You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
Identification
NameDofetilide
Accession NumberDB00204  (APRD00367)
Typesmall molecule
Groupsapproved
Description

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. [Wikipedia]

Structure
Thumb
Synonyms
SynonymLanguageCode
DofetilidaSpanishINN
DofetilidumLatinINN
SaltsNot Available
Brand names
NameCompany
TikosynNot Available
Brand mixturesNot Available
Categories
CAS number115256-11-6
WeightAverage: 441.565
Monoisotopic: 441.139212369
Chemical FormulaC19H27N3O5S2
InChI KeyIXTMWRCNAAVVAI-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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassSulfanilides
Direct parentSulfanilides
Alternative parentsPhenethylamines; Phenol Ethers; Alkyl Aryl Ethers; Sulfonyls; Sulfonamides; Tertiary Amines; Polyamines
Substituentsphenol ether; alkyl aryl ether; sulfonyl; sulfonamide; sulfonic acid derivative; tertiary amine; polyamine; ether; amine; organonitrogen compound
Classification descriptionThis compound belongs to the sulfanilides. These are organic aromatic compounds containing a sulfanilide moiety, with the general structure RS(=O)(=O)NC1=CC=CC=C1.
Pharmacology
IndicationFor 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
PharmacodynamicsDofetilide 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 actionThe 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).
Absorption>90%
Volume of distribution
  • 3 L/kg
Protein binding60% -70%
Metabolism

Hepatic

Route of eliminationNot Available
Half life10 hours
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9924
Blood Brain Barrier + 0.9179
Caco-2 permeable - 0.6257
P-glycoprotein substrate Substrate 0.6018
P-glycoprotein inhibitor I Inhibitor 0.6848
P-glycoprotein inhibitor II Non-inhibitor 0.7391
Renal organic cation transporter Non-inhibitor 0.7308
CYP450 2C9 substrate Non-substrate 0.7572
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.6699
CYP450 1A2 substrate Non-inhibitor 0.6359
CYP450 2C9 substrate Non-inhibitor 0.5189
CYP450 2D6 substrate Non-inhibitor 0.7709
CYP450 2C19 substrate Inhibitor 0.544
CYP450 3A4 substrate Non-inhibitor 0.7715
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6823
Ames test Non AMES toxic 0.6193
Carcinogenicity Non-carcinogens 0.6038
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.5430 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Strong inhibitor 0.8119
hERG inhibition (predictor II) Inhibitor 0.8258
Pharmacoeconomics
Manufacturers
  • Pfizer pharmaceuticals production corp ltd
Packagers
Dosage forms
FormRouteStrength
CapsuleOral
Prices
Unit descriptionCostUnit
Tikosyn 250 mcg capsule3.64USDcapsule
Tikosyn 125 mcg capsule3.63USDcapsule
Tikosyn 500 mcg capsule3.61USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States61243631998-10-092018-10-09
United States49593661992-09-252012-09-25
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP2.1Not Available
Predicted Properties
PropertyValueSource
water solubility1.98e-02 g/lALOGPS
logP2.17ALOGPS
logP0.24ChemAxon
logS-4.3ALOGPS
pKa (strongest acidic)10.15ChemAxon
pKa (strongest basic)8.99ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count6ChemAxon
hydrogen donor count2ChemAxon
polar surface area104.81ChemAxon
rotatable bond count9ChemAxon
refractivity113.27ChemAxon
polarizability46.03ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

DrugSyn.org

US4959366
General Reference
  1. Lenz TL, Hilleman DE: Dofetilide, a new class III antiarrhythmic agent. Pharmacotherapy. 2000 Jul;20(7):776-86. Pubmed
  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. Pubmed
  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. Pubmed
External Links
ResourceLink
KEGG DrugD00647
KEGG CompoundC07751
PubChem Compound71329
PubChem Substance46509127
ChemSpider64435
ChEBI4681
ChEMBLCHEMBL473
Therapeutic Targets DatabaseDAP000495
PharmGKBPA449389
IUPHAR2604
Guide to Pharmacology2604
RxListhttp://www.rxlist.com/cgi/generic2/dofetilide.htm
Drugs.comhttp://www.drugs.com/cdi/dofetilide.html
WikipediaDofetilide
ATC CodesC01BD04
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(1.45 MB)
MSDSNot Available
Interactions
Drug Interactions
Drug
ArtemetherAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
BendroflumethiazideIncreased risk of cardiotoxicity and arrhythmias
ChlorothiazideThiazide diuretics such as chlorothiazide may enhance the QTc-prolonging effect of dofetilide. Thiazide diuretics may increase the serum concentration of dofetilide. The concomitant use of hydrochlorothiazide and dofetilide is contraindicated by the manufacturer of dofetilide. Monitor for increased risk of QTc-prolongation and associated ventricular arrythmias during concomitant use of dofetilide and thiazide diuretics.
ChlorthalidoneIncreased risk of cardiotoxicity and arrythmias
CimetidineIncreases effect/toxicity of dofetilide
ClarithromycinIncreased risk of cardiotoxicity and arrhythmias
ErythromycinIncreased risk of cardiotoxicity and arrhythmias
FingolimodPharmacodynamic synergist. Contraindicated. Increased risk of bradycardia, AV block, and torsade de pointes.
HydrochlorothiazideIncreased risk of cardiotoxicity and arrhythmias
IndapamideIncreased risk of cardiotoxicity and arrhythmias
ItraconazoleThis strong CYP3A4 inhibitor increases the effect and toxicity of dofetilide
KetoconazoleThis strong CYP3A4 inhibitor increases the effect and toxicity of dofetilide
MesoridazineIncreased risk of cardiotoxicity and arrhythmias
MetolazoneIncreased risk of cardiotoxicity and arrhythmias
QuinupristinThis combination presents an increased risk of toxicity
RanolazinePossible additive effect on QT prolongation
TacrolimusAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
TelithromycinIncreased risk of cardiotoxicity and arrhythmias
ThioridazineIncreased risk of cardiotoxicity and arrhythmias
ThiothixeneMay cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
ToremifeneAdditive 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.
TrichlormethiazideTrichlormethiazide may increase Dofetilide serum concentrations and increase the QTc-prolonging effect of Dofetilide. Increased risk of ventricular arrhythmias.
TrimethoprimTrimethoprim may significantly reduced the clearance of Dofetilide. Trimethoprim is a cation transport inhibitor and may interfere with renal excretion of Dofetilide. Concomitant use is contraindicated.
TrimipramineAdditive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
VerapamilVerapamil may increase the plamsa levels of Dofetilide. Increased risk of torsade de pointes. Concomitant therapy is contraindicated.
VoriconazoleVoriconazole may increase the serum concentration of dofetilide by decreasing its metabolism. Concomitant therapy is contraindicated.
VorinostatAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
ZiprasidoneAdditive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
ZuclopenthixolAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Zuclopenthixol acetateAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Zuclopenthixol decanoateAdditive 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 InteractionsNot Available

Targets

1. Potassium voltage-gated channel subfamily H member 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Potassium voltage-gated channel subfamily H member 2 Q12809 Details

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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  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. Pubmed
  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. Pubmed

2. Potassium channel subfamily K member 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Potassium channel subfamily K member 2 O95069 Details

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. Pubmed
  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. Pubmed
  3. Roukoz H, Saliba W: Dofetilide: a new class III antiarrhythmic agent. Expert Rev Cardiovasc Ther. 2007 Jan;5(1):9-19. Pubmed

3. ATP-sensitive inward rectifier potassium channel 12

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
ATP-sensitive inward rectifier potassium channel 12 Q14500 Details

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. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

Comments
comments powered by Disqus
Drug created on June 13, 2005 07:24 / Updated on October 08, 2013 14:23