PharmGKB: The Pharmacogenomics Knowledge Base

Drug/Small Molecule:
dofetilide

2D structure

Overview

Generic Names: Dofetilida [INN-Spanish]; Dofetilidum [INN-Latin]
IUPAC Name: N-[4-[2-[2-(4-methanesulfonamidophenyl)ethyl-methylamino]ethoxy]phenyl]methanesulfonamide
Trade Names: Dofetilida; Tikosyn
PharmGKB Accession Id: PA449389

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]

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

ATC Therapeutic Category

  • C01BD:Antiarrhythmics, class III

Pharmacology and Interactions

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).

Pharmacology

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.

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Hepatic

Protein Binding

60% -70%

Absorption

>90%

Half Life

10 hours

Chemical Properties

Chemical Formula:

C19H27N3O5S2

SMILES Code:

CN(CCc1ccc(cc1)NS(=O)(=O)C)CCOc2ccc(cc2)NS(=O)(=O)C

(Format: OpenEye Isomeric)

Molecular Weight ( average / monoisotopic )

441.565 / 441.1392

Curated Annotations (Curated Annotation)

  1. rs36210421 at chr7:150275361 in KCNH2
    Results of in vitro assays from this study suggest that the R1047L polymorphism leads to a functional impairment of the channel, which may contribute to the higher incidence of Torsades de Pointes in 1047L carriers when challenged with a channel blocker.
    Variant Name:
    KCNH2: R1047L
    Related Drugs:
    dofetilide
    Related Diseases:
    Torsades de Pointes
    Evidence:
    PMID:15522280
Variant names are different names that have been used in the literature and other resources to refer to the same variant.

Curated Information

The following genes are in curated knowledge about this drug.

  Gene Relationship Evidence
No phenotype data Genotype Data Available Literature annotations available Not annotated
ABCC8
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  • PD
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Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
ABCC9
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  • PD
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Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
ADRA1D
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  • PD
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Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
ADRA2A
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  • PD
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Pathways
Phenotype data available Genotype Data Available Literature annotations available Has annotations
ADRB1
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  • PD
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Pathways
Phenotype data available Genotype Data Available Literature annotations available Has annotations
ADRB2
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  • PD
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Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
ANK2
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  • PD
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Pathways
Phenotype data available No genotype data Literature annotations available Not annotated
ATP1A1
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
ATP2A1
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
ATP2A2
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
CACNA1C
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  • PD
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Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
CACNA1D
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
CACNA1G
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  • PD
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Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
CACNA1H
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  • PD
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Pathways
No phenotype data No genotype data No literature annotations Not annotated
CACNB2
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
CASQ1
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
CASQ2
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  • PD
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Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
CHRM2
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
DSP
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
FKBP1B
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
GJA1
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
GJA5
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
GJD3
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
HCN2
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
HCN4
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  • PD
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Pathways
Phenotype data available No genotype data Literature annotations available Not annotated
JUP
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  • PD
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Pathways
Phenotype data available Genotype Data Available Literature annotations available Not annotated
KCNA5
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
KCNAB2
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  • PD
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Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
KCND3
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  • PD
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Pathways
Phenotype data available Genotype Data Available Literature annotations available Not annotated
KCNE1
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  • PD
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Pathways
No phenotype data Genotype Data Available No literature annotations Not annotated
KCNE1L
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  • PD
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Pathways
Phenotype data available Genotype Data Available Literature annotations available Not annotated
KCNE2
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  • PD
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Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
KCNE3
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  • PD
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Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
KCNE4
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  • PD
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Pathways
Phenotype data available Genotype Data Available Literature annotations available Has annotations
KCNH2
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  • PD
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  • FA
  • GN
Publications, Pathways, Variants
No phenotype data No genotype data Literature annotations available Not annotated
KCNIP2
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  • PD
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Pathways
No phenotype data Genotype Data Available Literature annotations available Has annotations
KCNJ11
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
KCNJ2
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
KCNJ3
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
KCNJ4
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
KCNJ5
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
KCNJ8
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
KCNK1
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
KCNK3
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  • PD
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Pathways
Phenotype data available Genotype Data Available Literature annotations available Not annotated
KCNQ1
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
LMNA
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
PLN
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
RYR2
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  • PD
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Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
SCN1B
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  • PD
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Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
SCN2B
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  • PD
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Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
SCN3B
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
SCN4B
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  • PD
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Pathways
Phenotype data available Genotype Data Available Literature annotations available Has annotations
SCN5A
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  • PD
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Pathways
No phenotype data No genotype data Literature annotations available Not annotated
SLC8A2
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  • PD
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Pathways
No phenotype data No genotype data No literature annotations Not annotated
SLC8A3
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  • PD
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Pathways

Non-Curated Information

A list of non-curated publications that mention this drug along with other genes is available.

Metabolizing Enzymes

Drug Targets

PharmGKB Curated Pathways

Non-Curated Information

A list of non-curated publications that mention this drug along with other drugs is available.

Curated Information

The following diseases are in curated knowledge about this drug.

  Disease Relationship Evidence
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Torsades de Pointes
  •   
  •   
  •   
  • FA
  • GN
Publications, Variants

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

Curated Phenotype Datasets

These datasets are sorted alphabetically by title.

  1. A modulator of HERG Potassium Channel block
    • Genotype data available
    • Phenotype data available
    • No literature annotations
    • Not annotated
    • FA
    Submitted by Dan Roden, MD involving ALG10, KCNH2, dofetilide, qt-prolonging drugs, and Torsades de Pointes
  2. Drug-Induced Long QT Intervals
    • Genotype data available
    • Phenotype data available
    • No literature annotations
    • Not annotated
    • PD
    Submitted by Dan Roden, MD involving ADRB1, ADRB2, KCNE1, KCNE2, KCNH2, KCNQ1, SCN5A, almokalant, amiodarone, amitriptyline, bretylium, bupivacaine, cisapride, disopyramide, dofetilide, encainide, fluconazole, haloperidol, hydroquinidine, isoflurane, itraconazole, ketoconazole, lithium, loratadine, metoclopramide, nortriptyline, procainamide, quinidine, sematilide, sotalol, sulfamethoxazole, thioridazine, trimethoprim, , Long QT Syndrome, Proarrhythmia and Torsades de Pointes

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

  1. Genetic Associations in Drug-induced QT Prolongation and Torsades
  2. Physicochemical determinants of human renal clearance

Downloads

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LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB00204
KEGG Compound ID:
C07751
KEGG Drug ID:
D00647
PubChem Compound ID:
71329
PubChem Substance ID:
213557

Common Searches

Search PubMed
Search Medline Plus
Search PubChem
Search CTD

Non-Curated Publications

A list of non-curated publications that mention this drug is available.

PharmGKB integrates drug information from different sources: DrugBank, Open Eye Scientific Software.
The PharmGKB is financially supported by the NIH/ NIGMS and is managed at Stanford University (U01GM61374).
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