Rapidly activating delayed rectifier K+ current (IKr, encoded by HERG gene) [1][2]

In vitro activity: Dofetilide blocks HERG currents in excised macro patches of Xenopus oocytes. Dofetilide (1 μM) reduces the amplitude of IKr to 61% of control currents in guinea pig cardiomyocytes, as measured by 200-ms test pulses and analysis of the deactivating tail currents of IKr. Dofetilide increases apico-basal disparity of repolarization, due to a more marked increase of ERPs in the apex than in the base in the intact canine heart.

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In isolated guinea pig, canine, and human ventricular myocytes, Dofetilide (UK 68789) (0.01-1 μM) potently and selectively blocks IKr in a concentration-dependent manner. At 0.1 μM, it inhibits IKr by 75% without affecting other potassium currents (e.g., IKs, IK1) or L-type calcium currents. The drug prolongs action potential duration (APD90) by 40-60% at therapeutic concentrations, with no significant effect on the maximum rate of depolarization (Vmax)[1]
- In HERG-expressing Xenopus oocytes and HEK293 cells, Dofetilide (UK 68789) (0.001-0.1 μM) dose-dependently suppresses IKr tail currents. The blocking effect is voltage-dependent, with higher affinity for the activated/inactivated states of the channel compared to the resting state[1]

Dofetilide (3~100 μg/kg; iv) selectively lengthens the activation-repolarization delay while maintaining an unchanged activation time, which lengthens the repolarization time [2]. The kidneys discharge a variety of inactive polar metabolites that are produced when CYP3A4 metabolizes dofetilide [1].

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In anesthetized dogs with pacing-induced atrial fibrillation (AF), intravenous administration of Dofetilide (UK 68789) (1-10 μg/kg) dose-dependently converts AF to sinus rhythm. The 5 μg/kg dose achieves a 70% conversion rate within 30 minutes. Electrocardiographic analysis shows a dose-dependent prolongation of QT interval (15-30% increase at therapeutic doses) without altering heart rate significantly[1]
- In conscious rabbits subjected to ventricular pacing, Dofetilide (UK 68789) (0.3 mg/kg, oral) reduces pacing-induced heterogeneity of repolarization. It decreases the spatial dispersion of QT interval by 45% and suppresses the occurrence of early afterdepolarizations (EADs), a major trigger for torsades de pointes (TdP)[2]

IKr channel activity assay: HERG-expressing Xenopus oocytes or HEK293 cells are seeded on glass coverslips and cultured for 24-48 hours. Whole-cell patch-clamp recordings are performed to measure IKr tail currents. Dofetilide (UK 68789) is applied to the extracellular solution at gradient concentrations (0.001-1 μM). The voltage protocol includes a holding potential of -80 mV, depolarizing steps to +40 mV (500 ms) to activate IKr, followed by repolarization to -50 mV to record tail currents. Peak tail current amplitude is normalized to the control to calculate the blocking rate[1]

Ventricular myocyte electrophysiology assay: Ventricular myocytes are isolated from guinea pigs, dogs, or humans via enzymatic dissociation and plated on glass coverslips. Dofetilide (UK 68789) (0.01-1 μM) is added to the recording chamber. Whole-cell patch-clamp recordings are conducted to measure IKr, other potassium currents, and L-type calcium currents. Action potentials are recorded using intracellular microelectrodes to quantify APD90 and Vmax[1]

Animal/Disease Models: Adult beagle dogs (13-15 kg)[2]
Doses: 3~100 μg/kg
Route of Administration: Iv
Experimental Results: Increased repolarisation time via a selective prolongation of activation repolarisation interval, activation time being unchanged.

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Pacing-induced AF dog model: Adult mongrel dogs (15-20 kg) are anesthetized, and atrial pacing electrodes are implanted to induce sustained AF (pacing frequency 400 beats/min for 2 hours). Dofetilide (UK 68789) is dissolved in normal saline and administered intravenously at 1 μg/kg, 5 μg/kg, or 10 μg/kg. Cardiac rhythm is monitored via electrocardiography for 60 minutes to assess AF conversion rate and QT interval changes[1]
- Pacing-induced repolarization heterogeneity rabbit model: Conscious New Zealand White rabbits (2-3 kg) are implanted with ventricular pacing electrodes and paced at 300 beats/min for 7 days. Dofetilide (UK 68789) is suspended in 0.5% carboxymethylcellulose sodium (CMC-Na) and administered orally at 0.3 mg/kg. QT interval dispersion is measured via surface electrocardiography before and 2 hours after drug administration, and EAD incidence is evaluated by intracardiac recordings[2]

Absorption, Distribution and Excretion
90% 3 L/kg After a single dose of dofetride, approximately 80% is excreted in the urine, of which approximately 80% is excreted unchanged, and the remaining 20% is excreted as inactive or very inactive metabolites. Renal clearance includes glomerular filtration and active tubular secretion (via cation transport systems, a process that can be inhibited by cimetidine, trimethoprim, prochlorperazine, medroxyprogesterone acetate, and ketoconazole). … The oral bioavailability of dofetride is >90%, reaching peak plasma concentrations in approximately 2–3 hours on an empty stomach. Food or antacids do not affect oral bioavailability. The terminal half-life of Tikosyn is approximately 10 hours; dofetride reaches steady-state plasma concentrations within 2–3 days, with a cumulative index of 1.5 to 2.0. Plasma concentrations are dose-dependent. Dofetride has a plasma protein binding rate of 60-70%, independent of plasma concentration and unaffected by renal impairment. Its volume of distribution is 3 L/kg. 1. Pharmacokinetics of dofetride were studied in humans, dogs, rats, and mice after single intravenous and oral administration of either dofetride or ¹⁴C-dofetride, respectively. 2. Dofetride was completely absorbed in all animals. Human metabolic clearance was low, with 100% bioavailability after oral administration. Higher metabolic clearance was observed in rodents (and less severely affected dogs), resulting in reduced bioavailability due to first-pass metabolism. 3. Following intravenous administration, the volume of distribution in all animals showed only moderate fluctuations (2.8-6.3 L/kg). High plasma clearance in rodents results in a short half-life (0.32 hours in mice, 0.5 hours in male rats, and 1.2 hours in female rats), while low plasma clearance in dogs and humans results in long terminal elimination half-lives (4.6 hours and 7.6 hours, respectively). 4. Following a single intravenous injection of (14)C-dofetride, the parent compound was the main component excreted in the urine of all species, along with various metabolites. 5. The metabolites identified in the urine of all species were formed by N-oxidation or N-dealkylation of the tertiary nitrogen atom of dofetride. 6. Following oral and intravenous injection of (14)C-dofetride, the only detectable component in the plasma was the parent compound, accounting for 75% of plasma radioactivity. No single metabolite accounted for more than 5% of plasma radioactivity.

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Metabolism/Metabolites
Hepatic
Dofetride is a class III antiarrhythmic drug that is cleared by the kidneys and metabolism. In vitro metabolic characterization helps explain species differences, while identifying human enzymes involved in metabolism aids in assessing potential drug interactions. In liver microsomes, the oxidative metabolic rate of dofetride followed the order: male rats > female rats > dogs > humans, consistent with the metabolic clearance observed in vivo. The in vitro oxidative metabolites (formed by N-dealkylation) were identical to those formed in vivo, with the N-demethylated product being the major product. This metabolic pathway of dofetride is mediated by cytochrome P450 (CYP). In humans, the KM value of N-demethylation is as high as 657 ± 116 μM, indicating a low affinity for the enzyme's active site. In various human liver microsomal formulations, this metabolic rate was positively correlated with CYP3A4 activity (r = 0.903). No correlation was found with other isoenzyme activities. Specific isoenzyme inhibitors also indicate CYP3A4 involvement; ketoconazole and trarotrine partially inhibit CYP3A4 metabolism, while the activator α-naphthylflavonoid increases CYP3A4 turnover. No inhibitory effects were observed with specific inhibitors of other isoenzymes or competitive substrates. In vitro studies showed that dofetilide at concentrations up to 100 μM had no significant inhibitory effect on CYP2C9, CYP2D6, or CYP3A4. Conversely, amiodarone (IC50, 25 μM) and flecainide (49 μM) inhibited CYP2C9, and quinidine (0.26 μM) and flecainide (0.44 μM) inhibited CYP2D6. Many antiarrhythmic drugs have active circulating metabolites, which complicates the dose-response relationship. In vitro pharmacological studies can assess the potential contribution of metabolites to pharmacological characterization. The potency of dofetride and its metabolites has been compared against class III (K+ channel blockade) and class I (Na+ channel blockade) antiarrhythmic activities. Three metabolites of dofetride exhibit class III activity, but at concentrations at least 20 times higher than dofetride. Dofetride N-oxide exhibits class I activity, but only at high concentrations. None of the metabolites affect the resting membrane potential or action potential amplitude. Dofetride lacks biological activity, consistent with the close correlation between plasma dofetride concentration and pharmacological response. After a single dose of dofetride, approximately 80% is excreted in the urine, of which approximately 80% is excreted unchanged, and the remaining 20% is excreted as inactive or very inactive metabolites. …In vitro human liver microsomal studies have shown that dofetride can be metabolized by CYP3A4, but has a low affinity for this isoenzyme. Metabolites are mainly formed through N-dealkylation and N-oxidation. No quantifiable metabolites were found in plasma, but five metabolites were identified in urine.

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Biological half-life
10 hours
After intravenous injection, ... high plasma clearance in rodents resulted in a short half-life (0.32 hours in mice, 0.5 hours in male rats, and 1.2 hours in female rats), while low plasma clearance in dogs and humans resulted in longer terminal elimination half-lives (4.6 hours and 7.6 hours, respectively). ...
The terminal half-life of Tikosyn is about 10 hours

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Absorption:Dofetilide (UK 68789) has an oral bioavailability of about 90% in humans and is rapidly absorbed (reaching peak plasma concentration within 2-3 hours)[1]
-Distribution: The volume of distribution of this drug in the human body is 3-4 L/kg, and it is widely distributed in myocardial tissue[1]
-Metabolism: Very little is metabolized by the liver; about 80% of the drug is excreted unchanged[1]
-Excretion: The main route of excretion is the kidneys (70-80% is excreted in urine), and a small amount is excreted in feces[1]
-Half-life: After oral administration, the elimination half-life in the human body is 10-15 hours[1]

Hepatotoxicity
In clinical trials, elevations in serum transaminases and alkaline phosphatase were not more common during dofetilide treatment than in placebo treatment. 15% of patients in the dofetilide group reported varying degrees of ALT elevation, a similar proportion in the placebo group; specifically, 1.5% of patients in the dofetilide group had ALT elevations exceeding three times the upper limit of normal, compared to 2.0% in the placebo group. Therefore, the background incidence of elevated serum ALT appears to be higher in atrial fibrillation patients eligible for dofetilide treatment. Nevertheless, dofetilide has not been associated with cases of significant liver injury presenting with clinical symptoms or jaundice. The dofetilide product label does not mention hepatotoxicity, nor does it explicitly recommend monitoring liver function. Probability Score: E (Unlikely to cause clinically significant liver injury). Protein Binding 60% -70% Interactions
Contraindicated with verapamil. Concomitant use of Tikosyn with verapamil resulted in a 42% increase in peak dofetilide plasma concentrations, but did not significantly increase overall dofetilide exposure. In analyses of patients with supraventricular arrhythmias and the Danish Dofetilide Arrhythmia and Mortality Study (DIAMOND), concomitant use of verapamil with dofetilide was associated with a higher incidence of torsades de pointes.
Concomitant use with cimetidine is contraindicated. Cimetidine 400 mg twice daily (usual prescription dose), combined with teicoplanin (500 mcg twice daily) for 7 days, increased dofetilide plasma concentrations by 58%. Cimetidine 100 mg twice daily (over-the-counter dose) increased dofetilide plasma concentrations by 13% (single dose 500 mcg). There are currently no studies on moderate doses of cimetidine. If a patient needs to take tekosyn and receive anti-ulcer treatment, it is recommended to use omeprazole, ranitidine, or antacids (aluminum hydroxide and magnesium hydroxide) instead of cimetidine, as these drugs do not affect the pharmacokinetic characteristics of tekosyn. The combined use of tekosyn with other QT-prolonging drugs has not been studied and is therefore not recommended. These drugs include phenothiazines, cisapride, benzprodil, tricyclic antidepressants, certain oral macrolide antibiotics, and certain fluoroquinolone antibiotics. At least three half-lives of a class I or III antiarrhythmic drug should be discontinued before taking Tikosyn. In clinical trials, Tikosyn was only used in patients who had previously received oral amiodarone treatment if their serum amiodarone level was below 0.3 mg/L or if they had discontinued amiodarone for at least three months. The use of potassium-depleting diuretics may lead to hypokalemia or hypomagnesemia, thereby increasing the risk of torsades de pointes. Before taking Tikosyn, serum potassium levels should be within the normal range and should be maintained within the normal range during Tikosyn treatment. For more complete (15) interaction data on dofetilide, please visit the HSDB records page.

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Plasma protein binding rate: Dofelith (UK 68789) has a low plasma protein binding rate in humans (60-70%) [1]
- Cardiovascular toxicity: Therapeutic doses can prolong the QT interval and increase the risk of torsades de pointes (TdP), especially in patients with renal insufficiency, hypokalemia, or hypomagnesemia [1]
- Nephrotoxicity: Renal excretion is the primary route of excretion, so dose adjustment is necessary in patients with reduced creatinine clearance [1]
- Drug interactions: Inhibitors of renal cation transporters (e.g., cimetidine, trimethoprim) can increase the risk of torsades de pointes (TdP) by reducing plasma concentrations of dofelith through decreased renal excretion [1]
- Other side effects: Common adverse reactions include headache, dizziness, and nausea; [1]

[1]. Cardiovascular drugs. Dofetilide. Circulation. 2000;102(21):2665-2670.

[2]. Dofetilide, a new class III antiarrhythmic agent, reduces pacing induced heterogeneity of repolarisation in vivo. Cardiovasc Res. 1992;26(11):1102-1108.

Therapeutic Uses

Antiarrhythmic drug, potassium channel blocker
Tikosyn is indicated for the conversion of atrial fibrillation and atrial flutter to a normal sinus rhythm. /US product label includes/
Tikosyn is indicated for the maintenance of a normal sinus rhythm in patients with atrial fibrillation/atrial flutter lasting more than one week and who have converted to a normal sinus rhythm (delaying recurrence of atrial fibrillation/atrial flutter). Because Tikosyn may cause life-threatening ventricular arrhythmias, it should only be used in patients with significant atrial fibrillation/atrial flutter symptoms. /US product label includes/
Drug Warnings
/Black Box Warning/ To minimize the risk of inducing arrhythmias, patients starting or restarting Tikosyn should be observed for at least 3 days in a facility capable of calculating creatinine clearance, continuous ECG monitoring, and cardiac resuscitation… Tikosyn is for use only in hospitals and by prescribing physicians who have received appropriate Tikosyn dosage and treatment initiation training. Tikosyn (dofetilide) can cause serious ventricular arrhythmias, primarily torsades de pointes (TdP), a polymorphic ventricular tachycardia associated with QT interval prolongation. QT interval prolongation is directly related to dofetilide plasma concentrations. Factors such as decreased creatinine clearance or certain dofetilide drug interactions can increase dofetilide plasma concentrations. The risk of torsades de pointes (TdP) can be reduced by adjusting the initial dofetilide dose according to creatinine clearance and monitoring for excessive QT interval prolongation on ECG. Therefore, dofetilide treatment must be administered in a facility capable of providing ECG monitoring for at least three days in the presence of personnel trained in the management of serious ventricular arrhythmias. Creatinine clearance must be calculated in all patients before their first dose of dofetilide. For patients with mild to moderate renal failure, the dose should be reduced based on creatinine clearance to minimize the risk of torsades de pointes. This drug should not be used in patients with advanced renal failure or those taking renal cation transport inhibitors. In clinical trials, with strict exclusion criteria (e.g., hypokalemia) and continuous ECG monitoring during hospitalization to detect significant QT prolongation, torsades de pointes occurred in 1–3% of patients. The incidence of this drug in more widespread use since its market launch in 2000 is unknown. In premarketing clinical trials, the incidence of other adverse events was not significantly different from the placebo group. For more complete data on drug warnings for dofetilide (16 in total), please visit the HSDB record page.

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Pharmacodynamics
Dofetilide is a class III (prolonged myocardial action potential duration) antiarrhythmic drug indicated for maintaining normal sinus rhythm.
Dofetilide prolongs the duration of monophasic action potentials in a predictable concentration-dependent manner, primarily due to repolarization delay. Across concentrations spanning several orders of magnitude, dofetilide blocks only IKr, without any associated blocking effect on other repolarizing potassium currents (e.g., IKs, IK1). At clinically relevant concentrations, dofetilide has no effect on sodium channels (associated with class I effects), adrenergic α-receptors, or adrenergic β-receptors.

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Dofelith (UK Medicines Code: 68789) is a potent, selective Class III antiarrhythmic drug[1][2]
- Clinical indications include converting atrial fibrillation/atrial flutter to sinus rhythm and maintaining sinus rhythm in patients with paroxysmal or persistent atrial fibrillation/atrial flutter[1]
- Its core mechanism of action is selective blocking of IKr channels, thereby prolonging myocardial repolarization (QT interval) and increasing myocardial refractory period, terminating reentrant arrhythmias[1][2]
- This drug is approved for oral administration, and initial hospitalization monitoring is required due to the risk of QT interval prolongation and torsades de pointes (TdP)[1]
- Unlike non-selective drugs, such as dofelith (UK Medicines Code: 68789), it does not block other potassium currents or calcium channels, thus minimizing the impact on cardiac conduction velocity[1]

C19H27N3O5S2

441.56

441.139

115256-11-6

Dofetilide-d4;1189700-56-8

71329

White to off-white solid powder

1.3±0.1 g/cm3

614.1±65.0 °C at 760 mmHg

147-1490C

325.2±34.3 °C

0.0±1.8 mmHg at 25°C

1.614

1.56

2

8

11

29

672

0

IXTMWRCNAAVVAI-UHFFFAOYSA-N

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

N-(4-(2-(methyl(2-(4-(methylsulfonamido)phenoxy)ethyl)amino)ethyl)phenyl)methanesulfonamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.66 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.66 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.66 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)