Absorption, Distribution and Excretion
In patients, average peak plasma concentrations of vernakalant were 3.9 μg/ml following a single 10 minute infusion of 3 mg/kg vernakalant hydrochloride, and 4.3 μg/ml following a second infusion of 2 mg/kg with a 15 minute interval between doses.
Mainly eliminated via renal excretion.
Approximately 2L/kg.
The typical total body clearance of vernakalant was estimated to be 0.41 l/hr/kg.

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Metabolism / Metabolites
Vernakalant is mainly eliminated by CYP2D6 mediated O-demethylation in CYP2D6 extensive metabolisers. Glucuronidation is the main metabolism pathway in CYP2D6 poor metabolisers.

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Biological Half-Life
Elimination half life in CYP2D6 extensive metabolizers is 3 hours and 5.5 hours in poor metabolizers.

Protein Binding
Displays low protein binding and the free fraction of vernakalant in human serum is 53-63% at concentration range of 1-5 μg/ml.

: Dorian, Paul MD et al. The Effect of Vernakalant (RSD1235), an Investigational Antiarrhythmic Agent, on Atrial Electrophysiology in Humans. Journal of Cardiovascular Pharmacology:July 2007 - Volume 50 -Issue 1 - pp 35-40. [2]. Jodene Eldstrom et al. The Molecular Basis of High-Affinity Binding of the Antiarrhythmic Compound Vernakalant (RSD1235) to Kv1.5 Channels. Molecular Pharmacology December 2007 vol. 72 no. 6 1522-1534 [3]. Vernakalant. Too dangerous in atrial fibrillation.Prescrire Int. 2012 May;21(127):119-22. [4]. Blomstr?m-Lundqvist C, Blomstr?m P.Safety and efficacy of pharmacological cardioversion of atrial fibrillation using intravenous vernakalant, a new antiarrhythmic drug with atrial selectivity.Expert Opin Drug Saf. 2012 Jul;11(4):671-9. Epub 2012 May 26. [5]. Bash LD, Buono JL, Davies GM, Martin A, Fahrbach K, Phatak H, Avetisyan R, Mwamburi M.Systematic review and meta-analysis of the efficacy of cardioversion by vernakalant and comparators in patients with atrial fibrillation.Cardiovasc Drugs Ther. 2012 Apr;

Vernakalant is an alcohol and a member of phenols.
Vernakalant was developed by Cardiome Pharma as as an antiarrhythmic drug intended for rapid conversion of atrial fibrillation to sinus rhythm. It acts as an atypical class III antiarrhythmic drug that potentiates its effect in higher heart rates. Intravenous formulation was approved in Europe in September 2010 as Brinavess and in Canada in April 2017. It is an investigational drug under regulatory review by FDA.
See also: Vernakalant Hydrochloride (annotation moved to).

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Drug Indication
Indicated for the rapid conversion of recent onset of atrial fibrillation to sinus rhythm in adults for non-surgery patients that lasts for less than 7 days of duration and post-cardiac surgery patients with atrial fibrillation lasting less than 3 days of duration.

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Mechanism of Action
Vernakalant blocks atrial voltage-gated sodium channels in a dose and frequency-dependent manner and inhibits late sodium current (INa)which confers its effect on intra-atrial conduction. This current blockade enhance and onset of drug action accelerates in higher heart rate as the affinity of vernakalant for INa also increases. Its binding offset is quick once the heart rate slows. It also blocks Kv 1.5 channel and its early activating potassium channels (IKur) and inhibits acetylcholine-activated potassium channels (IKAch), which are specific to the atrium and cause prolongation of atrial refractoriness. Vernakalant also blocks Kv4.3 channel and its cardiac transient outward potassium current (Ito), which is involved more with atrial than ventricular refractoriness. Vernakalant minimally blocks hERG channels and its rapidly activating/delayed rectifying potassium current (IKr) which accounts for mild QT prolongation. QRS widening due to INa blockade also contributes to QT prolongation.

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Pharmacodynamics
Vernakalant blocks currents in all phases of atrial action potential including atria-specific potassium currents (the ultra-rapid delayed rectifier and the acetylcholine dependent potassium currents) and prolongs the refractory period. It dose-dependently prolongs atrial refractoriness, prolongs AV nodal conduction and refractoriness, and slightly prolongs QRS duration without significantly affecting ventricular refractory period. Vernakalant has a high affinity to ion channels specifically involved in repolarization of atrial tissue and is thought to have a low proarrhythmic potential.

C20H31NO4

349.46444

349.225

794466-70-9

Vernakalant Hydrochloride;748810-28-8;Vernakalant-d6 hydrochloride;866455-16-5

9930049

Typically exists as solid at room temperature

1.1±0.1 g/cm3

479.0±45.0 °C at 760 mmHg

243.5±28.7 °C

0.0±1.3 mmHg at 25°C

1.557

2.4

1

5

7

25

394

3

O([C@@H]1CCCC[C@H]1N1C[C@H](O)CC1)CCC1C=CC(OC)=C(OC)C=1

VBHQKCBVWWUUKN-KZNAEPCWSA-N

InChI=1S/C20H31NO4/c1-23-19-8-7-15(13-20(19)24-2)10-12-25-18-6-4-3-5-17(18)21-11-9-16(22)14-21/h7-8,13,16-18,22H,3-6,9-12,14H2,1-2H3/t16-,17-,18-/m1/s1

(3R)-1-[(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]pyrrolidin-3-ol

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)

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

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.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).

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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)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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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).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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