| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| Other Sizes |
| Targets |
Rapid component of the Delayed Rectifier Potassium Current (IKr), which is conducted by the hERG (human Ether-à-go-go-Related Gene) potassium channel (Kv11.1). Dofetilide D4 acts as a selective and potent blocker of IKr channels in cardiac myocytes. By blocking these potassium channels, it prolongs the cardiac action potential duration and the effective refractory period (ERP). This results in prolongation of the QT interval on the surface ECG.
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| ln Vitro |
Dofetilide selectively inhibits IKr with an IC50 of 31.5 nM in patch-clamp electrophysiology studies using hERG-expressing HEK293 cells or guinea pig cardiomyocytes. At concentrations covering several orders of magnitude, dofetilide blocks only IKr with no relevant block of the other repolarizing potassium currents (IKs, IK1, Ito), sodium channels (INa), or L-type calcium channels (ICa,L).
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| ln Vivo |
In anesthetized guinea pigs, intravenous dofetilide (10-100 microg/kg) dose-dependently prolongs the QT interval on the ECG, increases the monophasic action potential duration (MAPD), and prolongs effective refractory period (ERP). These effects directly correlate with plasma dofetilide concentrations and are fully reversible. The D4-labeled analog is used as an internal standard to measure these concentrations.
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| Enzyme Assay |
HEK-293 cells stably expressing hERG (Kv11.1) potassium channels are cultured in DMEM with 10% FBS. Whole-cell patch-clamp recordings are performed at room temperature (22-24degC) using an extracellular solution (140 mM NaCl, 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 10 mM glucose, pH 7.4). A specific voltage protocol (depolarization to +20 mV for 2 s then repolarization to -40 mV for 2 s) is applied at a frequency of 0.1 Hz. Varying concentrations of Dofetilide D4 (1-1000 nM) are applied extracellularly via perfusion. Currents (IKr tail currents) are measured and IC50 values for the inhibition of IKr are calculated.
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| Cell Assay |
Not applicable (no direct cellular assay for the labeled internal standard). Guinea pig cardiomyocytes are isolated by enzymatic digestion (collagenase, protease) and plated on laminin-coated coverslips. The whole-cell patch-clamp technique is used to record IKr. Cells are held at -40 mV to inactivate sodium channels, and step depolarizations to +20 mV for 200 ms are applied. The deactivating tail currents of IKr are measured upon repolarization to -40 mV. Dofetilide D4 (1-1000 nM) is perfused, and the reduction in tail current amplitude is measured. IC50 is calculated.
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| Animal Protocol |
Male Hartley guinea pigs (250-350 g) are anesthetized (e.g., 1.5% isoflurane). Dofetilide D4 (with unlabeled as the analyte) is administered via a jugular vein catheter at 10-50 microg/kg over 5-10 min. The QT interval is continuously monitored using limb lead ECG (II or aVF). Blood samples (0.2-0.3 mL) are collected from a carotid artery or femoral vein catheter at pre-dose and 2, 5, 10, 15, 30, 45, 60, 90, and 120 min post-dose. Concentrations are quantified by LC-MS/MS using Dofetilide D4 as the internal standard.
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| ADME/Pharmacokinetics |
Dofetilide D4 is used as an internal standard (IS) for LC-MS/MS quantification. Dofetilide is 65-70% protein bound, has an oral bioavailability of >90%, and a terminal half-life of 8-10 h (humans). It is eliminated unchanged in the urine (80%) and feces (10%). The D4-labeled form has nearly identical chromatographic and mass spectrometric properties, providing high accuracy in quantification.
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| Toxicity/Toxicokinetics |
Dofetilide can cause serious ventricular arrhythmias, primarily Torsade de Pointes (TdP), a potentially fatal polymorphic ventricular tachycardia associated with QT prolongation. QT prolongation is directly related to plasma concentration, and risk is elevated in patients with reduced renal function, taking interacting drugs, or having a history of proarrhythmia. Other common AEs: headache, dizziness, chest pain.
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| Additional Infomation |
Dofetilide (Tikosyn) was FDA-approved in 1999 for the maintenance of normal sinus rhythm in highly symptomatic patients with atrial fibrillation/flutter. The D4-labeled version is a research internal standard for precise bioanalytical quantification in therapeutic drug monitoring (TDM), drug-drug interaction studies (especially with CYP3A4 and renal transporter inhibitors), and for forensic/clinical toxicology in cases of dofetilide overdose.
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| Molecular Formula |
C19H23D4N3O5S2
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|---|---|
| Molecular Weight |
445.589
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| Exact Mass |
445.164
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| CAS # |
1189700-56-8
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| Related CAS # |
Dofetilide;115256-11-6
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| PubChem CID |
45039110
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| Appearance |
White to off-white solid powder
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| Melting Point |
130-1350C
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| LogP |
1.8
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
29
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| Complexity |
672
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| Defined Atom Stereocenter Count |
0
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| SMILES |
[2H]C([2H])(C([2H])([2H])OC1=CC=C(C=C1)NS(=O)(=O)C)N(C)CCC2=CC=C(C=C2)NS(=O)(=O)C
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| InChi Key |
IXTMWRCNAAVVAI-QZPARXMSSA-N
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| 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/i14D2,15D2
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| Chemical Name |
N-[4-[2-[methyl-[1,1,2,2-tetradeuterio-2-[4-(methanesulfonamido)phenoxy]ethyl]amino]ethyl]phenyl]methanesulfonamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2442 mL | 11.2211 mL | 22.4422 mL | |
| 5 mM | 0.4488 mL | 2.2442 mL | 4.4884 mL | |
| 10 mM | 0.2244 mL | 1.1221 mL | 2.2442 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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