AMIODARONE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C25H29I2NO3
Molecular Weight	645.3116
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCCCC1=C(C(=O)C2=CC(I)=C(OCCN(CC)CC)C(I)=C2)C3=C(O1)C=CC=C3

InChI

InChIKey=IYIKLHRQXLHMJQ-UHFFFAOYSA-N

InChI=1S/C25H29I2NO3/c1-4-7-11-22-23(18-10-8-9-12-21(18)31-22)24(29)17-15-19(26)25(20(27)16-17)30-14-13-28(5-2)6-3/h8-10,12,15-16H,4-7,11,13-14H2,1-3H3

HIDE SMILES / InChI

Molecular Formula	C25H29I2NO3
Molecular Weight	645.3116
Charge	0
Count

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

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022325s002lbl.pdf
Curator's Comment: description was created based on several sources, including: https://www.drugs.com/pro/amiodarone.html | DOI: 10.1007/978-1-4613-2827-8_26

Amiodarone is an antiarrhythmic with mainly class III properties, but it possesses electrophysiologic characteristics of all four Vaughan Williams classes. Like class I drugs, amiodarone blocks sodium channels at rapid pacing frequencies, and like class II drugs, amiodarone exerts a noncompetitive antisympathetic action. In addition to blocking sodium channels, amiodarone blocks myocardial potassium channels, which contributes to slowing of conduction and prolongation of refractoriness. It is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation and hemodynamically unstable ventricular tachycardia in patients refractory to other therapy. The most common adverse reactions (1-2%) leading to discontinuation of intravenous amiodarone therapy are hypotension, asystole/cardiac arrest/pulseless electrical activity, VT, and cardiogenic shock. Other important adverse reactions are, torsade de pointes (TdP), congestive heart failure, and liver function test abnormalities. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Adrenergic receptor beta 87 Target ID: CHEMBL2094118 Sources: Collins, P. (2008) 'Mrcp 1 Pocket', p.84 Retrieved from https://books.google.ru/books?id=FbjdURJT99sC	Inhibitor 8297
HERG 92 Target ID: CHEMBL240 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10208308 \| https://www.ncbi.nlm.nih.gov/pubmed/27256139	Blocker 537	9.8 µM [IC50]
Voltage-gated T-type calcium channel (guinea pig) 2 Target ID: Voltage-gated T-type calcium channel (guinea pig) Sources: https://www.ncbi.nlm.nih.gov/pubmed/1281221	Blocker 537
Voltage-gated L-type calcium channel (guinea pig) 2 Target ID: Voltage-gated L-type calcium channel (guinea pig) Sources: https://www.ncbi.nlm.nih.gov/pubmed/1281221	Blocker 537
Cytochrome P450 3A 22 Target ID: CHEMBL2364675 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022325s002lbl.pdf	Substrate 661
Cytochrome P450 2C8 18 Target ID: CHEMBL3721 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022325s002lbl.pdf	Substrate 661

Conditions

Condition	Modality	Targets	Highest Phase	Product
Recurring ventricular fibrillation 2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022325s002lbl.pdf	Primary		Approved 8429	PACERONE Approved Use Amiodarone injection is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. Amiodarone also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. During or after treatment with amiodarone, patients may be transferred to oral amiodarone therapy. Launch Date 1998
Ventricular tachycardia 11 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022325s002lbl.pdf	Primary		Approved 8429	PACERONE Approved Use Amiodarone injection is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. Amiodarone also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. During or after treatment with amiodarone, patients may be transferred to oral amiodarone therapy [ see Dosage and Administration (2) Launch Date 1998

C_max

Value	Dose	Analyte	Population
23.8 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21052689/	2.5 mg/kg single, intravenous dose: 2.5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	DESETHYLAMIODARONE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
13660 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21052689/	5 mg/kg single, intravenous dose: 5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	AMIODARONE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
2920 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21052689/	1.25 mg/kg single, intravenous dose: 1.25 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	AMIODARONE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
7140 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21052689/	2.5 mg/kg single, intravenous dose: 2.5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	AMIODARONE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
41.2 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21052689/	5 mg/kg single, intravenous dose: 5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	DESETHYLAMIODARONE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
9 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21052689/	1.25 mg/kg single, intravenous dose: 1.25 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	DESETHYLAMIODARONE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
1.7 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/6851030/	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered:	AMIODARONE serum	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
16600 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21052689/	5 mg/kg single, intravenous dose: 5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	AMIODARONE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
3600 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21052689/	1.25 mg/kg single, intravenous dose: 1.25 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	AMIODARONE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
8100 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21052689/	2.5 mg/kg single, intravenous dose: 2.5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	AMIODARONE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
16900 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21052689/	5 mg/kg single, intravenous dose: 5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	DESETHYLAMIODARONE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
14.6 day EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21052689/	5 mg/kg single, intravenous dose: 5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	AMIODARONE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
14.2 day EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21052689/	5 mg/kg single, intravenous dose: 5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	DESETHYLAMIODARONE serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
4.62 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/6851030/	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered:	AMIODARONE serum	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.023% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3242577/	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:		AMIODARONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	inhibitor 1767	substrate 1217 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP3A 214 P-gp 1461	CYP2C8 693 CYP1A1 349 CYP1A2 1054 CYP2C19 991

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP2D6 1891	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613947/; https://pubmed.ncbi.nlm.nih.gov/15541258/	yes [IC50 15 uM]	yes (co-administration study) Comment: reversible inhibition; The area under the plasma concentration-time curve (AUC) of metoprolol increased from 767 before to 1,387 ug * hours/L after the amiodarone loading dose Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613947/; https://pubmed.ncbi.nlm.nih.gov/15541258/
P-gp 1650	inhibitor 3277 Sources: http://www.ncbi.nlm.nih.gov/pubmed/12499648	yes [IC50 5.48 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613947/; https://pubmed.ncbi.nlm.nih.gov/8891878/	yes [IC50 >50 uM]	yes (co-administration study) Comment: reversible inhibition; After treatment with 3 g amiodarone (phase I), this parameter (AUC of lidocaine) increased to 135.3 ± 34.6 (p = 0.016), whereas the AUC of MEGEX decreased from 19.2 ± 6.5 to 15.8 ± 8.3 μg/min/ml (p = 0.04). Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613947/; https://pubmed.ncbi.nlm.nih.gov/8891878/
CYP2C9 1819	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613947/; https://pubmed.ncbi.nlm.nih.gov/3621782/	yes [IC50 >50 uM]	yes (co-administration study) Comment: reversible inhibition; The mean warfarin AUC during the amiodarone regimen increased to 200% of the control value of anticoagulant alone, from 624 ± 59 Rg/ml-hr to 1249 ± 115 p,g/ml-hr, a significant difference Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613947/; https://pubmed.ncbi.nlm.nih.gov/3621782/
CYP3A 298	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613947/	yes [IC50 >50 uM]	yes (co-administration study) Comment: reversible inhibition; The mean warfarin AUC during the amiodarone regimen increased to 200% of the control value of anticoagulant alone, from 624 ± 59 Rg/ml-hr to 1249 ± 115 p,g/ml-hr, a significant difference Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613947/

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP1A1 349	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11038157/	yes	likely (co-administration study) Comment: CYP450 inhibitors: grapefruit juice, certain fluoroquinolone and macrolide antibiotics, azole antifungals, cimetidine, certain protease inhibitors: increased exposure of amiodarone. Avoid concomitant use. CYP450 inducers (St. John's Wort): reduced amiodarone serum levels Sources: https://pubmed.ncbi.nlm.nih.gov/11038157/
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11038157/	yes	likely (co-administration study) Comment: CYP450 inhibitors: grapefruit juice, certain fluoroquinolone and macrolide antibiotics, azole antifungals, cimetidine, certain protease inhibitors: increased exposure of amiodarone. Avoid concomitant use. CYP450 inducers (St. John's Wort): reduced amiodarone serum levels Sources: https://pubmed.ncbi.nlm.nih.gov/11038157/
CYP2C19 991	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11038157/	yes	likely (co-administration study) Comment: CYP450 inhibitors: grapefruit juice, certain fluoroquinolone and macrolide antibiotics, azole antifungals, cimetidine, certain protease inhibitors: increased exposure of amiodarone. Avoid concomitant use. CYP450 inducers (St. John's Wort): reduced amiodarone serum levels Sources: https://pubmed.ncbi.nlm.nih.gov/11038157/
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022325lbl.pdf#page=9; https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/018972s054lbl.pdf#page=6 Page: 9.0	yes	likely (co-administration study) Comment: CYP450 inhibitors: grapefruit juice, certain fluoroquinolone and macrolide antibiotics, azole antifungals, cimetidine, certain protease inhibitors: increased exposure of amiodarone. Avoid concomitant use. CYP450 inducers (St. John's Wort): reduced amiodarone serum levels Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022325lbl.pdf#page=9; https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/018972s054lbl.pdf#page=6 Page: 9.0
CYP2D6 1217	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11038157/	yes	likely (co-administration study) Comment: CYP450 inhibitors: grapefruit juice, certain fluoroquinolone and macrolide antibiotics, azole antifungals, cimetidine, certain protease inhibitors: increased exposure of amiodarone. Avoid concomitant use. CYP450 inducers (St. John's Wort): reduced amiodarone serum levels Sources: https://pubmed.ncbi.nlm.nih.gov/11038157/
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022325lbl.pdf#page=9; https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/018972s054lbl.pdf#page=6 Page: 9.0	yes	likely (co-administration study) Comment: CYP450 inhibitors: grapefruit juice, certain fluoroquinolone and macrolide antibiotics, azole antifungals, cimetidine, certain protease inhibitors: increased exposure of amiodarone. Avoid concomitant use. CYP450 inducers (St. John's Wort): reduced amiodarone serum levels Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022325lbl.pdf#page=9; https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/018972s054lbl.pdf#page=6 Page: 9.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959829/

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:2663	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:2663
ChemicalBook	CB5310616	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB5310616
MolPort	MolPort-003-703-670	https://www.molport.com/shop/molecule-link/MolPort-003-703-670
ZINC	ZINC000003830212	http://zinc15.docking.org/substances/ZINC000003830212
eMolecules	901372	https://www.emolecules.com/cgi-bin/more?vid=901372

PubMed

Title	Date	PubMed
Bilateral anterior ischaemic optic neuropathy following amiodarone.	1998	10070533
Drug-induced torsade de pointes.	1999 Apr 27	10217665
[Severe flecainide acetate poisoning. Apropos of a case].	1999 Feb	10078349
Amiodarone-induced delirium.	1999 Jul	10401472
[Treatment of cardiac insufficiency: does treatment depend on whether its cause is ischemic or idiopathic?].	1999 Jun	10410811
Interaction of amiodarone and triiodothyronine on the expression of beta-adrenoceptors in brown adipose tissue of rat.	1999 Mar	10217540
Efficacy and safety of intravenous amiodarone in recent-onset atrial fibrillation: experience in patients admitted to a general internal medicine department.	1999 May	10533631
Antiadrenergic effect of chronic amiodarone therapy in human heart failure.	1999 May	10334423
Amiodarone-induced angioedema.	2000 Dec	11117281
Positive Coombs' test results in two dogs treated with amiodarone.	2000 Jun 15	10863591
Amiodarone pulmonary, neuromuscular and ophthalmological toxicity.	2000 Mar-Apr	10859406
Polymorphic ventricular tachycardia after use of intravenous amiodarone for postoperative junctional ectopic tachycardia.	2000 Nov-Dec	11229410
[Amiodarone-associated optic neuropathy: an independent syndrome? Three patients with bilateral optic neuropathy].	2000 Sep	11076348
Amiodarone-related optic neuropathy.	2000 Sep-Oct	11033139
[Radiofrequency catheter ablation in children with Wolff-Parkinson-White syndrome and sudden cardiac death who had been resuscitated].	2001 Apr	11273819
Structure-activity relationships and electrophysiological effects of short-acting amiodarone homologs in guinea pig isolated heart.	2001 Apr	11259553
Amiodarone stimulates interleukin-6 production in cultured human thyrocytes, exerting cytotoxic effects on thyroid follicles in suspension culture.	2001 Feb	11288978
Inhibitory effects of CYP3A4 substrates and their metabolites on P-glycoprotein-mediated transport.	2001 Feb	11231118
Thyroid hormone and the cardiovascular system.	2001 Feb 15	11172193
Thyroidectomy for selected patients with thyrotoxicosis.	2001 Jan	11177016
Dofetilide: a new class III antiarrhythmic agent.	2001 Jan	11173316
Intravenous antiarrhythmic agents.	2001 Jan	11124714
Risk of torsades de pointes with non-cardiac drugs. Prolongation of QT interval is probably a class effect of fluoroquinolones.	2001 Jan 6	11141163
Moxifloxacin: clinical efficacy and safety.	2001 Mar 1	11258173
[Hyperthyroidism and heart].	2001 Mar 15	11293943
Circadian variation of paroxysmal atrial fibrillation. PA3 Investigators. Atrial Pacing Peri-ablation for Prevention of Atrial Fibrillation Trial.	2001 Mar 15	11249909
Oral amiodarone for prevention of atrial fibrillation after open heart surgery, the Atrial Fibrillation Suppression Trial (AFIST): a randomised placebo-controlled trial.	2001 Mar 17	11265951
How to manage atrial fibrillation: an update on recent clinical trials.	2001 Mar-Apr	11209144

Patents

Sample Use Guides

In Vivo Use Guide

Intravenous: Initial dose: 1000 mg over the first 24 hours of therapy, delivered by the following infusion regimen: -Loading infusions: 150 mg over the first 10 minutes (15 mg/min), followed by 360 mg over the next 6 hours (1 mg/min) -Maintenance infusion: 540 mg over the remaining 18 hours (0.5 mg/min) Maintenance dose: After the first 24 hours, continue the maintenance infusion rate of 0.5 mg/min; may increase infusion rate to achieve effective arrhythmia suppression. -Supplemental infusions: 150 mg over 10 minutes (15 mg/min) for breakthrough episodes of ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia(VT) Maximum dose: Initial infusion rate: 30 mg/min Oral: Loading dose: 800 to 1600 mg orally per day for 1 to 3 weeks (occasionally longer) until adequate arrhythmia control is achieved or if side effects become prominent, then switch to adjustment dose Adjustment dose: 600 to 800 mg orally per day for 1 month, then switch to maintenance dose Maintenance dose: 400 mg orally per day

Route of Administration: Other

In Vitro Use Guide

At concentrations ranging from 75-200 uM, amiodarone induced a significant and dose-dependent release of 51Cr in FRTL-5 cells. In the same molar concentrations, amiodarone was also cytotoxic in CHO cells. In hTF, the release of 51Cr produced by amiodarone occurred at a lower concentration (37.5 vs. 75 uM) and was significantly greater than that in FRTL-5 cells.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 15:25:00 GMT 2023` Edited by `admin` on `Fri Dec 15 15:25:00 GMT 2023`
Record UNII	N3RQ532IUT
Record Status	`Validated (UNII)`
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Name

Type

Language

AMIODARONE

Official Name

English

AMIODARONE [MI]

Common Name

English

AMIODARONE [VANDF]

Common Name

English

AMIODARONE [USAN]

Common Name

English

AMIODARONE [MART.]

Common Name

English

2-Butyl-3-benzofuranyl 4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl ketone

Systematic Name

English

Amiodarone [WHO-DD]

Common Name

English

amiodarone [INN]

Common Name

English

METHANONE, (2-BUTYL-3-BENZOFURANYL)(4-(2-(DIETHYLAMINO)ETHOXY)-3,5-DIIODOPHENYL)-

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C47793