Dronedarone

Các tên gọi khác (5 ) :

Multaq
N-(2-Butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)-5-benzofuranyl)-methanesulfonamide
N-(2-Butyl-3-(P-(3-(dibutylamino)propoxy)benzoyl)-5-benzofuranyl)methanesulfonamide
SR 33589
SR 33589b

Thuốc chống loạn nhịp

Thuốc Gốc

Small Molecule

CAS: 141626-36-0

ATC: C01BD07

CTHH: C₃₁H₄₄N₂O₅S

PTK: 556.756

Dronedarone is a sinus rhythm controller for management of paroxysmal or persistent atrial fibrillation. Classified as a Class III antiarrhythmic but displays properties of all four Vaughan-Williams classes, dronedarone blocks a multitude of channels (sodium, potassium, calcium), and demonstrates antiadrenergic properties. Chemically, it is a benzofuran derivative. FDA approved on July 1, 2009.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₃₁H₄₄N₂O₅S

Phân tử khối

556.756

Monoisotopic mass

556.297093218

InChI

InChI=1S/C31H44N2O5S/c1-5-8-12-29-30(27-23-25(32-39(4,35)36)15-18-28(27)38-29)31(34)24-13-16-26(17-14-24)37-22-11-21-33(19-9-6-2)20-10-7-3/h13-18,23,32H,5-12,19-22H2,1-4H3

InChI Key

InChIKey=ZQTNQVWKHCQYLQ-UHFFFAOYSA-N

IUPAC Name

N-[2-butyl-3-({4-[3-(dibutylamino)propoxy]phenyl}carbonyl)-1-benzofuran-5-yl]methanesulfonamide

Traditional IUPAC Name

multaq

SMILES

CCCCN(CCCC)CCCOC1=CC=C(C=C1)C(=O)C1=C(CCCC)OC2=C1C=C(NS(C)(=O)=O)C=C2

Độ hòa tan

Insoluble

logP

7.346

logS

-5.4

pKa (strongest acidic)

9.08

pKa (Strongest Basic)

9.79

PSA

88.85 Å²

Refractivity

158.13 m³·mol^-1

Polarizability

66.05 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

Number of Rings

Bioavailability

MDDR-Like Rule

true

Dược Lực Học : Dronedarone is a non-iodinated benzofuran derivative for the management of paroxysmal or persistent atrial fibrillation. Dronedarone inhibits human atrial sodium currents (INa) in a dose dependent manner in which a concentration of 0.3 μM is sufficient to completely inhibit INa. Chemically it is related to amiodarone, a popular antiarrhythmic the use of which is limited to toxicity due its high iodine content (pulmonary fibrosis, thyroid disease) as well as by liver disease. Dronedarone lacks the iodine, and is expected to have less toxicity, yet it displays amiodarone-like class III antiarrhytmic activity in vitro and in clinical trials. Despite this advantage over amiodarone, clinical trials of dronedarone have shown that it may increase risk of stroke and mortality from cardiovascular causes and arrhythmia. Furthermore, amiodarone more potently effects action potential and refractory periods than dronedarone.

Cơ Chế Tác Dụng : Dronedarone is a sinus rhythm controller for management of paroxysmal or persistent atrial fibrillation. Classified as a Class III antiarrhythmic but displays properties of all four Vaughan-Williams classes, dronedarone blocks a multitude of channels (sodium, potassium, calcium), and demonstrates antiadrenergic properties. Chemically, it is a benzofuran derivative. FDA approved on July 1, 2009. The antiarrhythmic effect of dronedarone may be due to at least two major actions. It prolongs the duration of action potential and refractory period in myocardial tissue via inhibition of sodium and potassium channels. Via inhibition of calcium channels and blockage of beta1-adrenergic receptors, a decrease in AV conduction and sinus node function can be observed. Dronedarone can also cause an increase in blood pressure by inhibition of alpha1-adrenergic receptors.

Dược Động Học :

▧ Absorption :
Because of presystemic first pass metabolism the absolute bioavailability of dronedarone without food is low, about 4%. It increases to approximately 15% when dronedarone is administered with a high fat meal. After oral administration in fed conditions, peak plasma concentrations of dronedarone and the main circulating active metabolite (N-debutyl metabolite) are reached within 3 to 6 hours. After repeated administration of 400 mg twice daily, steady state is reached within 4 to 8 days of treatment. The steady state Cmax and exposure of the main N-debutyl metabolite is similar to that of the parent compound.
▧ Volume of Distribution :
When intravenously administered, the volume of distribution is 1400 L.
▧ Protein binding :
Dronedarone and its N-debutyl metabolite is >98% protein bound - mainly to albumin.
▧ Metabolism :
Majority of dronedarone is eliminated by first-pass metabolism in the liver by CYP3A4 enzymes (>84%). Dronedarone is also metabolized by CYP2D6 to a lesser extent. N-DBD is its active metabolite (1/10 to 1/3 potency of dronedarone) which can penetrate the blood-brain barrier, placenta, and is excreted in breast milk. However, it does not significantly accumulate in plasma or tissue.
▧ Route of Elimination :
6% of the dose was excreted in the urine, mainly as metabolites (no unchanged compound excreted in urine), and 84% was excreted in feces, mainly as metabolites.
▧ Half Life :
Elimination half-life: 13-19 hours
▧ Clearance :
Plasma clearance = 130-150 L/h.

Độc Tính : Most common adverse reactions (≥2%) are diarrhea, nausea, abdominal pain, vomiting, and asthenia.

Chỉ Định : Management of paroxysmal or persistent atrial fibrillation via restoration of normal sinus rhythm.

Tương Tác Thuốc :

Artemether Additive QTc-prolongation may occur. Concomitant therapy is contraindicated.
Atorvastatin Dronedarone is a CYP2D6 inhibitor thus increasing serum concentrations of atorvastatin. Lower doses of atorvastatin or consider rosuvastatin as cholesterol lowering therapy as there is no significant interaction between rosuvastatin and dronedarone.
Clarithromycin Clarithromycin is a strong CYP3A4 inhibitor in which concomitant use with dronedarone will significantly increase its exposure. Avoid concomitant use.
Conivaptan CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronedarone. Concurrent use of strong CYP3A4 inhibitors with dronedarone is contraindicated according to dronedarone prescribing information.
Crizotinib Concurrent use with drugs that prolong QTc interval is contraindicated.
Cyclosporine Cyclosporine is a strong CYP3A4 inhibitor in which concomitant use with dronedarone will significantly increase its exposure. Avoid concomitant use.
Dabigatran etexilate Dronedarone inhibits P-glycoprotein transporter thus increasing serum concentrations of dabigatran 1.1-1.9-fold.
Digoxin Dronedarone inhibits P-glycoprotein transporter thus increasing serum concentrations of digoxin 2.5-fold.
Diltiazem Diltiazem is a moderate CYP3A4 inhibitor and will increase dronedarone levels 1.4-1.7 fold. Decrease doses of non-dihyropyridinic calcium-channel blocker.
Etravirine Dronedarone, when administered concomitantly with etravirine (a strong CYP3A4 inducer), may experience a decrease in serum concentration. It is recommended to avoid this combination.
Fingolimod Pharmacodynamic synergist. Contraindicated. Increased risk of bradycardia, AV block, and torsade de pointes.
Itraconazole Itraconazole is a strong CYP3A4 inhibitor in which concomitant use with dronedarone will significantly increase its exposure. Avoid concomitant use.
Ketoconazole Ketoconazole is a strong CYP3A4 inhibitor in which concomitant use with dronedarone will significantly increase its exposure. Avoid concomitant use.
Lumefantrine Additive QTc-prolongation may occur. Concomitant therapy is contraindicated.
Metoprolol Metoprolol is a CYP2D6 substrate and because dronedarone inhibits this enzyme, will increase metoprolol exposure 1.6-fold. Lower dose of metoprolol.
Nefazodone Nefazodone is a strong CYP3A4 inhibitor in which concomitant use with dronedarone will significantly increase its exposure. Avoid concomitant use.
Propranolol Propranolol is a CYP2D6 substrate and because dronedarone inhibits this enzyme, will increase propranolol exposure 1.3-fold. Lower dose of metoprolol.
Ritonavir Ritonavir is a strong CYP3A4 inhibitor in which concomitant use with dronedarone will significantly increase its exposure. Avoid concomitant use.
Simvastatin Dronedarone is a CYP2D6 inhibitor thus increasing serum concentrations of simvastatin 4-fold. Lower doses of simvastatin and doses should not exceed 20 mg to avoid statin-induced toxicities like myopathy. Consider rosuvastatin as cholesterol lowering therapy as there is no significant interaction between rosuvastatin and dronedarone.
Sirolimus Sirolimus is a CYP3A substrate with a narrow therapeutic index thus concomitant therapy with dronedarone will increase plasma levels of sirolimus. Monitor plasma concentrations and adjust dose accordingly.
Tacrolimus Tacrolimus is a CYP3A substrate with a narrow therapeutic index thus concomitant therapy with dronedarone will increase plasma levels of tacrolimus. Monitor plasma concentrations and adjust dose accordingly.
Telithromycin Telithromycin is a strong CYP3A4 inhibitor in which concomitant use with dronedarone will significantly increase its exposure. Avoid concomitant use.
Verapamil Verapamil is a moderate CYP3A4 inhibitor and will increase dronedarone levels 1.4-1.7 fold. Decrease doses of non-dihyropyridinic calcium-channel blocker.
Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration by decreasing its metabolism. Additive QTc prolongation may also occur. Concomitant therapy is contraindicated.
Voriconazole Voriconazole is a strong CYP3A4 inhibitor in which concomitant use with dronedarone will significantly increase its exposure. Avoid concomitant use.
Vorinostat Additive QTc prolongation may occur. Concomitant therapy is contraindicated.
Warfarin Dronedarone is a moderate inhibitor of CYP3A4 which is responsible for warfarin metabolism. Increases serum concentration of S-isomer warfarin by 1.2 fold
Ziprasidone Additive QTc-prolongation may occur. Concomitant therapy is contraindicated.
Zuclopenthixol Additive or synergistic QTc-prolonging effects may occur. Concomitant therapy is contraindicated.

Liều Lượng & Cách Dùng : Tablet - Oral - 400 mg

Dữ Kiện Thương Mại

Nhà Sản Xuất

Công ty : Sanofi-Aventis

Sản phẩm biệt dược : Multaq

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB04855

PubChem Compound

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=208898

PubChem Substance

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=14861729

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D02537

ChemSpider

http://www.chemspider.com/Chemical-Structure.180996.html

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/54868-3086-0

PharmGKB

http://www.pharmgkb.org/drug/PA153619853

Wikipedia

http://en.wikipedia.org/wiki/Dronedarone

RxList

http://www.rxlist.com/multaq-drug.htm

Drugs.com

http://www.drugs.com/ppa/dronedarone.html

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