QuickView for Dofetilide (compound)

Summary
General Info

PubChem

PubChem Compound 71329

Name:	dofetilide
PubChem Compound ID:	71329
Molecular formula:	C₁₉H₂₇N₃O₅S₂
Molecular weight:	441.567 g/mol
Synonyms:	Dofetilide [USAN:BAN:INN]; beta-((p-Methanesulfonamidophenethyl)methylamino)methanesulfono-p-phenetidide; Tikosyn (TN); 115256-11-6; Dofetilida [INN-Spanish]; Xelide; UK-68798; Dofetilide (JAN/USAN); Dofetilidum [INN-Latin]; D00647. show more » Dofetilide [USAN:BAN:INN]; beta-((p-Methanesulfonamidophenethyl)methylamino)methanesulfono-p-phenetidide; Tikosyn (TN); 115256-11-6; Dofetilida [INN-Spanish]; Xelide; UK-68798; Dofetilide (JAN/USAN); Dofetilidum [INN-Latin]; D00647; LS-90151; Dofetilidum; Dofetilide; C07751; Dofetilida; Methanesulfonamide, N-(4-(2-(methyl(2-(4-((methylsulfonyl)amino)phenoxy)ethyl)amino)ethyl)phenyl)-; UK 68,798; Tikosyn show less «

DrugBank

Identification

Name:	dofetilide
Name (isomeric):	DB00204
Drug Type:	small molecule
Synonyms:	Dofetilida [INN-Spanish]; Dofetilidum [INN-Latin]
Brand:	Dofetilida, Tikosyn
Category:	Potassium Channel Blockers, Antiarrhythmic Agents, Anti-Arrhythmia Agents
CAS number:	115256-11-6

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
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... show more » 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. show less «
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 conductio... show more » 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). show less «
Absorption:	>90%
Protein binding:	60% -70%
Biotransformation:	Hepatic
Half Life:	10 hours
Affected organisms:	Humans and other mammals

Interactions

Drug interaction:

Erythromycin	Increased risk of cardiotoxicity and arrhythmias
Telithromycin	Increased risk of cardiotoxicity and arrhythmias
Verapamil	Verapamil may increase the plamsa levels of Dofetilide. Increased risk of torsade de pointes. Concomitant therapy is contraindicated.
Cimetidine	Increases effect/toxicity of dofetilide
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).

Erythromycin	Increased risk of cardiotoxicity and arrhythmias
Telithromycin	Increased risk of cardiotoxicity and arrhythmias
Verapamil	Verapamil may increase the plamsa levels of Dofetilide. Increased risk of torsade de pointes. Concomitant therapy is contraindicated.
Cimetidine	Increases effect/toxicity of dofetilide
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).
Trimethoprim	Trimethoprim 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.
Voriconazole	Voriconazole may increase the serum concentration of dofetilide by decreasing its metabolism. Concomitant therapy is contraindicated.
Bendroflumethiazide	Increased risk of cardiotoxicity and arrhythmias
Ranolazine	Possible additive effect on QT prolongation
Itraconazole	This strong CYP3A4 inhibitor increases the effect and toxicity of dofetilide
Mesoridazine	Increased risk of cardiotoxicity and arrhythmias
Chlorthalidone	Increased risk of cardiotoxicity and arrythmias
Clarithromycin	Increased risk of cardiotoxicity and arrhythmias
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.
Metolazone	Increased risk of cardiotoxicity and arrhythmias
Thioridazine	Increased risk of cardiotoxicity and arrhythmias
Vorinostat	Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Hydrochlorothiazide	Increased risk of cardiotoxicity and arrhythmias
Trichlormethiazide	Trichlormethiazide may increase Dofetilide serum concentrations and increase the QTc-prolonging effect of Dofetilide. Increased risk of ventricular arrhythmias.
Ziprasidone	Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
Quinupristin	This combination presents an increased risk of toxicity
Artemether	Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Tacrolimus	Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Chlorothiazide	Thiazide 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.
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.
Ketoconazole	This strong CYP3A4 inhibitor increases the effect and toxicity of dofetilide
Trimipramine	Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Indapamide	Increased risk of cardiotoxicity and arrhythmias

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Targets

Potassium voltage-gated channel subfamily H member 2

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

UniProt ID:

Q12809

Gene:

KCNH2

Actions:

inhibitor

References:

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.
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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.
View Article

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.
View Article

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.
View Article

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

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.
View Article

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.
View Article

Potassium channel subfamily K member 2

ATP-sensitive inward rectifier potassium channel 12

Enzymes

Cytochrome P450 3A4