DRONEDARONE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C31H44N2O5S
Molecular Weight	556.756
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CCCCN(CCCC)CCCOC1=CC=C(C=C1)C(=O)C2=C(CCCC)OC3=CC=C(NS(C)(=O)=O)C=C23

InChI

InChIKey=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

HIDE SMILES / InChI

Molecular Formula	C31H44N2O5S
Molecular Weight	556.756
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description

Dronedarone is an antiarrhythmic that is FDA approved for the treatment of atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation (AF). Dronedarone is multichannel blocker. Common adverse reactions include abdominal pain, diarrhea, indigestion, nausea, vomiting, asthenia and raised serum creatinine. Dronedarone has potentially important pharmacodynamics interactions: Digoxin: Consider discontinuation or halve dose of digoxin before treatment and monitor; Calcium channel blockers (CCB): Initiate CCB with low dose and increase after ECG verification of tolerability; Beta-blockers: May provoke excessive bradycardia, Initiate with low dose and increase after ECG verification of tolerability.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Inward rectifier potassium channel 2 5	Blocker 537
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 14	Blocker 537	1.0 µM [IC50]
Cytochrome P450 3A4 127	Substrate 661

Conditions

Condition	Modality	Targets	Highest Phase	Product
Atrial fibrillation 131	Primary		Approved 8,429	MULTAQ
Atrial flutter 6	Primary		Approved 8,429	MULTAQ

C_max

Value	Dose	Co-administered	Analyte	Population
96.2 ng/mL	1600 mg single, oral	METOPROLOL	DRONEDARONE plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
1386 ng × h/mL	1600 mg single, oral	METOPROLOL	DRONEDARONE plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
12 h	1600 mg single, oral	METOPROLOL	DRONEDARONE plasma	Homo sapiens

Doses

Dose	Population	Adverse events
400 mg 2 times / day steady, oral Recommended	unhealthy, 20-97 years n = 3282	Disc. AE: Gastrointestinal disorders, QT interval prolonged...
1600 mg 2 times / day multiple, oral Highest studied dose	healthy, 21-40 years
400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989	Disc. AE: Diarrhea, Nausea...
400 mg 2 times / day steady, oral	unhealthy, adult	Other AEs: Heart failure...
600 mg 2 times / day multiple, oral	unhealthy, adult n = 66	Disc. AE: Diarrhea, Vomiting...
800 mg 2 times / day multiple, oral	unhealthy, adult n = 62	Disc. AE: Diarrhea, Nausea...

AEs

AE	Significance	Dose	Population
QT interval prolonged	1.5% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, 20-97 years n = 3282
Gastrointestinal disorders	3.2% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, 20-97 years n = 3282
Blood urea increased	0.4% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Cardiac failure	0.8% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Palpitations	1.1% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Hepatic enzyme increased	1.2% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Cardiac failure congestive	1.3% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Dyspepsia	1.3% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Vertigo	1.3% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Vomiting	1.7% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Abdominal pain	1.9% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Abdominal pain upper	2% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Pain in extremity	2.1% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Cough	2.2% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Dyspnoea	2.3% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Blood creatinine increased	2.5% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Bradycardia	2.6% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Fatigue	2.7% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Upper respiratory tract infection	2.9% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Arthralgia	3.1% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Back pain	3.3% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Dizziness	3.4% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Nasopharyngitis	3.7% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Nausea	3.9% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Oedema peripheral	4.2% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Diarrhea	6.7% Disc. AE	400 mg 2 times / day steady, oral Recommended	unhealthy, adult n = 989
Heart failure	grade 5	400 mg 2 times / day steady, oral	unhealthy, adult
Abdominal pain	1.5% Disc. AE	600 mg 2 times / day multiple, oral	unhealthy, adult n = 66
Blood creatinine increased	1.5% Disc. AE	600 mg 2 times / day multiple, oral	unhealthy, adult n = 66
Bradycardia	1.5% Disc. AE	600 mg 2 times / day multiple, oral	unhealthy, adult n = 66
Cough	1.5% Disc. AE	600 mg 2 times / day multiple, oral	unhealthy, adult n = 66
Electrocardiogram QT prolonged	1.5% Disc. AE	600 mg 2 times / day multiple, oral	unhealthy, adult n = 66
Vomiting	1.5% Disc. AE	600 mg 2 times / day multiple, oral	unhealthy, adult n = 66
Blood urea increased	3% Disc. AE	600 mg 2 times / day multiple, oral	unhealthy, adult n = 66
Dyspepsia	3% Disc. AE	600 mg 2 times / day multiple, oral	unhealthy, adult n = 66
Hypokalemia	3% Disc. AE	600 mg 2 times / day multiple, oral	unhealthy, adult n = 66
Cardiac failure congestive	4.5% Disc. AE	600 mg 2 times / day multiple, oral	unhealthy, adult n = 66
Cardiac failure	4.5% Disc. AE	600 mg 2 times / day multiple, oral	unhealthy, adult n = 66
Fatigue	4.5% Disc. AE	600 mg 2 times / day multiple, oral	unhealthy, adult n = 66
Hepatic enzyme increased	4.5% Disc. AE	600 mg 2 times / day multiple, oral	unhealthy, adult n = 66
Nasopharyngitis	4.5% Disc. AE	600 mg 2 times / day multiple, oral	unhealthy, adult n = 66
Vertigo	4.5% Disc. AE	600 mg 2 times / day multiple, oral	unhealthy, adult n = 66
Palpitations	6.1% Disc. AE	600 mg 2 times / day multiple, oral	unhealthy, adult n = 66
Diarrhea	7.6% Disc. AE	600 mg 2 times / day multiple, oral	unhealthy, adult n = 66
Cardiac failure congestive	1.6% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62
Cardiac failure	1.6% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62
Hepatic enzyme increased	1.6% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62
Upper respiratory tract infection	1.6% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62
Diarrhea	29% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62
Abdominal pain	3.2% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62
Blood urea increased	3.2% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62
Electrocardiogram QT prolonged	3.2% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62
Fatigue	3.2% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62
Influenza	3.2% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62
Vertigo	3.2% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62
Vomiting	3.2% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62
Atrial tachycardia	4.8% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62
Cough	4.8% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62
Dizziness	4.8% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62
Palpitations	4.8% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62
Bradycardia	6.5% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62
Nausea	8.1% Disc. AE	800 mg 2 times / day multiple, oral	unhealthy, adult n = 62

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1,587	inducer 389 inhibitor 1,767	substrate 1,217 inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1,524 CYP2C19 1,478 CYP2E1 882 P-gp 1,461 OAT1 599 OAT3 642 OCT1 512 OATP1B1 788 OATP1B3 706	CYP3A 191 CYP1A2 1,054 P-gp 1,537	CYP1A2 701 CYP2A6 79 CYP3A 129 CYP2C8 168 CYP2C19 293

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
OATP1B1 803	inhibitor 3,277	likely
OATP1B3 715	inhibitor 3,277	likely
CYP3A4 1,925	inhibitor 3,277	moderate [Ki 8.12 uM]	yes (co-administration study)
CYP1A2 1,692	inducer 1,573	no
CYP2A6 739	inducer 1,573	no
CYP2C19 1,553	inducer 1,573	no
CYP2C8 965	inducer 1,573	no
CYP2C9 1,819	inducer 1,573	no
CYP3A 298	inducer 1,573	no
CYP1A2 1,692	inhibitor 3,277	not significant
CYP2C19 1,553	inhibitor 3,277	not significant
CYP2E1 970	inhibitor 3,277	not significant
OAT1 603	inhibitor 3,277	not significant
OAT3 644	inhibitor 3,277	not significant
OCT1 543	inhibitor 3,277	not significant
CYP2C9 1,819	inhibitor 3,277	not significant	weak (co-administration study)
P-gp 1,650	inhibitor 3,277	strong [IC50 0.97 uM]	yes (co-administration study)
CYP2D6 1,891	inhibitor 3,277	weak [Ki 4.37 uM]	yes (co-administration study)

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A 191	substrate 3,367	major	yes (co-administration study)
CYP1A2 1,054	substrate 3,367	no
CYP2D6 1,217	substrate 3,367	no
P-gp 1,537	substrate 3,367	unlikely

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

Sourcing

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:50659	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:50659
ChemicalBook	CB11117179	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB11117179
MolPort	MolPort-006-170-000	https://www.molport.com/shop/molecule-link/MolPort-006-170-000
ZINC	ZINC000049933061	http://zinc15.docking.org/substances/ZINC000049933061
eMolecules	30152747	https://www.emolecules.com/cgi-bin/more?vid=30152747

PubMed

Title	Date	PubMed
Hemodynamic and antiadrenergic effects of dronedarone and amiodarone in animals with a healed myocardial infarction.	2000 Sep	10975596
Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone.	2001 Jul	11429385
IKr channel blockers: novel antiarrhythmic agents.	2003 Oct	15326913
Trials of new antiarrhythmic drugs for maintenance of sinus rhythm in patients with atrial fibrillation.	2004	14739742
Dronedarone: an amiodarone analogue.	2004 Apr	15102590
Effects of metabolites and analogs of amiodarone on alveolar macrophages: structure-activity relationship.	2004 Aug	15075249
Involvement of nitric oxide in amiodarone- and dronedarone-induced coronary vasodilation in guinea pig heart.	2004 Aug 2	15288583
Pharmacokinetic and pharmacodynamic interactions between metoprolol and dronedarone in extensive and poor CYP2D6 metabolizers healthy subjects.	2004 Feb	14748763
Theoretical possibilities for the development of novel antiarrhythmic drugs.	2004 Jan	14754422
A benefit-risk assessment of class III antiarrhythmic agents.	2004 Nov	15500415
[Safety of new anti-arrhythmic drugs].	2005 Apr	15881847
Do we need pharmacological therapy for atrial fibrillation in the ablation era?	2006 Dec	17340189
Comment on dronedarone.	2006 Dec	17096652
Dose-dependent effects of oral dronedarone on the circadian variation of RR and QT intervals in healthy subjects: implications for antiarrhythmic actions.	2006 Sep	17056831
Drug evaluation: dronedarone, a novel non-iodinated anti-arrhythmic agent.	2006 Sep	17002263
Effect of dronedarone on renal function in healthy subjects.	2007 Dec	17662087
Pharmacological inhibition of TRalpha1 receptor potentiates the thyroxine effect on body weight reduction in rats: potential therapeutic implications in controlling body weight.	2007 Jan	17199732
New antiarrhythmic treatment of atrial fibrillation.	2007 Jul	17605649
Maintaining sinus rhythm--making treatment better than the disease.	2007 Sep 6	17804851
Rationale and design of ATHENA: A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter.	2008 Jan	18031520
Is dronedarone effective for the prevention of recurrent atrial fibrillation?	2008 Mar	18087298

Patents

Sample Use Guides

In Vivo Use Guide

One tablet of 400 mg twice a day with morning and evening meals.

Route of Administration: Oral

In Vitro Use Guide

In isolated ventricular myocytes, dronedarone inhibited rapidly activating delayed-rectifier K+ current (I(Kr)) (median inhibitory concentration [IC50] /= 30 uM).

Substance Class	Chemical
Record UNII	JQZ1L091Y2
Record Status	`Validated (UNII)`
Record Version

Name

Type

Language

DRONEDARONE

Official Name

English

dronedarone [INN]

Common Name

English

METHANESULFONAMIDE, N-(2-BUTYL-3-(4-(3-(DIBUTYLAMINO)PROPOXY)BENZOYL)-5-BENZOFURANYL)-

Systematic Name

English

SR33589

Code

English

SR-33589

Code

English

DRONEDARONE [VANDF]

Common Name

English

N-(2-BUTYL-3-(4-(3-(DIBUTYLAMINO)PROPROXY)BENZOYL)BENZOFURAN-5-YL)METHANESULFONAMIDE

Common Name

English

DRONEDARONE [EMA EPAR]

Common Name

English

Dronedarone [WHO-DD]

Common Name

English

DRONEDARONE [MI]

Common Name

English

DRONEDARONE [MART.]

Common Name

English

Classification Tree

Code System

Code

Antiarrhythmics, class III

WHO-VATC

QC01BD07

Anti-arrhythmic

LIVERTOX

NBK548208

Established Pharmacologic Class

NDF-RT

N0000175426

Antiarrhythmics, class III

WHO-ATC

C01BD07

Agent Affecting Cardiovascular System

NCI_THESAURUS

C47793

Code System

Code

Type

Description

WIKIPEDIA

DRONEDARONE

PRIMARY

DRUG BANK

DB04855

PRIMARY

NDF-RT

N0000185503

PRIMARY

P-Glycoprotein Inhibitors [MoA]

RXCUI

233698

PRIMARY

RxNorm

SMS_ID

100000081006

PRIMARY

PUBCHEM

208898

PRIMARY

MESH

C118667

PRIMARY

EPA CompTox

DTXSID3048653

PRIMARY

HSDB

7928

PRIMARY

MERCK INDEX

m4768

PRIMARY

Merck Index

NDF-RT

N0000182137

PRIMARY

Cytochrome P450 2D6 Inhibitors [MoA]

IUPHAR

7465

PRIMARY

CAS

141626-36-0

PRIMARY

EVMPD

SUB06408MIG

PRIMARY

DAILYMED

JQZ1L091Y2

PRIMARY

ChEMBL

CHEMBL184412

PRIMARY

NDF-RT

N0000190114

PRIMARY

Cytochrome P450 3A Inhibitors [MoA]

CHEBI

50659

PRIMARY

NCI_THESAURUS

C65485

PRIMARY

INN

7382

PRIMARY

FDA UNII

JQZ1L091Y2

PRIMARY

DRUG CENTRAL

4112

PRIMARY

Related Record Type Details


					8E4LAA4357

CYTOCHROME P450 2D6

METABOLIC ENZYME -> SUBSTRATE

Interaction Type:

MINOR


					JQZ1L091Y2

DRONEDARONE

EXCRETED UNCHANGED

Comments:

Mass balance indicates that orally administered dronedarone is ultimately excreted in the urine (6 %) and feces (84 %) primarily as metabolites. Dronedarone was extensively metabolized; only low amounts of dronedarone were detected in feces and dronedarone was non-existent in urine.

Interaction Type:

AMOUNT EXCRETED

Qualification:

URINE

Amount:


					FA36DV299Q

DRONEDARONE HYDROCHLORIDE

SALT/SOLVATE -> PARENT


					6D53G0FD0Z

PLASMA PROTEIN FRACTION (HUMAN)

BINDER->LIGAND

Interaction Type:

BINDING

Amount:

[>98] % (average)


					8E4LAA4357

CYTOCHROME P450 2D6

METABOLIC ENZYME -> INHIBITOR

Interaction Type:

LOW

Qualification:

Ki

Amount:

12 MICROMOLAR (average)


					L0423Z5LDW

CYTOCHROME P450 2C8

METABOLIC ENZYME -> INHIBITOR

Interaction Type:

LOW

Qualification:

Ki

Amount:

[>100] MICROMOLAR (average)


					PUO0521HZV

CYTOCHROME P450 3A4

METABOLIC ENZYME -> SUBSTRATE

Interaction Type:

MAJOR


					22ES734693

MULTIDRUG RESISTANCE PROTEIN 1

TRANSPORTER -> INHIBITOR

Related Record Type Details


					N9M9R8L6HY

N-(2-BUTYL-3-(4-(3-HYDROXYPROPOXY)BENZOYL)-5-BENZOFURANYL)METHANESULFONAMIDE

METABOLITE -> PARENT

Qualification:

FECAL; URINE


					P7K8A6HQU5

3-(4-((2-BUTYL-5-((METHYLSULFONYL)AMINO)-3-BENZOFURANYL)CARBONYL)PHENOXY)PROPANOIC ACID

METABOLITE -> PARENT

Interaction Type:

MAJOR

Qualification:

PLASMA


					V4SVV994JM

N-(2-BUTYL-3-(4-(3-(2-HYDROXYETHYLAMINO)PROPOXY)BENZOYL)BENZOFURAN-5-YL)METHANESULFONAMIDE

METABOLITE -> PARENT

Qualification:

FECAL; URINE


					HJS89VA2WC

(5-AMINO-2-BUTYL-3-BENZOFURANYL)(4-(3-(DIBUTYLAMINO)PROPOXY)PHENYL)METHANONE

METABOLITE -> PARENT

Amount:


					4QS7YH22HT

(2S,3S,4S,5R,6S)-6-(4-(3-(DIBUTYLAMINO)PROPOXY)BENZOYL)OXY-3,4,5-TRIHYDROXY-TETRAHYDROPYRAN-2-CARBOXYLIC ACID

METABOLITE -> PARENT

Qualification:

FECAL; URINE


					C3801M93QC

DEBUTYLDRONEDARONE

METABOLITE LESS ACTIVE -> PARENT

Comments:

Dronedarone is extensively metabolized, mainly by CYP 3A

Interaction Type:

MAJOR

Qualification:

PLASMA

Related Record Type Details


					JQZ1L091Y2

DRONEDARONE

ACTIVE MOIETY

Name	Property Type	Amount	Parameters
Volume of Distribution	PHARMACOKINETIC	20 Liters/Kilogram (average)

Tmax	PHARMACOKINETIC	3.5 hours [2 to 6] (average)	IN HEPATICALLY IMPAIRED PATIENTS DOSE 400 mg (average) BID

Biological Half-life	PHARMACOKINETIC	[13 to 19] hours (average)

Tmax	PHARMACOKINETIC	2.5 hours [1 to 5] (average)	IN HEALTHY SUBJECTS DOSE 400 mg (average) BID

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

Drug as perpetrator