NAV

Dofetilide

Identification

Summary

Dofetilide is a class III antiarrhythmic drug used for the maintenance of normal sinus rhythm and cardioversion in cases of atrial fibrillation and atrial flutter.

Brand Names
Tikosyn
Generic Name
Dofetilide
DrugBank Accession Number
DB00204
Background

Dofetilide is a class III antiarrhythmic agent that is approved by the Food and Drug Administration (FDA) for the maintenance of sinus rhythm in individuals prone to the formation of atrial fibrillation and flutter, and for the chemical cardioversion to sinus rhythm from atrial fibrillation and flutter.

Type
Small Molecule
Groups
Approved, Investigational
Structure
3D
Similar Structures
Weight
Average: 441.565
Monoisotopic: 441.139212369
Chemical Formula
C19H27N3O5S2
Synonyms
  • beta-((p-Methanesulfonamidophenethyl)methylamino)methanesulfono-p-phenetidide
  • Dofetilida
  • Dofetilide
  • Dofetilidum
External IDs
  • UK-68,798
  • UK-68798
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Pharmacology

Indication

For the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Maintenance ofNormal sinus rhythm••••••••••••••••••••••• •••••• •••••••
Maintenance ofNormal sinus rhythm•••••••••••••••••••••••• ••••••••• •••••• ••••••••••••
Management ofSymptomatic atrial fibrillation••••••••••••
Management ofSymptomatic atrial flutter••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Dofetilide is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties and is indicated for the maintenance of normal sinus rhythm. Dofetilide increases the monophasic action potential duration in a predictable, concentration-dependent manner, primarily due to delayed repolarization. At concentrations covering several orders of magnitude, Dofetilide blocks only IKr with no relevant block of the other repolarizing potassium currents (e.g., IKs, IK1). At clinically relevant concentrations, Dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors.

Mechanism of action

The mechanism of action of Dofetilide is a blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, IKr. This inhibition of potassium channels results in a prolongation of action potential duration and the effective refractory period of accessory pathways (both anterograde and retrograde conduction in the accessory pathway).

TargetActionsOrganism
APotassium voltage-gated channel subfamily H member 2
inhibitor
Humans
APotassium channel subfamily K member 2
inhibitor
Humans
AATP-sensitive inward rectifier potassium channel 12
inhibitor
Humans
Absorption

>90%

Volume of distribution
  • 3 L/kg
Protein binding

60% -70%

Metabolism

Hepatic

Route of elimination

Not Available

Half-life

10 hours

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
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interactions in your software
AbametapirThe serum concentration of Dofetilide can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Dofetilide can be increased when combined with Abatacept.
AcalabrutinibThe metabolism of Dofetilide can be decreased when combined with Acalabrutinib.
AcebutololDofetilide may increase the arrhythmogenic activities of Acebutolol.
AcetaminophenThe metabolism of Dofetilide can be increased when combined with Acetaminophen.
Food Interactions
  • Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of dofetilide.
  • Exercise caution with St. John's Wort. Dofetilide is partially metabolized by CYP3A4, and St. John's Wort is a CYP3A4 inducer, coadministration may reduce dofetilide serum levels.
  • Take with or without food.

Products

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Product Images
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DofetilideCapsule0.125 mg/1OralGreenstone LLC2016-05-012021-03-31US flag
DofetilideCapsule0.5 mg/1OralGreenstone LLC2016-05-012021-03-31US flag
DofetilideCapsule0.25 mg/1OralGreenstone LLC2016-05-012021-03-31US flag
TikosynCapsule0.125 mg/1OralPfizer Laboratories Div Pfizer Inc1999-10-01Not applicableUS flag
TikosynCapsule0.5 mg/1OralAvera McKennan Hospital2016-03-28Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DofetilideCapsule0.25 mg/1OralNorthstar RxLLC2023-02-07Not applicableUS flag
DofetilideCapsule0.125 mg/1OralAurobindo Pharma Limited2019-01-22Not applicableUS flag
DofetilideCapsule0.5 mg/1OralIngenus Pharmaceuticals, LLC2020-01-07Not applicableUS flag
DofetilideCapsule0.125 mg/1OralNorthStar Rx LLC2018-06-182024-03-31US flag
DofetilideCapsule0.5 mg/1OralBionpharma Inc.2018-04-11Not applicableUS flag

Categories

ATC Codes
C01BD04 — Dofetilide
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as sulfanilides. These are organic aromatic compounds containing a sulfanilide moiety, with the general structure RS(=O)(=O)NC1=CC=CC=C1.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Sulfanilides
Direct Parent
Sulfanilides
Alternative Parents
Phenethylamines / Phenoxy compounds / Phenol ethers / Aralkylamines / Alkyl aryl ethers / Organosulfonamides / Organic sulfonamides / Aminosulfonyl compounds / Trialkylamines / Organopnictogen compounds
show 2 more
Substituents
Alkyl aryl ether / Amine / Aminosulfonyl compound / Aralkylamine / Aromatic homomonocyclic compound / Ether / Hydrocarbon derivative / Organic nitrogen compound / Organic oxide / Organic oxygen compound
show 15 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
tertiary amino compound, aromatic ether, sulfonamide (CHEBI:4681)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
R4Z9X1N2ND
CAS number
115256-11-6
InChI Key
IXTMWRCNAAVVAI-UHFFFAOYSA-N
InChI
InChI=1S/C19H27N3O5S2/c1-22(13-12-16-4-6-17(7-5-16)20-28(2,23)24)14-15-27-19-10-8-18(9-11-19)21-29(3,25)26/h4-11,20-21H,12-15H2,1-3H3
IUPAC Name
N-[4-(2-{[2-(4-methanesulfonamidophenoxy)ethyl](methyl)amino}ethyl)phenyl]methanesulfonamide
SMILES
CN(CCOC1=CC=C(NS(C)(=O)=O)C=C1)CCC1=CC=C(NS(C)(=O)=O)C=C1

References

Synthesis Reference
US4959366
General References
  1. Lenz TL, Hilleman DE: Dofetilide, a new class III antiarrhythmic agent. Pharmacotherapy. 2000 Jul;20(7):776-86. [Article]
  2. Lenz TL, Hilleman DE: Dofetilide: A new antiarrhythmic agent approved for conversion and/or maintenance of atrial fibrillation/atrial flutter. Drugs Today (Barc). 2000 Nov;36(11):759-71. [Article]
  3. Torp-Pedersen C, Moller M, Bloch-Thomsen PE, Kober L, Sandoe E, Egstrup K, Agner E, Carlsen J, Videbaek J, Marchant B, Camm AJ: Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med. 1999 Sep 16;341(12):857-65. [Article]
Human Metabolome Database
HMDB0014349
KEGG Drug
D00647
KEGG Compound
C07751
PubChem Compound
71329
PubChem Substance
46509127
ChemSpider
64435
BindingDB
50031720
RxNav
49247
ChEBI
4681
ChEMBL
CHEMBL473
ZINC
ZINC000000596731
Therapeutic Targets Database
DAP000495
PharmGKB
PA449389
Guide to Pharmacology
GtP Drug Page
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Dofetilide
FDA label
Download (1.45 MB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
4CompletedNot AvailableParoxysmal Atrial Fibrillation (PAF)1
4WithdrawnTreatmentAtrial Fibrillation1
3SuspendedTreatmentAtrial Fibrillation1
3TerminatedTreatmentAtrial Fibrillation / Heart Failure1
1CompletedBasic ScienceDrug-induced QT Interval Prolongation / Pharmacodynamics / Pharmacokinetics1

Pharmacoeconomics

Manufacturers
  • Pfizer pharmaceuticals production corp ltd
Packagers
  • Pfizer Inc.
Dosage Forms
FormRouteStrength
CapsuleOral0.250 mg/1
CapsuleOral0.500 mg/1
CapsuleOral125 ug/1
CapsuleOral250 ug/1
CapsuleOral500 ug/1
CapsuleOral0.125 mg/1
CapsuleOral0.25 mg/1
CapsuleOral0.5 mg/1
Prices
Unit descriptionCostUnit
Tikosyn 250 mcg capsule3.64USD capsule
Tikosyn 125 mcg capsule3.63USD capsule
Tikosyn 500 mcg capsule3.61USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US4959366No1990-09-252012-09-25US flag
US6124363No2000-09-262018-10-09US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP2.1Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0198 mg/mLALOGPS
logP2.17ALOGPS
logP0.24Chemaxon
logS-4.4ALOGPS
pKa (Strongest Acidic)10.15Chemaxon
pKa (Strongest Basic)8.99Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area104.81 Å2Chemaxon
Rotatable Bond Count9Chemaxon
Refractivity113.27 m3·mol-1Chemaxon
Polarizability46.03 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9924
Blood Brain Barrier+0.9179
Caco-2 permeable-0.6257
P-glycoprotein substrateSubstrate0.6018
P-glycoprotein inhibitor IInhibitor0.6848
P-glycoprotein inhibitor IINon-inhibitor0.7391
Renal organic cation transporterNon-inhibitor0.7308
CYP450 2C9 substrateNon-substrate0.7572
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.6699
CYP450 1A2 substrateNon-inhibitor0.6359
CYP450 2C9 inhibitorNon-inhibitor0.5189
CYP450 2D6 inhibitorNon-inhibitor0.7709
CYP450 2C19 inhibitorInhibitor0.544
CYP450 3A4 inhibitorNon-inhibitor0.7715
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6823
Ames testNon AMES toxic0.6193
CarcinogenicityNon-carcinogens0.6038
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.5430 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.8119
hERG inhibition (predictor II)Inhibitor0.8258
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0bvl-4932000000-66e362c3fe81fb58fcc7
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0006-1610900000-368db21beef81a5319f4
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0006-0300900000-47394a7ed027cb5ab3cf
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-0030900000-03b7900eb964be6d0b22
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-002f-8000900000-dfdab03bc8946fd6ea7c
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-06r2-0983200000-253cae94a9d47c70455a
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-9020200000-cbfa3c4482d4d10a060b
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-11ba-0910000000-6e396253b8ea5d7623e0
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-9200300000-e9fa891327f30c89d57b
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-221.4559268
predicted
DarkChem Lite v0.1.0
[M-H]-228.8388268
predicted
DarkChem Lite v0.1.0
[M-H]-197.56929
predicted
DeepCCS 1.0 (2019)
[M+H]+221.5667268
predicted
DarkChem Lite v0.1.0
[M+H]+229.7354268
predicted
DarkChem Lite v0.1.0
[M+H]+199.92729
predicted
DeepCCS 1.0 (2019)
[M+Na]+221.1060268
predicted
DarkChem Lite v0.1.0
[M+Na]+228.8362268
predicted
DarkChem Lite v0.1.0
[M+Na]+206.44478
predicted
DeepCCS 1.0 (2019)

Targets

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Details1. Potassium voltage-gated channel subfamily H member 2
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function
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 ...
Gene Name
KCNH2
Uniprot ID
Q12809
Uniprot Name
Potassium voltage-gated channel subfamily H member 2
Molecular Weight
126653.52 Da
References
  1. Lees-Miller JP, Duan Y, Teng GQ, Duff HJ: Molecular determinant of high-affinity dofetilide binding to HERG1 expressed in Xenopus oocytes: involvement of S6 sites. Mol Pharmacol. 2000 Feb;57(2):367-74. [Article]
  2. Overholt JL, Ficker E, Yang T, Shams H, Bright GR, Prabhakar NR: HERG-Like potassium current regulates the resting membrane potential in glomus cells of the rabbit carotid body. J Neurophysiol. 2000 Mar;83(3):1150-7. [Article]
  3. Finlayson K, Pennington AJ, Kelly JS: [3H]dofetilide binding in SHSY5Y and HEK293 cells expressing a HERG-like K+ channel? Eur J Pharmacol. 2001 Feb 2;412(3):203-12. [Article]
  4. Finlayson K, Turnbull L, January CT, Sharkey J, Kelly JS: [3H]dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen. Eur J Pharmacol. 2001 Oct 26;430(1):147-8. [Article]
  5. Ficker E, Jarolimek W, Brown AM: Molecular determinants of inactivation and dofetilide block in ether a-go-go (EAG) channels and EAG-related K(+) channels. Mol Pharmacol. 2001 Dec;60(6):1343-8. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  7. Ficker E, Jarolimek W, Kiehn J, Baumann A, Brown AM: Molecular determinants of dofetilide block of HERG K+ channels. Circ Res. 1998 Feb 23;82(3):386-95. [Article]
  8. Kang J, Chen XL, Wang H, Ji J, Cheng H, Incardona J, Reynolds W, Viviani F, Tabart M, Rampe D: Discovery of a small molecule activator of the human ether-a-go-go-related gene (HERG) cardiac K+ channel. Mol Pharmacol. 2005 Mar;67(3):827-36. Epub 2004 Nov 17. [Article]
Details2. Potassium channel subfamily K member 2
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Potassium ion leak channel activity
Specific Function
Ion channel that contributes to passive transmembrane potassium transport (PubMed:23169818). Reversibly converts between a voltage-insensitive potassium leak channel and a voltage-dependent outward...
Gene Name
KCNK2
Uniprot ID
O95069
Uniprot Name
Potassium channel subfamily K member 2
Molecular Weight
47092.215 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
  3. Roukoz H, Saliba W: Dofetilide: a new class III antiarrhythmic agent. Expert Rev Cardiovasc Ther. 2007 Jan;5(1):9-19. [Article]
Details3. ATP-sensitive inward rectifier potassium channel 12
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Inward rectifier potassium channel activity
Specific Function
Inward rectifying potassium channel that is activated by phosphatidylinositol 4,5-bisphosphate and that probably participates in controlling the resting membrane potential in electrically excitable...
Gene Name
KCNJ12
Uniprot ID
Q14500
Uniprot Name
ATP-sensitive inward rectifier potassium channel 12
Molecular Weight
49000.6 Da
References
  1. Kiehn J, Wible B, Lacerda AE, Brown AM: Mapping the block of a cloned human inward rectifier potassium channel by dofetilide. Mol Pharmacol. 1996 Aug;50(2):380-7. [Article]

Enzymes

Details1. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Walker DK, Alabaster CT, Congrave GS, Hargreaves MB, Hyland R, Jones BC, Reed LJ, Smith DA: Significance of metabolism in the disposition and action of the antidysrhythmic drug, dofetilide. In vitro studies and correlation with in vivo data. Drug Metab Dispos. 1996 Apr;24(4):447-55. [Article]
  2. Yamreudeewong W, DeBisschop M, Martin LG, Lower DL: Potentially significant drug interactions of class III antiarrhythmic drugs. Drug Saf. 2003;26(6):421-38. doi: 10.2165/00002018-200326060-00004. [Article]

Transporters

Details1. Solute carrier family 22 member 2
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Quaternary ammonium group transmembrane transporter activity
Specific Function
Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creat...
Gene Name
SLC22A2
Uniprot ID
O15244
Uniprot Name
Solute carrier family 22 member 2
Molecular Weight
62579.99 Da
References
  1. Safety Data Sheet, Netupitant [Link]

Drug created at June 13, 2005 13:24 / Updated at January 02, 2024 23:43