DT-Web

DB00308 - Ibutilide


Identification
Name Ibutilide
Accession Number DB00308 (APRD01025)
Type small molecule
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
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 384.576
Groups approved
Monoisotopic Weight 384.244663718
Pharmacology
Indication Indicated for the rapid conversion of atrial fibrillation or atrial flutter of recent onset to sinus rhythm.
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
Protein binding 40%
Biotransformation 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.
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
Interactions
Drug Interactions
Drug Mechanism of 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


Voltage-dependent L-type calcium channel subunit alpha-1C
Name Voltage-dependent L-type calcium channel subunit alpha-1C
Gene Name CACNA1C
Pharmacological action yes
Actions activator
References
  • 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
  • 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
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
DTHybrid score 0.501
Voltage-dependent L-type calcium channel subunit beta-1
Name Voltage-dependent L-type calcium channel subunit beta-1
Gene Name CACNB1
Pharmacological action yes
Actions activator
References
  • 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
  • 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
DTHybrid score 0.3875
Potassium voltage-gated channel subfamily H member 2
Name Potassium voltage-gated channel subfamily H member 2
Gene Name KCNH2
Pharmacological action yes
Actions inhibitor
References
  • 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
  • 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
  • Wolpert C, Schimpf R, Veltmann C, Borggrefe M: [Short QT syndrome] Herz. 2007 May;32(3):206-10. - Pubmed
  • 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
  • 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
  • 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
DTHybrid score 0.4938
Voltage-dependent calcium channel subunit alpha-2/delta-1
Name Voltage-dependent calcium channel subunit alpha-2/delta-1
Gene Name CACNA2D1
Pharmacological action unknown
Actions activator
References
  • 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
  • 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
DTHybrid score 0.4949
Voltage-dependent calcium channel gamma-1 subunit
Name Voltage-dependent calcium channel gamma-1 subunit
Gene Name CACNG1
Pharmacological action unknown
Actions activator
References
  • 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
  • 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
DTHybrid score 0.5109
Potassium channel subfamily K member 1
Name Potassium channel subfamily K member 1
Gene Name KCNK1
Pharmacological action unknown
Actions inhibitor
References
  • 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
  • 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
DTHybrid score 0.428
Potassium channel subfamily K member 6
Name Potassium channel subfamily K member 6
Gene Name KCNK6
Pharmacological action unknown
Actions inhibitor
References
  • 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
  • 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
DTHybrid score 0.3543
Potassium voltage-gated channel subfamily H member 6
Name Potassium voltage-gated channel subfamily H member 6
Gene Name KCNH6
Pharmacological action unknown
Actions inhibitor
References
  • 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
  • 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
DTHybrid score 0.4661
Potassium voltage-gated channel subfamily H member 7
Name Potassium voltage-gated channel subfamily H member 7
Gene Name KCNH7
Pharmacological action unknown
Actions inhibitor
References
  • 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
  • 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
DTHybrid score 0.4658
ATP-sensitive inward rectifier potassium channel 11
Name ATP-sensitive inward rectifier potassium channel 11
Gene Name KCNJ11
Pharmacological action unknown
Actions inhibitor
References
  • 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
  • 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
DTHybrid score 0.4115

Predictions


Id Partner name Gene Name Score
4110 Voltage-dependent L-type calcium channel subunit beta-2 CACNB2 0.266
4111 Voltage-dependent L-type calcium channel subunit alpha-1S CACNA1S 0.2649
4115 Voltage-dependent L-type calcium channel subunit alpha-1D CACNA1D 0.1911
1588 Multidrug resistance protein 1 ABCB1 0.1906
4512 Cytochrome P450 3A4 CYP3A4 0.1563
4119 Cytochrome P450 2D6 CYP2D6 0.1501
789 Alpha-1D adrenergic receptor ADRA1D 0.1425
632 Alpha-1B adrenergic receptor ADRA1B 0.1316
4757 Cytochrome P450 2C9 CYP2C9 0.1251
6107 Cytochrome P450 3A7 CYP3A7 0.121
556 Alpha-1A adrenergic receptor ADRA1A 0.1182
4118 Cytochrome P450 3A5 CYP3A5 0.1174
4160 Voltage-dependent calcium channel subunit alpha-2/delta-2 CACNA2D2 0.0978
4209 ATP-sensitive inward rectifier potassium channel 8 KCNJ8 0.0948
964 Voltage-dependent T-type calcium channel subunit alpha-1H CACNA1H 0.0912
220 Sodium channel protein type 5 subunit alpha SCN5A 0.0888
4200 Cytochrome P450 1A2 CYP1A2 0.0842
1181 Alpha-1-acid glycoprotein 1 ORM1 0.0832
4113 Voltage-dependent L-type calcium channel subunit alpha-1F CACNA1F 0.0813
4924 Cytochrome P450 2C8 CYP2C8 0.0795
6016 Cytochrome P450 2C19 CYP2C19 0.0773
4112 Voltage-dependent L-type calcium channel subunit beta-4 CACNB4 0.0756
4114 Voltage-dependent L-type calcium channel subunit beta-3 CACNB3 0.0748
6024 Cytochrome P450 1A1 CYP1A1 0.0679
872 Gamma-aminobutyric-acid receptor subunit alpha-1 GABRA1 0.0646
1561 Troponin C, slow skeletal and cardiac muscles TNNC1 0.0605
6013 Cytochrome P450 2E1 CYP2E1 0.0577
6030 Cytochrome P450 2B6 CYP2B6 0.0554
831 D(2) dopamine receptor DRD2 0.0515
6145 Solute carrier family 22 member 1 SLC22A1 0.0513
502 5-hydroxytryptamine 2A receptor HTR2A 0.0481
6144 Solute carrier family 22 member 2 SLC22A2 0.0458
3970 Voltage-dependent N-type calcium channel subunit alpha-1B CACNA1B 0.0454
709 ATP-sensitive inward rectifier potassium channel 1 KCNJ1 0.0454
921 Glutamate receptor 2 GRIA2 0.0436
230 ATP-binding cassette transporter sub-family C member 8 ABCC8 0.0428
423 Gamma-aminobutyric-acid receptor subunit alpha-2 GABRA2 0.0424
233 Potassium channel subfamily K member 2 KCNK2 0.0415
4604 Liver carboxylesterase 1 CES1 0.0409
610 Calcium-activated potassium channel subunit alpha 1 KCNMA1 0.0384
776 Bile salt export pump ABCB11 0.0372
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.037
5718 Cytochrome P450 2A6 CYP2A6 0.0368
6045 Voltage-dependent calcium channel subunit alpha-2/delta-3 CACNA2D3 0.0362
485 cGMP-inhibited 3',5'-cyclic phosphodiesterase A PDE3A 0.0354
833 Organic cation/carnitine transporter 1 SLC22A4 0.0347
6139 Solute carrier organic anion transporter family member 1A2 SLCO1A2 0.0337
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.0334
1971 cAMP-specific 3',5'-cyclic phosphodiesterase 4A PDE4A 0.0332
465 Calmodulin CALM1 0.0326
193 Beta-1 adrenergic receptor ADRB1 0.032
15 Voltage-dependent T-type calcium channel subunit alpha-1I CACNA1I 0.0313
118 Organic cation/carnitine transporter 2 SLC22A5 0.0302
1490 Solute carrier organic anion transporter family member 1B1 SLCO1B1 0.0297
6931 Calcium-activated potassium channel subunit beta-1 KCNMB1 0.0296
6933 Calcium-activated potassium channel subunit beta-4 KCNMB4 0.0296
6932 Calcium-activated potassium channel subunit beta-3 KCNMB3 0.0296
6934 Small conductance calcium-activated potassium channel protein 1 KCNN1 0.0296
6935 Small conductance calcium-activated potassium channel protein 2 KCNN2 0.0296
6936 Small conductance calcium-activated potassium channel protein 3 KCNN3 0.0296
535 Voltage-dependent T-type calcium channel subunit alpha-1G CACNA1G 0.0295
6048 Troponin C, skeletal muscle TNNC2 0.0279
6147 Solute carrier family 22 member 3 SLC22A3 0.0273
737 Mineralocorticoid receptor NR3C2 0.0271
805 Cytochrome P450 11B1, mitochondrial CYP11B1 0.0266
1968 ATP-sensitive inward rectifier potassium channel 12 KCNJ12 0.0252
295 Carbonic anhydrase 1 CA1 0.0246
5463 Calcium-activated potassium channel subunit beta 2 KCNMB2 0.0241
6220 Aryl hydrocarbon receptor AHR 0.0239
466 Solute carrier family 12 member 3 SLC12A3 0.0222
6047 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A PDE1A 0.0219
3426 Glutamine synthetase glnA 0.0219
3987 Glutamine synthetase GLUL 0.0219
1108 Calpastatin CAST 0.0211
1089 Cartilage oligomeric matrix protein COMP 0.0211
462 Intermediate conductance calcium-activated potassium channel protein 4 KCNN4 0.0206
6142 Solute carrier family 22 member 8 SLC22A8 0.0205
1709 Canalicular multispecific organic anion transporter 2 ABCC3 0.0203
5692 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B PDE1B 0.0203
574 Branched-chain-amino-acid aminotransferase, cytosolic BCAT1 0.0199
806 Sodium/potassium-transporting ATPase alpha-1 chain ATP1A1 0.0194
16 Adenosine A1 receptor ADORA1 0.0189
766 Beta-2 adrenergic receptor ADRB2 0.0179
260 Cytochrome P450 51 ERG11 0.0168
761 Cytochrome P450 51 ERG11 0.0168
3163 Cytochrome P450 51 cyp51 0.0168
6046 Voltage-gated calcium channel beta 1 subunit splice variant CavB1d CACNB1 0.016
6182 Cytochrome P450 2J2 CYP2J2 0.0143
158 Sodium channel protein type 1 subunit alpha SCN1A 0.0142
392 Voltage-dependent P/Q-type calcium channel subunit alpha-1A CACNA1A 0.0135
357 Carbonic anhydrase 2 CA2 0.0133
7 Nitric oxide synthase, inducible NOS2 0.0131
817 DNA topoisomerase 2-alpha TOP2A 0.013
3811 Cytochrome P450 19A1 CYP19A1 0.0128
291 Nitric-oxide synthase, endothelial NOS3 0.0127
6023 Cytochrome P450 11B2, mitochondrial CYP11B2 0.0125
862 Multidrug resistance-associated protein 1 ABCC1 0.0124
3086 Plasmepsin-2 Not Available 0.012
492 Histamine H1 receptor HRH1 0.0119
587 Serum albumin ALB 0.0118
2132 Protein S100-B S100B 0.0117
3961 G protein-activated inward rectifier potassium channel 4 KCNJ5 0.0112
378 Alpha-2C adrenergic receptor ADRA2C 0.0109
629 Alpha-2B adrenergic receptor ADRA2B 0.0107
6148 Multidrug resistance-associated protein 7 ABCC10 0.0102
318 Alpha-2A adrenergic receptor ADRA2A 0.0095
241 Calcium-transporting ATPase type 2C member 1 ATP2C1 0.0095
6106 Cytochrome P450 2C18 CYP2C18 0.0093
521 ATP-binding cassette transporter sub-family C member 9 ABCC9 0.0089
51 Muscarinic acetylcholine receptor M3 CHRM3 0.0089
824 Sodium-dependent serotonin transporter SLC6A4 0.0085
2164 Multidrug resistance-associated protein 4 ABCC4 0.0084
132 ATP-binding cassette sub-family A member 1 ABCA1 0.0081
858 Potassium voltage-gated channel subfamily A member 1 KCNA1 0.0078
2184 Cystic fibrosis transmembrane conductance regulator CFTR 0.0075
1256 5-hydroxytryptamine 6 receptor HTR6 0.0063
274 Muscarinic acetylcholine receptor M5 CHRM5 0.0056
1374 Natriuretic peptides B NPPB 0.0056
1827 Gap junction alpha-1 protein GJA1 0.0056
1908 Vascular cell adhesion protein 1 VCAM1 0.0056
450 Muscarinic acetylcholine receptor M4 CHRM4 0.0055
94 5-hydroxytryptamine 4 receptor HTR4 0.0051
1632 Solute carrier organic anion transporter family member 2B1 SLCO2B1 0.0049
617 Muscarinic acetylcholine receptor M2 CHRM2 0.0048
6143 Solute carrier family 22 member 7 SLC22A7 0.0048
590 5-hydroxytryptamine 2C receptor HTR2C 0.0047
1974 Oligopeptide transporter, kidney isoform SLC15A2 0.0047
103 Muscarinic acetylcholine receptor M1 CHRM1 0.0046
194 NADH dehydrogenase [ubiquinone] 1 subunit C2 NDUFC2 0.0046
1539 Oligopeptide transporter, small intestine isoform SLC15A1 0.0045
3923 Cholinesterase BCHE 0.0045
638 D(3) dopamine receptor DRD3 0.0042
183 Vascular endothelial growth factor A VEGFA 0.0041
1729 Solute carrier family 22 member 6 SLC22A6 0.0039
341 5-hydroxytryptamine 3 receptor HTR3A 0.0038
23 D(1A) dopamine receptor DRD1 0.0037
3947 Xanthine dehydrogenase/oxidase XDH 0.0029
20 Prostaglandin G/H synthase 1 PTGS1 0.0022
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