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Identification
Name Ibutilide
Accession Number DB00308 (APRD01025)
Type small molecule
Groups approved
Description

Ibutilide is a Class III antiarrhythmic agent that is indicated for acute cardioconversion of atrial fibrillation and atrial flutter of a recent onset to sinus rhythm. [Wikipedia]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Ibutilida [INN-Spanish]
Ibutilide Fumarate
Ibutilidum [INN-Latin]
Salts Not Available
Brand names
Name Company
Corvert
Brand mixtures Not Available
Categories
  • Anti-Arrhythmia Agents
CAS number 122647-32-9
Weight Average: 384.576
Monoisotopic: 384.244663718
Chemical Formula C20H36N2O3S
InChI Key InChIKey=ALOBUEHUHMBRLE-UHFFFAOYSA-N
InChI
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
Plain Text
IUPAC Name
N-(4-{4-[ethyl(heptyl)amino]-1-hydroxybutyl}phenyl)methanesulfonamide
SMILES
CCCCCCCN(CC)CCCC(O)C1=CC=C(NS(C)(=O)=O)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Benzyl Alcohols and Derivatives
  • Anilines
Substructures
  • Hydroxy Compounds
  • Benzyl Alcohols and Derivatives
  • Sulfonyls
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Aromatic compounds
  • Sulfonamides
  • Alcohols and Polyols
  • Anilines
Pharmacology
Indication Indicated for the rapid conversion of atrial fibrillation or atrial flutter of recent onset to sinus rhythm.
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.
Mechanism of action Ibutilide is a 'pure' class III antiarrhythmic drug, used intravenously against atrial flutter and fibrillation. At a cellular level it exerts two main actions: induction of a persistent Na+ current sensitive to dihydropyridine Ca2+ channel blockers and potent inhibition of the cardiac rapid delayed rectifier K+ current, by binding within potassium channel pores. In other words, Ibutilide binds to and alters the activity of hERG potassium channels, delayed inward rectifier potassium (IKr) channels and L-type (dihydropyridine sensitive) calcium channels
Absorption Rapid after intravenous injection
Volume of distribution
  • 11 L/kg
Protein binding 40%
Metabolism 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.
Route of elimination 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.
Half life 6 hours (ranges from 2-12 hours)
Clearance
  • 29 mL/min/kg
Toxicity Acute overdose in animals results in CNS toxicity; notably, CNS depression, rapid gasping breathing, and convulsions. The intravenous median lethal dose in the rat was more than 50 mg/kg which is, on a mg/m2 basis, at least 250 times the maximum recommended human dose.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00332 Ibutilide Pathway SMP00332
Pharmacoeconomics
Manufacturers
  • Pharmacia and upjohn co
  • Bioniche pharma usa llc
  • Pharmaforce inc
Packagers
Dosage forms
Form Route Strength
Solution Intravenous
Prices
Unit description Cost Unit
Corvert 1 mg/10 ml vial 54.27 USD ml
Ibutilide fum 1 mg/10 ml vial 33.6 USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 5155268 1992-12-28 2009-12-28
Properties
State solid
Experimental Properties
Property Value Source
water solubility 100 mg/mL Not Available
logP 4.6 Not Available
Predicted Properties
Property Value Source
water solubility 4.73e-03 g/l ALOGPS
logP 4.72 ALOGPS
logP 2.54 ChemAxon
logS -4.9 ALOGPS
pKa (strongest acidic) 9.72 ChemAxon
pKa (strongest basic) 10.4 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 4 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 69.64 ChemAxon
rotatable bond count 13 ChemAxon
refractivity 109.18 ChemAxon
polarizability 46.45 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00648 Link_out
KEGG Compound C07753 Link_out
PubChem Compound 60753 Link_out
PubChem Substance 46507904 Link_out
ChemSpider 54755 Link_out
BindingDB 50131432 Link_out
Therapeutic Targets Database DAP000279 Link_out
PharmGKB PA449958 Link_out
Drug Product Database 2242470 Link_out
RxList http://www.rxlist.com/cgi/generic/ibutilide.htm Link_out
Drugs.com http://www.drugs.com/cdi/ibutilide.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Ibutilide Link_out
ATC Codes
  • C01BD05
AHFS Codes
  • 24:04.04.20
PDB Entries Not Available
FDA label show (878 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Artemether Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Cisapride Increased risk of cardiotoxicity and arrhythmias
Fingolimod Pharmacodynamic synergist. Contraindicated. Increased risk of bradycardia, AV block, and torsade de pointes.
Lumefantrine Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Ranolazine Possible additive effect on QT prolongation
Tacrolimus Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Telavancin Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Thiothixene May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
Toremifene Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.
Trimipramine Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Voriconazole Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Vorinostat Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Ziprasidone Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
Zuclopenthixol Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Food Interactions Not Available
Targets

1. Voltage-dependent L-type calcium channel subunit alpha-1C

Pharmacological action: yes
Actions: activator

Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1C gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the "high-voltage activated" (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1C subunit play an important role in excitation-contraction coupling in the heart. The various isoforms display marked differences in the sensitivity to DHP compounds

Organism class: human
UniProt ID: Q13936 Link_out
Gene: CACNA1C Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Doggrell SA, Hancox JC: Ibutilide—recent molecular insights and accumulating evidence for use in atrial flutter and fibrillation. Expert Opin Investig Drugs. 2005 May;14(5):655-69. Pubmed
  2. Foster RH, Wilde MI, Markham A: Ibutilide. A review of its pharmacological properties and clinical potential in the acute management of atrial flutter and fibrillation. Drugs. 1997 Aug;54(2):312-30. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Voltage-dependent L-type calcium channel subunit beta-1

Pharmacological action: yes
Actions: activator

The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition and controlling the alpha-1 subunit membrane targeting

Organism class: human
UniProt ID: Q02641 Link_out
Gene: CACNB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Doggrell SA, Hancox JC: Ibutilide—recent molecular insights and accumulating evidence for use in atrial flutter and fibrillation. Expert Opin Investig Drugs. 2005 May;14(5):655-69. Pubmed
  2. Foster RH, Wilde MI, Markham A: Ibutilide. A review of its pharmacological properties and clinical potential in the acute management of atrial flutter and fibrillation. Drugs. 1997 Aug;54(2):312-30. Pubmed

3. Potassium voltage-gated channel subfamily H member 2

Pharmacological action: yes
Actions: inhibitor

Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr). Isoform 3 has no channel activity by itself, but modulates channel characteristics when associated with isoform 1

Organism class: human
UniProt ID: Q12809 Link_out
Gene: KCNH2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Perry M, de Groot MJ, Helliwell R, Leishman D, Tristani-Firouzi M, Sanguinetti MC, Mitcheson J: Structural determinants of HERG channel block by clofilium and ibutilide. Mol Pharmacol. 2004 Aug;66(2):240-9. Pubmed
  2. Perry M, Stansfeld PJ, Leaney J, Wood C, de Groot MJ, Leishman D, Sutcliffe MJ, Mitcheson JS: Drug binding interactions in the inner cavity of HERG channels: molecular insights from structure-activity relationships of clofilium and ibutilide analogs. Mol Pharmacol. 2006 Feb;69(2):509-19. Epub 2005 Nov 16. Pubmed
  3. Wolpert C, Schimpf R, Veltmann C, Borggrefe M: [Short QT syndrome] Herz. 2007 May;32(3):206-10. Pubmed
  4. Wolpert C, Schimpf R, Veltmann C, Giustetto C, Gaita F, Borggrefe M: Clinical characteristics and treatment of short QT syndrome. Expert Rev Cardiovasc Ther. 2005 Jul;3(4):611-7. Pubmed
  5. Yang T, Snyders D, Roden DM: Drug block of I(kr): model systems and relevance to human arrhythmias. J Cardiovasc Pharmacol. 2001 Nov;38(5):737-44. Pubmed
  6. Doggrell SA, Hancox JC: Ibutilide—recent molecular insights and accumulating evidence for use in atrial flutter and fibrillation. Expert Opin Investig Drugs. 2005 May;14(5):655-69. Pubmed

4. Voltage-dependent calcium channel subunit alpha-2/delta-1

Pharmacological action: unknown
Actions: activator

Calcium channel protein which plays an important role in excitation-contraction coupling

Organism class: human
UniProt ID: P54289 Link_out
Gene: CACNA2D1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Doggrell SA, Hancox JC: Ibutilide—recent molecular insights and accumulating evidence for use in atrial flutter and fibrillation. Expert Opin Investig Drugs. 2005 May;14(5):655-69. Pubmed
  2. Foster RH, Wilde MI, Markham A: Ibutilide. A review of its pharmacological properties and clinical potential in the acute management of atrial flutter and fibrillation. Drugs. 1997 Aug;54(2):312-30. Pubmed

5. Voltage-dependent calcium channel gamma-1 subunit

Pharmacological action: unknown
Actions: activator

This protein is a subunit of the dihydropyridine (DHP) sensitive calcium channel. Plays a role in excitation-contraction coupling. The skeletal muscle DHP-sensitive Ca(2+) channel may function only as a multiple subunit complex

Organism class: human
UniProt ID: Q06432 Link_out
Gene: CACNG1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Doggrell SA, Hancox JC: Ibutilide—recent molecular insights and accumulating evidence for use in atrial flutter and fibrillation. Expert Opin Investig Drugs. 2005 May;14(5):655-69. Pubmed
  2. Foster RH, Wilde MI, Markham A: Ibutilide. A review of its pharmacological properties and clinical potential in the acute management of atrial flutter and fibrillation. Drugs. 1997 Aug;54(2):312-30. Pubmed

6. Potassium channel subfamily K member 1

Pharmacological action: unknown
Actions: inhibitor

Weakly inward rectifying potassium channel

Organism class: human
UniProt ID: O00180 Link_out
Gene: KCNK1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Doggrell SA, Hancox JC: Ibutilide—recent molecular insights and accumulating evidence for use in atrial flutter and fibrillation. Expert Opin Investig Drugs. 2005 May;14(5):655-69. Pubmed
  2. Foster RH, Wilde MI, Markham A: Ibutilide. A review of its pharmacological properties and clinical potential in the acute management of atrial flutter and fibrillation. Drugs. 1997 Aug;54(2):312-30. Pubmed

7. Potassium channel subfamily K member 6

Pharmacological action: unknown
Actions: inhibitor

Exhibits outward rectification in a physiological K(+) gradient and mild inward rectification in symmetrical K(+) conditions

Organism class: human
UniProt ID: Q9Y257 Link_out
Gene: KCNK6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Doggrell SA, Hancox JC: Ibutilide—recent molecular insights and accumulating evidence for use in atrial flutter and fibrillation. Expert Opin Investig Drugs. 2005 May;14(5):655-69. Pubmed
  2. Foster RH, Wilde MI, Markham A: Ibutilide. A review of its pharmacological properties and clinical potential in the acute management of atrial flutter and fibrillation. Drugs. 1997 Aug;54(2):312-30. Pubmed

8. Potassium voltage-gated channel subfamily H member 6

Pharmacological action: unknown
Actions: inhibitor

Pore-forming (alpha) subunit of voltage-gated potassium channel. Elicits a slowly activating, rectifying current. Channel properties may be modulated by cAMP and subunit assembly

Organism class: human
UniProt ID: Q9H252 Link_out
Gene: KCNH6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Doggrell SA, Hancox JC: Ibutilide—recent molecular insights and accumulating evidence for use in atrial flutter and fibrillation. Expert Opin Investig Drugs. 2005 May;14(5):655-69. Pubmed
  2. Foster RH, Wilde MI, Markham A: Ibutilide. A review of its pharmacological properties and clinical potential in the acute management of atrial flutter and fibrillation. Drugs. 1997 Aug;54(2):312-30. Pubmed

9. Potassium voltage-gated channel subfamily H member 7

Pharmacological action: unknown
Actions: inhibitor

Pore-forming (alpha) subunit of voltage-gated potassium channel. Channel properties may be modulated by cAMP and subunit assembly

Organism class: human
UniProt ID: Q9NS40 Link_out
Gene: KCNH7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Doggrell SA, Hancox JC: Ibutilide—recent molecular insights and accumulating evidence for use in atrial flutter and fibrillation. Expert Opin Investig Drugs. 2005 May;14(5):655-69. Pubmed
  2. Foster RH, Wilde MI, Markham A: Ibutilide. A review of its pharmacological properties and clinical potential in the acute management of atrial flutter and fibrillation. Drugs. 1997 Aug;54(2):312-30. Pubmed

10. ATP-sensitive inward rectifier potassium channel 11

Pharmacological action: unknown
Actions: inhibitor

This receptor is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium

Organism class: human
UniProt ID: Q14654 Link_out
Gene: KCNJ11 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Doggrell SA, Hancox JC: Ibutilide—recent molecular insights and accumulating evidence for use in atrial flutter and fibrillation. Expert Opin Investig Drugs. 2005 May;14(5):655-69. Pubmed
  2. Foster RH, Wilde MI, Markham A: Ibutilide. A review of its pharmacological properties and clinical potential in the acute management of atrial flutter and fibrillation. Drugs. 1997 Aug;54(2):312-30. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19