Tìm theo
Dabigatran etexilate
Các tên gọi khác (3) :
  • Dabigatran
  • Ethyl 3-[[[4-[[[(hexyloxyl)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino] propanoate
  • Pradaxa
antithrombins
Thuốc Gốc
Small Molecule
CAS: 211915-06-9
ATC: B01AE07
CTHH: C34H41N7O5
PTK: 627.7332
Dabigatran etexilate is an oral prodrug that is metabolized by a serum esterase to dabigatran. It is a synthetic, competitive and reversible direct thrombin inhibitor. Inhibition of thrombin disrupts the coagulation cascade and inhibits the formation of clots. Dabigatran etexilate may be used to decrease the risk of venous thromboembolic events in patients who have undergone total hip or knee replacement surgery, or to prevent stroke and systemic embolism in patients with atrial fibrillation, in whom anticoagulation therapy is indicated. In contrast to warfarin, because its anticoagulant effects are predictable, lab monitoring is not necessary. FDA approved on October 19, 2010.
Nhận Dạng Quốc Tế & Đặc Tính Hóa Học
Công thức hóa học
C34H41N7O5
Phân tử khối
627.7332
Monoisotopic mass
627.316917457
InChI
InChI=1S/C34H41N7O5/c1-4-6-7-10-21-46-34(44)39-32(35)24-12-15-26(16-13-24)37-23-30-38-27-22-25(14-17-28(27)40(30)3)33(43)41(20-18-31(42)45-5-2)29-11-8-9-19-36-29/h8-9,11-17,19,22,37H,4-7,10,18,20-21,23H2,1-3H3,(H2,35,39,44)
InChI Key
InChIKey=KSGXQBZTULBEEQ-UHFFFAOYSA-N
IUPAC Name
ethyl 3-(1-{2-[({4-[amino({[(hexyloxy)carbonyl]imino})methyl]phenyl}amino)methyl]-1-methyl-1H-1,3-benzodiazol-5-yl}-N-(pyridin-2-yl)formamido)propanoate
Traditional IUPAC Name
ethyl 3-(1-{2-[({4-[amino({[(hexyloxy)carbonyl]imino})methyl]phenyl}amino)methyl]-1-methyl-1,3-benzodiazol-5-yl}-N-(pyridin-2-yl)formamido)propanoate
SMILES
CCCCCCOC(=O)N=C(N)C1=CC=C(NCC2=NC3=C(C=CC(=C3)C(=O)N(CCC(=O)OCC)C3=CC=CC=N3)N2C)C=C1
Độ tan chảy
180 +/- 3 (DSC: 10 K min^-1 heating rate)
Độ hòa tan
1.8mg/ml, partly soluble
logP
3.8
logS
-5.1
pKa (strongest acidic)
17.89
pKa (Strongest Basic)
3.87
PSA
154.03 Å2
Refractivity
176.43 m3·mol-1
Polarizability
71.11 Å3
Rotatable Bond Count
17
H Bond Acceptor Count
8
H Bond Donor Count
2
Physiological Charge
0
Number of Rings
4
Bioavailability
0
MDDR-Like Rule
true
Dược Lực Học : Dabigatran directly inhibits thrombin in a concentration-dependent, reversible, specific, and competitive manner which results in a prolongation of aPTT (partial thromboplastin time), ECT (Ecarin clotting time), and TT (thrombin time). It may increase INR but this laboratory parameter is relatively insensitive to the activity of dabigatran.
Cơ Chế Tác Dụng : Dabigatran etexilate is an oral prodrug that is metabolized by a serum esterase to dabigatran. It is a synthetic, competitive and reversible direct thrombin inhibitor. Inhibition of thrombin disrupts the coagulation cascade and inhibits the formation of clots. Dabigatran etexilate may be used to decrease the risk of venous thromboembolic events in patients who have undergone total hip or knee replacement surgery, or to prevent stroke and systemic embolism in patients with atrial fibrillation, in whom anticoagulation therapy is indicated. In contrast to warfarin, because its anticoagulant effects are predictable, lab monitoring is not necessary. FDA approved on October 19, 2010. Dabigatran etexilate is an inactive pro-drug that is converted to dabigatran, the active form, by esterase-catalyzed hydrolysis in the plasma and liver. Dabigatran, the main active principle in plasma, is a rapid-acting competitive and reversible direct inhibitor of thrombin. Thrombin, a serine protease, is responsible for the conversion of fibrinogen to fibrin in the coagulation cascade. Inhibition of thrombin consequently prevents thrombus development. Dabigatran inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation.
Dược Động Học :
▧ Absorption :
Peak plasma concentrations were achieved in 6 hours in post surgical patients. In healthy patients, maximum concentrations were achieved in 0.5 to 2 hours. The absolute bioavailability of dabigatran in the body after administration of dabigatran etexilate was 6.5%. Food does not affect the bioavailability of dabigatran etexilate, but it delays the time to peak plasma concentrations by 2 hours. Oral bioavailability may increase by up to 75% when pellets are taken out of the hydroxypropylmethylcellulose (HPMC) capsule. Therefore, capsules should not be opened and pellets taken alone. Furthermore, although absorption of dabigatran etexilate is independent of gastrointestinal acidity, coadministration of pantoprazole (proton pump inhibitor) may reduce the bioavailability of dabigatran. Despite this finding, dose adjustment is not required.
▧ Volume of Distribution :
Moderate tissue distribution with a Vd of 60-70L. Accumulation factor, twice daily dosing = 2
▧ Protein binding :
Relatively low binding (34-35%) to plasma proteins.
▧ Metabolism :
CYP450 enzymes are not involved in the metabolism of dabigatran thus is not expected to interact with drugs metabolized by CYP isoenzymes. Dabigatran is typically metabolised by esterases and microsomal carboxylesterases. Pharmacologically active acylglucoronides are formed via conjugation. Four positional isomers, 1-O, 2-O, 3-O, and 4-O, acylglucuronides exist, each accounting for less than 10% of total plasma dabagatran.
▧ Route of Elimination :
Mainly excreted in urine (85%). Fecal excretion accounts for 6% of the orally administered dose. Dabigatran is primarily eliminated unchanged via the kidneys at a rate of 100 ml/min corresponding to the glomerular filtration rate.
▧ Half Life :
12-14 hours in healthy volunteers. 14-17 hours in patients treated for prevention of venous thromboembolism following hip- or knee-replacement surgery.
Độc Tính : The most common adverse reactions include dyspepsia or gastritis-like symptoms. The approximate lethal dose (LD50) in rats and mice was observed at single oral doses of > 2000 mg/kg. Oral doses of 600 mg/kg did not induce any toxicologically meaningful changes in dogs and Rhesus monkeys. Dabigatran was well-tolerated in rats and Rhesus monkeys during repeat-dose toxicity studies. No evidence of mutagenic potential.
Chỉ Định : Dabigatran is indicated for the prevention of venous thromboembolic events in patients who have undergone elective hip or knee replacement surgery (based on RE-NOVATE, RE-MODEL, and RE-MOBILIZE trials). In 2010, it was approved in the US and Canada for prevention of stroke and systemic embolism in patients with atrial fibrillation (approval based on the RE-LY trial). Contraindications: severe renal impairment (CrCL < 30 ml/min); haemorrhagic manifestations, bleeding diathesis or spontaneous or pharmacologic impairment of haemostasis; lesions at risk of clinically significant bleeding (e.g. extensive cerebral infarction (haemorrhagic or ischemic) in the last 6 months, active peptic ulcer disease); concomitant treatment with P-glycoprotein inhibitors (e.g. oral ketoconazole, verapamil); and those with known hypersensitivity to dabigatran, dabigatran etexilate or any ingredient used in the formulation or component of the container. As of December 2012, dabigatran is contraindicated in patients with mechanical prosthetic heart valves.
Tương Tác Thuốc :
  • Amiodarone Amiodarone may increase the serum concentration of dabigatran etexilate, resulting in increased risk of bleeding. Consider modifying therapy.
  • Apixaban Concomitant therapy with another anticoagulant may increase bleed risk. Monitor closely for adverse effects.
  • Carbamazepine P-Glycoprotein inducers such as carbamazepine may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
  • Dexamethasone P-Glycoprotein inducers such as dexamethasone may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
  • Doxorubicin P-Glycoprotein inducers such as doxorubicin may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
  • Dronedarone Dronedarone inhibits P-glycoprotein transporter thus increasing serum concentrations of dabigatran 1.1-1.9-fold.
  • Eptifibatide Monitor therapy due to increased bleeding.
  • Ginkgo biloba Additive anticoagulant/antiplatelet effects of gingko may increase bleed risk for patients on dabigatran. Concomitant therapy should be avoided.
  • Ketoconazole Coadministration with a strong p-glycoprotein inhibitor may increase the level or effect of dabigatran. Monitor closely for adverse effects.
  • Lomitapide Dabigatran is a p-glycoprotien (P-gp) substrate. Levels of dabigatran may increase if coadministered with lomipatide, which is a P-gp inhibitor. Thus, it is recommended to dose reduce P-gp substrates (such as ambrisentan, aliskiren, colchicine, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan) with the concomitant use of lomipatide.
  • Mifepristone May lead to excessive post-abortion bleeding in patients on anticoagulant therapy. Concomitant therapy is contraindicated.
  • Nefazodone P-Glycoprotein inducers such as nefazodone may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
  • Pantoprazole Proton pump inhibitors may decrease the bioavailability of dabigatran by 28% and increase inter-patient pharmacokinetic variability, especially in females. However, dose adjustment is not required.
  • Prazosin P-Glycoprotein inducers such as prazosin may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
  • Quinidine Quinidine may increase the serum concentration of dabigatran etexilate, resulting in increased bleeding. Consider modification of therapy.
  • Rifampicin P-Glycoprotein inducers such as rifampin may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
  • Rivaroxaban Using additional anticoagulants such as dabigatran can increase the anticoagulant effect of rivaroxaban. Avoid concurrent use of rivaroxaban with other anticoagulants whenever possible, other than during transition periods, due to the possible increased for bleeding.
  • Tipranavir P-Glycoprotein inducers such as tipranavir may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
  • Trazodone P-Glycoprotein inducers such as trazodone may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
  • Verapamil Verapamil may increase serum concentrations of the active metabolite(s) of dabigatran etexilate, resulting in an increased risk of bleeding. It is also a strong p-glycoprotein inhibitor. Therapy modification should be considered.
  • Vinblastine P-Glycoprotein inducers such as vinblastine may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
Liều Lượng & Cách Dùng : Capsule - Oral - 110 mg
Capsule - Oral - 150 mg
Capsule - Oral - 75 mg
Dữ Kiện Thương Mại
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Tài Liệu Tham Khảo Thêm
drugbank
http://www.drugbank.ca/drugs/DB06695
PubChem Compound
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=6445226
PubChem Substance
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=99443249
KEGG Drug
http://www.genome.jp/dbget-bin/www_bget?drug:D07144
ChemSpider
http://www.chemspider.com/Chemical-Structure.4948999.html
National Drug Code Directory
http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/21695-899-60
PharmGKB
http://www.pharmgkb.org/drug/PA165958369
Wikipedia
http://en.wikipedia.org/wiki/Dabigatran
RxList
http://www.rxlist.com/pradaxa-drug.htm
PDRhealth
http://www.pdrhealth.com/drugs/pradaxa
Drugs.com
http://www.drugs.com/cdi/dabigatran.html
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