100 times more effective than that of amiodarone [1]. Dronedarone binds non-competitively to β-adrenergic receptors (IC50=1.8 μM) to produce its anti-adrenergic effect by preventing the rise in adenylyl cyclase activity that an agonist causes [1]. In isolated guinea pig hearts, dose-dependent reduction in coronary perfusion pressure is induced by dose-daronedarone (0.01-1 μM). Its calcium current blockage may be connected to this action, which is not dependent on the nitric oxide synthase pathway [1].

Dronedarone (intraperitoneal injection; 25-100 mg/kg) shows dose-dependent anticonvulsant effects and raises the mouse electroconvulsive threshold [2].

Animal/Disease Models: Tonic-clonic seizures in male albino Swiss outbred mice [2]
Doses: 25 mg/kg; 50 mg/kg; 75 mg/kg; 100 mg/kg
Route of Administration: intraperitoneal (ip) injection
Experimental Results: Shown Produces significant anticonvulsant effects.

Absorption, Distribution and Excretion
Dronedarone is well absorbed (>70%) after oral administration. Its systemic bioavailability is low due to extensive first-pass metabolism. The absolute bioavailability of dronedarone is 4% on an empty stomach and 15% when taken with a high-fat meal. Peak plasma concentrations of dronedarone and its major circulating metabolite, N-debutyl metabolite, are reached within 3 to 6 hours after administration with food. Steady-state concentrations are reached within 4 to 8 days after repeated twice-daily administration of 400 mg dronedarone. Steady-state Cmax and systemic exposure to the N-debutyl metabolite are similar to those of the parent compound. Approximately 84% of the labeled dose is excreted in feces and 6% in urine after oral administration, primarily as metabolites. The total radioactivity of the unmodified parent compound and its N-debutyl metabolite in plasma is less than 15%. The steady-state volume of distribution after intravenous administration is 1200 to 1400 liters.
After intravenous administration, clearance is 130 to 150 L/h.
In vitro plasma protein binding rates are 99.7% and 98.5% for dronedarone and its N-debutyl metabolite, respectively, and are unsaturated. Both compounds are primarily bound to albumin. The steady-state volume of distribution (Vss) after intravenous administration is 1200 to 1400 L.
Drondarone is well absorbed (at least 70%) after oral administration with food. However, due to first-pass metabolism, the absolute bioavailability of dronedarone (with food) is 15%. Co-administration with food increases the bioavailability of dronedarone by an average of 2 to 4 times. Peak plasma concentrations of dronedarone and its main circulating active metabolite (N-debutyl metabolite) are reached within 3 to 6 hours after oral administration with food. Steady-state is reached after 4 to 8 days of repeated dosing of 400 mg twice daily, with a mean cumulative ratio of 2.6 to 4.5 for dronedarone. At steady state, dronedarone's mean Cmax is 84-147 ng/mL, and the exposure of its major N-debutyl metabolite is similar to that of the parent compound. The pharmacokinetics of dronedarone and its N-debutyl metabolite deviate somewhat from the dose ratio: a 2-fold increase in dose results in approximately a 2.5-3.0-fold increase in Cmax and AUC. Following oral administration, approximately 6% of the labeled dose is excreted primarily as metabolites in the urine (no parent drug is excreted in the urine), and 84% is excreted primarily as metabolites in the feces. Following intravenous administration, dronedarone's plasma clearance is 130-150 L/h. The terminal elimination half-life of dronedarone is approximately 25-30 hours, and that of its N-debutyl metabolite is approximately 20-25 hours. In patients treated with 400 mg twice daily, amiodarone and its metabolites are completely cleared from plasma within 2 weeks.

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Metabolism/Metabolites
Amiodarone is primarily metabolized in the liver via CYP3A-mediated metabolism. The initial metabolism of amiodarone involves N-debutylation to N-debutylamiodarone, which retains 1/10 to 1/3 of the pharmacological activity of the parent compound. N-debutylamiodarone can be further metabolized to phenol amiodarone via O-dealkylation and to amiodarone propionate via oxidative deamination. Amiodarone can also be metabolized via CYP2D6 to benzofuran hydroxyamiodarone. Other detectable metabolites include C-dealkyl-dronedalone and dibutylamine-hydroxy-dronedalone, as well as several other minor downstream metabolites with undetermined chemical structures.
Dronedalone is extensively metabolized via CYP 3A4 (see Section 4.5). Its main metabolic pathways include N-debutylation to the major circulating active metabolite, followed by oxidation; oxidative deamination to the inactive propionic acid metabolite, followed by oxidation; and direct oxidation. The N-debutyl metabolite possesses pharmacological activity, but its potency is 3 to 10 times lower than that of dronedarone. This metabolite contributes to the pharmacological activity of amiodarone in the human body.

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Biological Half-Life
The elimination half-life is 13 to 19 hours.
The terminal elimination half-life of amiodarone is approximately 25-30 hours, while the terminal elimination half-life of its N-debutyl metabolite is approximately 20-25 hours.

Hepatotoxicity
Up to 12% of patients treated with dronedarone long-term experience mild elevations in serum enzymes, but similar rates have been observed in the control group and even the placebo group. Elevated serum transaminases during long-term dronedarone treatment are usually mild to moderate, asymptomatic, and rarely require discontinuation or dose adjustment. No clinically significant liver injury was described in premarket clinical trials. However, since dronedarone's approval and widespread use, several cases of clinically significant liver injury with jaundice have been identified, some of which were severe. The onset of injury ranged from 2 to 11 months, with clinical presentations similar to acute viral hepatitis, including fatigue and abdominal discomfort, followed by jaundice and hepatocellular elevations in serum enzymes. Some cases ultimately led to acute liver failure requiring emergency liver transplantation. However, the specific clinical features of clinically significant liver injury caused by dronedarone are not yet fully understood, and the relationship between dronedarone and the aforementioned liver injury is not always adequately confirmed. Probability Score: C (Possibly a cause of clinically significant liver injury).

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Protein Binding
Dronedarone and its N-debutyl metabolite showed in vitro plasma protein binding rates of 99.7% and 98.5%, respectively. Both primarily bind to albumin and do not reach saturation.Drug Interactions
Oral dronedarone can increase plasma concentrations of tacrolimus, sirolimus, and other CYP3A substrates with a narrow therapeutic window. Plasma concentrations should be monitored and the dose adjusted appropriately.
Dronedarone increased simvastatin/simvastatin acid exposure by 4-fold and 2-fold, respectively. Due to the multiple interaction mechanisms between statins (CYP enzymes and transporters), please follow the recommendations in the statin package insert when using them in combination with CYP3A and P-gP inhibitors (such as dronedarone).
Pantralazole is a drug that can increase gastric pH and has no significant effect on the pharmacokinetics of dronedarone. Verapamil and diltiazem are moderate CYP 3A inhibitors that can increase dronedarone exposure by approximately 1.4 to 1.7 times. For more complete (16 items) data on dronedarone drug interactions, please visit the HSDB record page.

[1]. Dronedarone. Circulation. 2009 Aug 18;120(7):636-44.

[2]. Influence of dronedarone (a class III antiarrhythmic drug) on the anticonvulsant potency of four classical antiepileptic drugs in the tonic-clonic seizure model in mice. J Neural Transm (Vienna). 2019 Feb;126(2):115-122.

Therapeutic Uses

Antiarrhythmic Drug
Multaq is indicated for reducing the cardiovascular hospitalization risk in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL) who have recently experienced AF/AFL and have associated cardiovascular risk factors (e.g., age >70 years, hypertension, diabetes, history of stroke, left atrial diameter ≥50 mm or left ventricular ejection fraction (LVEF) <40%), and who are currently in sinus rhythm or will receive electrical cardioversion. /US Product Label Contains/

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Drug Warnings
/Black Box Warning/ Warning: Increased risk of death, stroke, and heart failure in patients with decompensated heart failure or permanent atrial fibrillation. Multaq doubles the risk of death in patients with symptomatic heart failure requiring recent hospitalization or NYHA class IV heart failure. Multaq is contraindicated in patients with symptomatic heart failure requiring recent hospitalization or NYHA class IV heart failure. For patients with permanent atrial fibrillation, Multaq doubles the risk of death, stroke, and hospitalization for heart failure. Multaq is contraindicated in patients with atrial fibrillation who cannot or do not wish to have their normal sinus rhythm restored by electrical cardioversion. Multaq is contraindicated in patients with NYHA class IV heart failure, or NYHA class II-III heart failure who have recently experienced a worsening condition requiring hospitalization or referral to a specialist heart failure clinic. In a placebo-controlled study (ANDROMEDA study) of patients recently hospitalized for severe heart failure or referred to a specialist heart failure clinic due to worsening symptoms, patients receiving dronedarone experienced a more than twofold increase in mortality. Such patients should not receive dronedarone. Post-marketing surveillance data have reported new or worsening cases of heart failure during Multaq treatment. Patients are advised to consult a physician if they experience signs or symptoms of heart failure, such as weight gain, lower extremity edema, or worsening dyspnea. If heart failure or a worsening of heart failure occurs, consider pausing or discontinuing Multaq use. Post-marketing surveillance data have reported hepatocellular injury, including acute liver failure requiring liver transplantation, in patients treated with Multaq. Patients treated with Multaq are advised to seek immediate medical attention if they experience symptoms suggestive of liver injury (e.g., anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, or itching). Regular serum liver enzyme monitoring is recommended, especially during the first 6 months of treatment. It is currently unclear whether routine monitoring of serum enzymes can prevent serious liver injury. If liver injury is suspected, Multaq should be discontinued immediately, and serum enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase, as well as serum bilirubin, should be tested to determine if liver injury is present. If liver injury is diagnosed, appropriate treatment should be initiated and the possible causes investigated. Multaq should not be restarted in patients for whom no other cause of liver injury has been identified. For more complete data on drug warnings for dronedarone (18 in total), please visit the HSDB record page.

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Pharmacodynamics
Dronedalone is an antiarrhythmic drug that restores normal sinus rhythm and reduces heart rate in patients with atrial fibrillation. In another model, it prevents ventricular tachycardia and ventricular fibrillation. Dronedalone prolongs the QTc interval by an average of approximately 10 milliseconds. Dronedalone lowers arterial blood pressure and reduces oxygen consumption. It reduces myocardial contractility but does not alter left ventricular ejection fraction. Dronedalone dilates coronary arteries by activating the nitric oxide pathway. Clinical studies have shown that dronedalone reduces hospitalization rates for acute coronary syndromes and the incidence of stroke. Dronedalone exerts its antiadrenergic effect by reducing the blood pressure response of α-adrenergic receptors to adrenaline and the response of β1 and β2 receptors to isoproterenol. Studies have shown that dronedalone inhibits triiodothyronine (T3) signaling by binding to TRα1, but its binding effect with TRβ1 is weaker.
In patients with severe heart failure and left ventricular systolic dysfunction, dronedarone treatment has been associated with increased early mortality related to worsening heart failure. Animal studies have shown that use of dronedarone at doses equivalent to the recommended human dose can cause fetal injury. Clinical studies and post-marketing reports have shown that dronedarone can cause hepatocellular damage and pulmonary toxicity, such as interstitial lung disease, pneumonia, and pulmonary fibrosis. Compared to the related compound amiodarone, dronedarone has a faster onset of action, a faster decline in effect, a shorter elimination half-life, and lower tissue accumulation.

C31H44N2O5S

556.76

556.297

141626-36-0

Dronedarone Hydrochloride;141625-93-6;Dronedarone-d6 hydrochloride;1329809-23-5

208898

White to off-white solid powder

1.1±0.1 g/cm3

683.9±65.0 °C at 760 mmHg

137-145
149-153 °C

367.4±34.3 °C

0.0±2.1 mmHg at 25°C

1.564

7.58

1

7

18

39

800

0

ZQTNQVWKHCQYLQ-UHFFFAOYSA-N

InChI=1S/C31H44N2O5S/c1-5-8-12-29-30(27-23-25(32-39(4,35)36)15-18-28(27)38-29)31(34)24-13-16-26(17-14-24)37-22-11-21-33(19-9-6-2)20-10-7-3/h13-18,23,32H,5-12,19-22H2,1-4H3

N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-yl]methanesulfonamide

SR 33589 SR33589D03914 S7529D4689 W3083 RL01735D-03914 S-7529D-4689 W-3083 RL-01735Multaq

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)

DMSO : ~50 mg/mL (~89.81 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.49 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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.49 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), suspension 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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.49 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension 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.

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