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Dofetilide (formerly UK-68789; UK68789; Dofetilidum; Tikosyn) is a potent and selective potassium channel (hERG) blocker approved for use as a Class III antiarrhythmic drug.
Physicochemical Properties
| Molecular Formula | C19H27N3O5S2 | |
| Molecular Weight | 441.56 | |
| Exact Mass | 441.139 | |
| CAS # | 115256-11-6 | |
| Related CAS # | Dofetilide-d4;1189700-56-8 | |
| PubChem CID | 71329 | |
| Appearance | White to off-white solid powder | |
| Density | 1.3±0.1 g/cm3 | |
| Boiling Point | 614.1±65.0 °C at 760 mmHg | |
| Melting Point | 147-1490C | |
| Flash Point | 325.2±34.3 °C | |
| Vapour Pressure | 0.0±1.8 mmHg at 25°C | |
| Index of Refraction | 1.614 | |
| LogP | 1.56 | |
| Hydrogen Bond Donor Count | 2 | |
| Hydrogen Bond Acceptor Count | 8 | |
| Rotatable Bond Count | 11 | |
| Heavy Atom Count | 29 | |
| Complexity | 672 | |
| Defined Atom Stereocenter Count | 0 | |
| InChi Key | IXTMWRCNAAVVAI-UHFFFAOYSA-N | |
| InChi Code | 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 | |
| Chemical Name | N-(4-(2-(methyl(2-(4-(methylsulfonamido)phenoxy)ethyl)amino)ethyl)phenyl)methanesulfonamide | |
| Synonyms |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
Rapidly activating delayed rectifier K+ current (IKr, encoded by HERG gene) [1][2] |
| ln Vitro |
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. 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] |
| ln Vivo |
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]. 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] |
| Enzyme Assay |
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] |
| Cell Assay |
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 Protocol |
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. 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] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion >90% 3 L/kg Approximately 80% of a single dose of dofetilide is excreted in urine, of which approximately 80% is excreted as unchanged dofetilide with the remaining 20% consisting of inactive or minimally active metabolites. Renal elimination involves both glomerular filtration and active tubular secretion (via the cation transport system, a process that can be inhibited by cimetidine, trimethoprim, prochlorperazine, megestrol and ketoconazole). ... The oral bioavailability of dofetilide is >90%, with maximal plasma concentrations occurring at about 2-3 hours in the fasted state. Oral bioavailability is unaffected by food or antacid. The terminal half life of Tikosyn is approximately 10 hours; steady state plasma concentrations are attained within 2-3 days, with an accumulation index of 1.5 to 2.0. Plasma concentrations are dose proportional. Plasma protein binding of dofetilide is 60-70%, is independent of plasma concentration, and is unaffected by renal impairment. Volume of distribution is 3 L/kg. 1. Pharmacokinetics of dofetilide were studied in man, dog, rat and mouse after single IV and oral doses of dofetilide or (14)C-dofetilide. 2. Dofetilide was absorbed completely in all species. Low metabolic clearance in man resulted in complete bioavailability following oral administration. Higher metabolic clearance in rodents, and to a lesser extent dogs, resulted in decreased bioavailability because of first-pass metabolism. 3. Following IV administration, the volume of distribution showed only moderate variation in all species (2.8-6.3 l/kg). High plasma clearance in rodents resulted in short half-life values (mouse 0.32, male rat 0.5 and female rat 1.2 hr), while lower clearance in dog and man gave longer terminal elimination half-lives (4.6 and 7.6 hr respectively). 4. After single IV doses of (14)C-dofetilide, unchanged drug was the major component excreted in urine of all species with several metabolites also present. 5. Metabolites identified in urine from all species were formed by N-oxidation or N-dealkylation of the tertiary nitrogen atom of dofetilide. 6. After oral and IV administration of (14)C-dofetilide to man, parent compound was the only detectable component present in plasma and represented 75% of plasma radioactivity. No single metabolite accounted for greater than 5% of plasma radioactivity. Metabolism / Metabolites Hepatic Dofetilide, a class III antidysrhythmic agent, undergoes both renal and metabolic clearance. Characterization of the metabolism in vitro allows explanation of species differences, whereas identification of the human enzymes involved permits assessment of potential drug interaction. In liver microsomes, the rate of oxidative metabolism of dofetilide is in the order: male rat > female rat > dog > humans, which correlates with the metabolic clearance seen in vivo. In vitro products of oxidative metabolism, formed by N-dealkylation, are the same as those formed in vivo, with the N-desmethyl being the major product. This route of dofetilide metabolism is mediated by cytochrome P450 (CYP). In humans, N-demethylation has a high KM of 657 +/- 116 uM, indicating low affinity for the enzyme's active site. In a number of human liver microsomal preparations, this rate correlated (r = 0.903) with the activity of CYP3A4. There was no correlation with the activities of other isozymes. Specific isozyme inhibitors also indicated the involvement of CYP3A4, with partial inhibition being observed with ketoconazole and troleandeomycin, whereas the activator, alpha-naphthaflavone, caused increased turnover. No inhibition was observed with specific inhibitors or competing substrates for other isozymes. Dofetilide did not significantly inhibit CYP2C9, CYP2D6, or CYP3A4 at concentrations up to 100 microM in vitro. In contrast, amiodarone (IC50, 25 uM) and flecainide (49 microM) inhibited CYP2C9 and quinidine (0.26 uM), and flecainide (0.44 uM) inhibited CYP2D6. Many antidysrhythmic drugs have active, circulating metabolites, complicating the relationship of dose and clinical response. In vitro pharmacology studies allow assessment of the potential contribution to the pharmacological profile by metabolites. Potency of dofetilide and metabolites has been compared for class III (K+ channel blockade) and class I (Na+ channel blockade) antidysrhythmic activities. Three of the metabolites of dofetilide displayed class III activity but at concentrations at least 20-fold higher than dofetilide. Dofetilide N-oxide showed class I activity, but only at high concentration. Neither resting membrane potential or action potential amplitude were affected by any metabolite. This lack of biologically relevant activity is in accord with the close correlation between plasma concentrations of dofetilide and pharmacological response. Approximately 80% of a single dose of dofetilide is excreted in urine, of which approximately 80% is excreted as unchanged dofetilide with the remaining 20% consisting of inactive or minimally active metabolites. ... In vitro studies with human liver microsomes show that dofetilide can be metabolized by CYP3A4, but it has a low affinity for this isoenzyme. Metabolites are formed by N-dealkylation and N-oxidation. There are no quantifiable metabolites circulating in plasma, but 5 metabolites have been identified in urine Biological Half-Life 10 hours Following IV administration, ... high plasma clearance in rodents resulted in short half-life values (mouse 0.32, male rat 0.5 and female rat 1.2 hr), while lower clearance in dog and man gave longer terminal elimination half-lives (4.6 and 7.6 hr respectively). ... The terminal half life of Tikosyn is approximately 10 hours Absorption: Oral bioavailability of Dofetilide (UK 68789) in humans is approximately 90%, with rapid absorption (peak plasma concentration achieved within 2-3 hours)[1] - Distribution: The drug has a volume of distribution of 3-4 L/kg in humans, with extensive distribution into cardiac tissue[1] - Metabolism: Minimal hepatic metabolism; approximately 80% of the drug is excreted as the parent compound[1] - Excretion: Primary route of excretion is via the kidneys (70-80% in urine), with a small portion excreted in feces[1] - Half-life: Elimination half-life in humans is 10-15 hours after oral administration[1] |
| Toxicity/Toxicokinetics |
Hepatotoxicity In clinical trials, serum aminotransferase and alkaline phosphatase elevations were no more common during dofetilide than placebo therapy. Some degree of ALT elevation was reported in 15% of dofetilide but a similar proportion of placebo recipients; these elevations were above 3 times the upper limit of normal in 1.5% vs 2.0%. Thus, the background rate of serum ALT elevations in patients with atrial fibrillation eligible for dofetilide treatment appears to be high. Despite this, dofetilide has not been linked to instances of clinically apparent liver injury with symptoms or jaundice. The product label for dofetilide does not mention hepatotoxicity and does not specifically recommend monitoring of liver tests. Likelihood score: E (unlikely cause of clinically apparent liver injury). Protein Binding 60% -70% Interactions Concomitant use of verapamil is contraindicated. Co-administration of Tikosyn with verapamil resulted in increases in dofetilide peak plasma levels of 42%, although overall exposure to dofetilide was not significantly increased. In an analysis of the supraventricular arrhythmia and The Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) patient populations, the concomitant administration of verapamil with dofetilide was associated with a higher occurrence of torsade de pointes. Concomitant use of cimetidine is contraindicated. Cimetidine at 400 mg BID (the usual prescription dose) co-administered with Tikosyn (500 mcg BID) for 7 days has been shown to increase dofetilide plasma levels by 58%. Cimetidine at doses of 100 mg BID (OTC dose) resulted in a 13% increase in dofetilide plasma levels (500 mcg single dose). No studies have been conducted at intermediate doses of cimetidine. If a patient requires Tikosyn and anti-ulcer therapy, it is suggested that omeprazole, ranitidine, or antacids (aluminum and magnesium hydroxides) be used as alternatives to cimetidine, as these agents have no effect on the pharmacokinetic profile of Tikosyn. The use of Tikosyn in conjunction with other drugs that prolong the QT interval has not been studied and is not recommended. Such drugs include phenothiazines, cisapride, bepridil, tricyclic antidepressants, certain oral macrolides, and certain fluoroquinolones. Class I or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to dosing with Tikosyn. In clinical trials, Tikosyn was administered to patients previously treated with oral amiodarone only if serum amiodarone levels were below 0.3 mg/L or amiodarone had been withdrawn for at least three months. Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting diuretics, increasing the potential for torsade de pointes. Potassium levels should be within the normal range prior to administration of Tikosyn and maintained in the normal range during administration of Tikosyn. For more Interactions (Complete) data for Dofetilide (15 total), please visit the HSDB record page. Plasma protein binding rate: Dofetilide (UK 68789) is weakly bound to plasma proteins (60-70%) in humans[1] - Cardiovascular toxicity: Therapeutic doses prolong the QT interval, increasing the risk of torsades de pointes (TdP), especially in patients with renal impairment, hypokalemia, or hypomagnesemia[1] - Renal toxicity: Renal excretion is the major route, so dose adjustment is required in patients with reduced creatinine clearance[1] - Drug-drug interactions: Inhibitors of renal cation transporters (e.g., cimetidine, trimethoprim) increase plasma dofetilide concentrations by reducing renal excretion, enhancing TdP risk[1] - Other side effects: Common adverse reactions include headache, dizziness, and nausea; [1] |
| References |
[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. |
| Additional Infomation |
Therapeutic Uses Anti-Arrhythmia Agents, Potassium Channel Blockers Tikosyn is indicated for the conversion of atrial fibrillation and atrial flutter to normal sinus rhythm. /Included in US product label/ Tikosyn is indicated 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. Because Tikosyn can cause life threatening ventricular arrhythmias, it should be reserved for patients in whom atrial fibrillation/atrial flutter is highly symptomatic. /Included in US product label/ Drug Warnings /BOXED WARNING/ To minimize the risk of induced arrhythmia, patients initiated or re-initiated on Tikosyn should be placed for a minimum of 3 days in a facility that can provide calculations of creatinine clearance, continuous electrocardiographic monitoring, and cardiac resuscitation ... . Tikosyn is available only to hospitals and prescribers who have received appropriate Tikosyn dosing and treatment initiation education; Tikosyn (dofetilide) can cause serious ventricular arrhythmias, primarily torsade de pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. QT interval prolongation is directly related to dofetilide plasma concentration. Factors such as reduced creatinine clearance or certain dofetilide drug interactions will increase dofetilide plasma concentration. The risk of TdP can be reduced by controlling the plasma concentration through adjustment of the initial dofetilide dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval. Treatment with dofetilide must therefore be started only in patients placed for a minimum of three days in a facility that can provide electrocardiographic monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Calculation of the creatinine clearance for all patients must precede administration of the first dose of dofetilide. In patients with mild to moderate renal failure, decreases in dosage based on creatinine clearance are required to minimize the risk of torsades de pointes. The drug should not be used in patients with advanced renal failure or with inhibitors of renal cation transport. Torsades de pointes occurred in 1-3% of patients in clinical trials where strict exclusion criteria (e.g., hypokalemia) were applied and continuous ECG monitoring was used to detect marked QT prolongation in the hospital. The incidence of this adverse effect during more widespread use of the drug, marketed since 2000, is unknown. Other adverse effects were no more common than with placebo during premarketing clinical trials. For more Drug Warnings (Complete) data for Dofetilide (16 total), please visit the HSDB record page. 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. Dofetilide (UK 68789) is a potent, selective class III antiarrhythmic drug[1][2] - Clinical indications include the conversion of atrial fibrillation/flutter to sinus rhythm and the maintenance of sinus rhythm in patients with paroxysmal or persistent atrial fibrillation/flutter[1] - Its core mechanism of action is the selective blockade of IKr, which prolongs cardiac repolarization (QT interval) and increases myocardial refractoriness, terminating reentrant arrhythmias[1][2] - The drug is approved for oral administration and requires initial in-hospital monitoring due to the risk of QT interval prolongation and TdP[1] - Unlike non-selective agents, Dofetilide (UK 68789) does not block other potassium currents or calcium channels, minimizing effects on cardiac conduction velocity[1] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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. 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. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2647 mL | 11.3235 mL | 22.6470 mL | |
| 5 mM | 0.4529 mL | 2.2647 mL | 4.5294 mL | |
| 10 mM | 0.2265 mL | 1.1323 mL | 2.2647 mL |