Dabigatran etexilate

Identification

Summary

Dabigatran etexilate is an anticoagulant used for the prevention of venous thromboembolic events or stroke in patients with recent elective hip or knee replacement surgery and atrial fibrillation.

Brand Names
Pradaxa
Generic Name
Dabigatran etexilate
DrugBank Accession Number
DB06695
Background

Dabigatran etexilate is an oral prodrug that is hydrolyzed to the competitive and reversible direct thrombin inhibitor dabigatran.5,17,18 Dabigatran etexilate may be used to decrease the risk of venous thromboembolic events in patients in whom anticoagulation therapy is indicated.5 In contrast to warfarin, because its anticoagulant effects are predictable, lab monitoring is not necessary.5 Dabigatran etexilate was approved by the FDA in 2010.16

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 627.7332
Monoisotopic: 627.316917457
Chemical Formula
C34H41N7O5
Synonyms
  • Dabigatran etexilate
External IDs
  • BIBR 1048
  • BIBR 1048 BS RS1
  • BIBR-1048
  • BIBR-1048-BS-RS1

Pharmacology

Indication

Dabigatran etexilate is available in both oral pellet and capsule form. Dabigatran etexilate pellets are indicated for the treatment of venous thromboembolic events (VTE) in pediatric patients between three months and 12 years of age who have been treated with a parenteral anticoagulant for at least 5 days. They are also indicated in the same age group to reduce the risk of recurrence of VTE in patients who have been previously treated.17

In capsule form, dabigatran etexilate is indicated in adults to reduce the risk of stroke and systemic embolism associated with non-valvular atrial fibrillation and for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days. It is also indicated in adults to reduce the risk of recurrence of DVT and PE in patients who have been previously treated and for the prophylaxis of DVT and PE in patients who have undergone hip replacement surgery. Lastly, it is indicated in pediatric patients between eight and 18 years of age for the treatment of venous thromboembolic events (VTE) in patients who have been treated with a parenteral anticoagulant for at least 5 days and to reduce the risk of recurrence of VTE in patients who have been previously treated.18

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Dabigatran etexilate is a double prodrug that is hydrolyzed to the active dabigatran by intestinal and hepatic carboxylesterases.12,13,14 Dabigatran is a reversible competitive thrombin inhibitor that directly inhibits the conversion by thrombin of fibrinogen to fibrin, impairing the clotting process and acting as an anticoagulant.4,7,8,17,18 Dabigatran use prolongs coagulation markers such as the activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), thrombin time (TT), and dilute thrombin time (dTT), but not the international normalized ratio (INR), which cannot be used in this context as it can in warfarin monitoring.17,18

As with all anticoagulant therapies, dabigatran carries a risk of bleeding, which may increase with concomitant use of antiplatelet agents, fibrinolytic therapy, heparins, or chronic NSAID use, and should be monitored for. Premature discontinuation of dabigatran, in the absence of an alternative anticoagulant, also carries an increased risk of thromboembolic events. Due to the risk of an epidural or spinal hematoma, dabigatran should generally not be used in the context of neuraxial anesthesia or spinal puncture; if such use is unavoidable, careful monitoring should be employed. Dabigatran should not be used in patients with prosthetic heart valves due to an increased occurrence of major bleeding and thromboembolic events. Dabigatran is a substrate of the P-gp transporter and should generally not be administered together with P-gp inhibitors or inducers, especially in patients with impaired renal function. Lastly, dabigatran or any other direct-acting oral anticoagulant should not be administered in patients with triple-positive antiphospholipid syndrome (APS) due to an increased risk of recurrent thrombotic events. In case of the need for emergency reversal, idarucizumab is available for use in adult patients; the safety and efficacy of idarucizumab has not been established in pediatric patients yet, for whom reversal may be achieved through hemodialysis, prothrombin complex concentrates, or recombinant FVIIa. However, none of these have been sufficiently evaluated in clinical trials.17,18

Mechanism of action

Hemostasis is a complex process that balances coagulation to prevent excessive thrombus formation or excessive bleeding. Central to the coagulation process is the serine protease thrombin (FIIa), which is synthesized as inactive prothrombin (FII) and subsequently activated by FXa/FVa, leading to a positive feedback loop and the production of large quantities of thrombin; once enough thrombin is formed, it cleaves soluble fibrinogen to form insoluble fibrin fibres that, together with aggregated platelets, form a clot. Although beneficial in wound healing, aberrant thrombus formation can lead to serious health consequences.6

Dabigatran is a univalent reversible direct thrombin inhibitor (DTI) that competitively inhibits thrombin with a Ki of 4.5 ± 0.2 nmol/L.7,8,17,18 Furthermore, the reversible nature of the inhibition is believed to allow for some normal physiological thrombin function, which may help alleviate some adverse effects associated with anticoagulation therapy.9 In addition, dabigatran has several glucuronidated metabolites, all of which have been shown to possess in vitro activity similar to the parent compound.4

In addition to a direct effect on thrombin activity, dabigatran has also been shown to inhibit platelet aggregation, another step in the coagulation pathway. However, the mechanism remains unclear as dabigatran inhibits platelet aggregation stimulated by thrombin and von Willebrand factor (vWF), but not by other pathways such as ADP- or thromboxane A2-induced aggregation.8,10,11,17,18

TargetActionsOrganism
AProthrombin
inhibitor
Humans
Absorption

Oral dabigatran has a bioavailability of 3-7%, although the relative bioavailability of dabigatran pellets is 37% higher than that for capsules and the bioavailability increases to 75% when the capsule shell is removed; dabigatran capsules should not be tampered with in any way prior to administration. The Cmax is achieved by one hour following oral dosing, which is extended to two hours if accompanied by a high-fat meal. Dabigatran can be taken with or without food. Dabigatran pharmacokinetics are approximately linear over a range of 10-400 mg in healthy adults and adult patients and it has an accumulation factor of two in adult and pediatric patients.17,18

Volume of distribution

Dabigatran has a volume of distribution of 50-70L.17,18

Protein binding

Dabigatran is ~35% bound to plasma proteins, including human serum albumin.15,17,18

Metabolism

Dabigatran is administered as the orally available prodrug dabigatran etexilate that is subsequently metabolized to the active form.12,17,18 In vitro studies and observations regarding the oral bioavailability and levels of plasma prodrug suggest extensive first-pass metabolism by carboxylesterases, first by intestinal CES2 to form BIBR0951 (also known as M2) and then subsequently by hepatic CES1 to form dabigatran. Dabigatran etexilate can also first undergo CES1-mediated hydrolysis to BIBR1087 (M1) followed by CES2-mediated hydrolysis to dabigatran, though it is hypothesized that the former pathway accounts for most of the active form in plasma.13,14 Dabigatran can undergo 1-O-acyl glucuronidation by UGT1A9, UGT2B7, and UGT2B15 followed by acyl migration to form the corresponding 2-O-, 3-O-, and 4-O-acyl glucuronides; all of these acyl glucuronides exhibit activity similar to dabigatran but account for a small fraction of recovered metabolites.12,4,17,18

In addition to these better characterized metabolic pathways, detailed LC/MS characterization suggests a wide variety of possible metabolites following oral or intravenous administration, most of which are present in only trace amounts in plasma, urine, or feces. These include a variety of oxidation, hydrolysis, and conjugation products, including through the addition of mannitol.12

Hover over products below to view reaction partners

Route of elimination

Dabigatran is primarily eliminated in the urine. Following oral administration of radiolabeled dabigatran, 7% of the radioactivity is recovered in urine and 86% is recovered in feces.17,18

Half-life

Dabigatran has a half-life of 12-17 hours in adult patients and 12-14 hours in pediatric patients.17,18

Clearance

Following intravenous administration, renal clearance constitutes ~80% of total dabigatran clearance.17,18

Adverse Effects
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Toxicity

No human studies involving pregnancy, labor and delivery, nursing, or pediatricsLabel. Geriatric patients are at higher risk of adverse effects than younger patients but the risk to benefit ratio is generally still favourable for older patientsLabel. Patients with a creatinine clearance of 15-30mL/min should have their doses of dabigatran etexilate reduced, and no data is available for patients with a creatinine clearance below 15mL/minLabel.

In animal studies, dabigatran increases the rates of dead offspring and causes uterine and vaginal bleeding close to birthLabel. Dabigatran may or may not be excreted in breast milk so the risk and benefit of stopping the drug or stopping breast feeding must be consideredLabel.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Dabigatran etexilate which could result in a higher serum level.
AbciximabDabigatran etexilate may increase the anticoagulant activities of Abciximab.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Dabigatran etexilate.
AceclofenacThe risk or severity of bleeding and hemorrhage can be increased when Aceclofenac is combined with Dabigatran etexilate.
AcemetacinThe risk or severity of bleeding and hemorrhage can be increased when Acemetacin is combined with Dabigatran etexilate.
AcenocoumarolDabigatran etexilate may increase the anticoagulant activities of Acenocoumarol.
AcetaminophenAcetaminophen may decrease the excretion rate of Dabigatran etexilate which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Dabigatran etexilate which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may increase the anticoagulant activities of Dabigatran etexilate.
AclidiniumDabigatran etexilate may decrease the excretion rate of Aclidinium which could result in a higher serum level.
Interactions
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Food Interactions
  • Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.
  • Avoid St. John's Wort. This herb induces PGP which may reduce the serum levels of dabigatran.
  • Take with a full glass of water.
  • Take with or without food.

Products

Products
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Product Ingredients
IngredientUNIICASInChI Key
Dabigatran etexilate mesilateSC7NUW5IIT872728-81-9XETBXHPXHHOLOE-UHFFFAOYSA-N
Active Moieties
NameKindUNIICASInChI Key
DabigatranprodrugI0VM4M70GC211914-51-1YBSJFWOBGCMAKL-UHFFFAOYSA-N
International/Other Brands
Pradax (Boehringer Ingelheim) / Rendix
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
PradaxaCapsule20 mgOralBoehringer Ingelheim2021-02-10Not applicableEU flag
PradaxaCapsule75 mg/1OralBoehringer Ingelheim Pharmaceuticals Inc.2011-08-082019-09-30US flag
PradaxaCapsule75 mgOralBoehringer Ingelheim2016-09-08Not applicableEU flag
PradaxaCapsule110 mgOralBoehringer Ingelheim2016-09-08Not applicableEU flag
PradaxaCapsule75 mg/1OralBoehringer Ingelheim Pharmaceuticals Inc.2010-11-082010-10-25US flag
PradaxaCapsule110 mgOralBoehringer Ingelheim (Canada) Ltd Ltee2008-07-03Not applicableCanada flag
PradaxaCapsule75 mgOralBoehringer Ingelheim2016-09-08Not applicableEU flag
PradaxaCapsule150 mgOralBoehringer Ingelheim2021-02-10Not applicableEU flag
PradaxaCapsule110 mgOralBoehringer Ingelheim2016-09-08Not applicableEU flag
PradaxaCapsule150 mg/1OralBoehringer Ingelheim Pharmaceuticals Inc.2017-07-28Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Apo-dabigatranCapsule110 mgOralApotex Corporation2019-02-04Not applicableCanada flag
Apo-dabigatranCapsule75 mgOralApotex Corporation2019-08-14Not applicableCanada flag
Apo-dabigatranCapsule150 mgOralApotex Corporation2019-02-04Not applicableCanada flag
Dabigatran EtexilateCapsule, coated pellets75 mg/1OralAscend Laboratories, LLC2020-03-132020-03-13US flag
Dabigatran EtexilateCapsule, coated pellets150 mg/1OralAscend Laboratories, LLC2020-03-132020-03-13US flag
Teva-dabigatranCapsule75 mgOralTEVA Canada LimitedNot applicableNot applicableCanada flag
Teva-dabigatranCapsule150 mgOralTEVA Canada LimitedNot applicableNot applicableCanada flag

Categories

ATC Codes
B01AE07 — Dabigatran etexilate
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as benzimidazoles. These are organic compounds containing a benzene ring fused to an imidazole ring (five member ring containing a nitrogen atom, 4 carbon atoms, and two double bonds).
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzimidazoles
Sub Class
Not Available
Direct Parent
Benzimidazoles
Alternative Parents
Phenylalkylamines / Aniline and substituted anilines / Secondary alkylarylamines / Pyridines and derivatives / N-substituted imidazoles / Imidolactams / Tertiary carboxylic acid amides / Heteroaromatic compounds / Amino acids and derivatives / Carboxylic acid esters
show 10 more
Substituents
Amidine / Amine / Amino acid or derivatives / Aniline or substituted anilines / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenoid / Benzimidazole
show 27 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
carboxylic ester, carboxamidine, beta-alanine derivative, pyridines, aromatic amide, benzimidazoles (CHEBI:70746)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
2E18WX195X
CAS number
211915-06-9
InChI Key
KSGXQBZTULBEEQ-UHFFFAOYSA-N
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)
IUPAC Name
ethyl 3-(1-{2-[({4-[(1E)-amino({[(hexyloxy)carbonyl]imino})methyl]phenyl}amino)methyl]-1-methyl-1H-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=NC=CC=C3)N2C)C=C1

References

Synthesis Reference

Christian Filser, Wolfgang Dersch, Rainer Hamm, Arndt Hausherr, Gunter Koch, Ulrich Scholz, Georg Zerban, "METHOD FOR PRODUCING AN INTERMEDIATE PRODUCT OF DABIGATRAN ETEXILATE." U.S. Patent US20110118471, issued May 19, 2011.

US20110118471
General References
  1. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Kalebo P, Christiansen AV, Hantel S, Hettiarachchi R, Schnee J, Buller HR: Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007 Nov;5(11):2178-85. [Article]
  2. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Prins MH, Hettiarachchi R, Hantel S, Schnee J, Buller HR: Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007 Sep 15;370(9591):949-56. [Article]
  3. Scaglione F: New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clin Pharmacokinet. 2013 Feb;52(2):69-82. doi: 10.1007/s40262-012-0030-9. [Article]
  4. Ebner T, Wagner K, Wienen W: Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity. Drug Metab Dispos. 2010 Sep;38(9):1567-75. doi: 10.1124/dmd.110.033696. Epub 2010 Jun 15. [Article]
  5. van Ryn J, Goss A, Hauel N, Wienen W, Priepke H, Nar H, Clemens A: The discovery of dabigatran etexilate. Front Pharmacol. 2013 Feb 12;4:12. doi: 10.3389/fphar.2013.00012. eCollection 2013. [Article]
  6. Negrier C, Shima M, Hoffman M: The central role of thrombin in bleeding disorders. Blood Rev. 2019 Nov;38:100582. doi: 10.1016/j.blre.2019.05.006. Epub 2019 May 22. [Article]
  7. Wienen W, Stassen JM, Priepke H, Ries UJ, Hauel N: In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb Haemost. 2007 Jul;98(1):155-62. [Article]
  8. Eisert WG, Hauel N, Stangier J, Wienen W, Clemens A, van Ryn J: Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin. Arterioscler Thromb Vasc Biol. 2010 Oct;30(10):1885-9. doi: 10.1161/ATVBAHA.110.203604. Epub 2010 Jul 29. [Article]
  9. Stangier J: Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285-95. doi: 10.2165/00003088-200847050-00001. [Article]
  10. Vinholt PJ, Nielsen C, Soderstrom AC, Brandes A, Nybo M: Dabigatran reduces thrombin-induced platelet aggregation and activation in a dose-dependent manner. J Thromb Thrombolysis. 2017 Aug;44(2):216-222. doi: 10.1007/s11239-017-1512-2. [Article]
  11. Trabold K, Makhoul S, Gambaryan S, van Ryn J, Walter U, Jurk K: The Direct Thrombin Inhibitors Dabigatran and Lepirudin Inhibit GPIbalpha-Mediated Platelet Aggregation. Thromb Haemost. 2019 Jun;119(6):916-929. doi: 10.1055/s-0039-1685139. Epub 2019 Apr 20. [Article]
  12. Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W: The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos. 2008 Feb;36(2):386-99. doi: 10.1124/dmd.107.019083. Epub 2007 Nov 15. [Article]
  13. Hu ZY, Parker RB, Herring VL, Laizure SC: Conventional liquid chromatography/triple quadrupole mass spectrometry based metabolite identification and semi-quantitative estimation approach in the investigation of in vitro dabigatran etexilate metabolism. Anal Bioanal Chem. 2013 Feb;405(5):1695-704. doi: 10.1007/s00216-012-6576-4. Epub 2012 Dec 14. [Article]
  14. Laizure SC, Parker RB, Herring VL, Hu ZY: Identification of carboxylesterase-dependent dabigatran etexilate hydrolysis. Drug Metab Dispos. 2014 Feb;42(2):201-6. doi: 10.1124/dmd.113.054353. Epub 2013 Nov 8. [Article]
  15. De Simone G, Pasquadibisceglie A, di Masi A, Buzzelli V, Trezza V, Macari G, Polticelli F, Ascenzi P: Binding of direct oral anticoagulants to the FA1 site of human serum albumin. J Mol Recognit. 2021 Mar;34(3):e2877. doi: 10.1002/jmr.2877. Epub 2020 Oct 9. [Article]
  16. FDA Drug Approval Package for Dabigatran Etexilate [Link]
  17. FDA Approved Drug Products: PRADAXA (dabigatran) oral pellets [Link]
  18. FDA Approved Drug Products: PRADAXA (dabigatran) oral capsules [Link]
  19. Apotex Inc. Product Monograph: Dabigatran Etexilate [File]
Human Metabolome Database
HMDB0015641
KEGG Drug
D07144
PubChem Compound
6445226
PubChem Substance
99443249
ChemSpider
4948999
BindingDB
50432209
RxNav
1037042
ChEBI
70746
ChEMBL
CHEMBL539697
ZINC
ZINC000003943279
PharmGKB
PA165958369
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Dabigatran
FDA label
Download (731 KB)
MSDS
Download (99.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedPreventionArthroplasty, Replacement / Moderate Renal Impairment (CrCl 30-50 mL/Min) / Prevention of Venous Thromboembolism1
4CompletedTreatmentAtrial Fibrillation1
4RecruitingPreventionAtrial Fibrillation2
4RecruitingPreventionAtrial Fibrillation / Venous Thromboembolism1
4Unknown StatusTreatmentAtrial Fibrillation1
4Unknown StatusTreatmentDeep Vein Thrombosis / Pulmonary Embolism1
4WithdrawnTreatmentThromboembolism1
3CompletedPreventionArthroplasty, Replacement, Hip / Thromboembolism1
3CompletedPreventionArthroplasty; Replacement; Knee / Thromboembolism2
3CompletedPreventionSecondary Prevention / Stroke1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Capsule, coated pelletsOral150 mg/1
Capsule, coated pelletsOral75 mg/1
CapsuleOral
CapsuleOral110 mg/1
CapsuleOral150 mg/1
CapsuleOral20 mg
CapsuleOral30 mg
CapsuleOral40 mg
CapsuleOral50 mg
CapsuleOral6.25 mg/ml
CapsuleOral75 mg/1
Capsule, coatedOral150 mg
CapsuleOral110 mg
CapsuleOral150 mg
CapsuleOral75 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9034822Yes2015-05-192031-07-20US flag
US6087380Yes2000-07-112022-06-28US flag
US7932273Yes2011-04-262026-03-07US flag
US7866474Yes2011-01-112028-03-02US flag
US9925174Yes2018-03-272023-12-14US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)132http://www.chemspider.com/Chemical-Structure.8615298.html
water solubility1.8mg/ml, partly soluble MSDS
logP3.8Apotex Inc. Product Monograph: Dabigatran Etexilate
Predicted Properties
PropertyValueSource
Water Solubility0.00466 mg/mLALOGPS
logP5.17ALOGPS
logP4.59ChemAxon
logS-5.1ALOGPS
pKa (Strongest Acidic)17.89ChemAxon
pKa (Strongest Basic)4.48ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area154.03 Å2ChemAxon
Rotatable Bond Count17ChemAxon
Refractivity176.43 m3·mol-1ChemAxon
Polarizability70.65 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.942
Blood Brain Barrier+0.8673
Caco-2 permeable-0.7014
P-glycoprotein substrateSubstrate0.7412
P-glycoprotein inhibitor IInhibitor0.7539
P-glycoprotein inhibitor IIInhibitor0.8443
Renal organic cation transporterNon-inhibitor0.701
CYP450 2C9 substrateNon-substrate0.858
CYP450 2D6 substrateNon-substrate0.837
CYP450 3A4 substrateSubstrate0.6154
CYP450 1A2 substrateNon-inhibitor0.6906
CYP450 2C9 inhibitorNon-inhibitor0.5102
CYP450 2D6 inhibitorNon-inhibitor0.8417
CYP450 2C19 inhibitorInhibitor0.5157
CYP450 3A4 inhibitorInhibitor0.781
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5789
Ames testNon AMES toxic0.6292
CarcinogenicityNon-carcinogens0.8065
BiodegradationNot ready biodegradable0.9931
Rat acute toxicity2.7093 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9047
hERG inhibition (predictor II)Inhibitor0.6181
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00kk-0981100000-78856b63936cf67ebce2
MS/MS Spectrum - , positiveLC-MS/MSsplash10-004r-0292116000-55b368cbe92da888e681

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
Dabigatran is a reversible, dose-dependent, competitive thrombin inhibitor with a Ki of 4.5 ± 0.2 nmol/L. In addition, the various acyl glucuronide metabolites of dabigatran also display in vitro activity.
General Function
Thrombospondin receptor activity
Specific Function
Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostas...
Gene Name
F2
Uniprot ID
P00734
Uniprot Name
Prothrombin
Molecular Weight
70036.295 Da
References
  1. Squizzato A, Dentali F, Steidl L, Ageno W: New direct thrombin inhibitors. Intern Emerg Med. 2009 Dec;4(6):479-84. doi: 10.1007/s11739-009-0314-8. Epub 2009 Sep 15. [Article]
  2. Liesenfeld KH, Schafer HG, Troconiz IF, Tillmann C, Eriksson BI, Stangier J: Effects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population model analysis. Br J Clin Pharmacol. 2006 Nov;62(5):527-37. [Article]
  3. Karthikeyan G, Eikelboom JW, Hirsh J: Dabigatran: ready for prime time? Pol Arch Med Wewn. 2010 Apr;120(4):137-42. [Article]
  4. Wienen W, Stassen JM, Priepke H, Ries UJ, Hauel N: In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb Haemost. 2007 Jul;98(1):155-62. [Article]
  5. Ebner T, Wagner K, Wienen W: Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity. Drug Metab Dispos. 2010 Sep;38(9):1567-75. doi: 10.1124/dmd.110.033696. Epub 2010 Jun 15. [Article]
  6. Eisert WG, Hauel N, Stangier J, Wienen W, Clemens A, van Ryn J: Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin. Arterioscler Thromb Vasc Biol. 2010 Oct;30(10):1885-9. doi: 10.1161/ATVBAHA.110.203604. Epub 2010 Jul 29. [Article]
  7. FDA Approved Drug Products: PRADAXA (dabigatran) oral pellets [Link]
  8. FDA Approved Drug Products: PRADAXA (dabigatran) oral capsules [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Triglyceride lipase activity
Specific Function
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acy...
Gene Name
CES1
Uniprot ID
P23141
Uniprot Name
Liver carboxylesterase 1
Molecular Weight
62520.62 Da
References
  1. Hu ZY, Parker RB, Herring VL, Laizure SC: Conventional liquid chromatography/triple quadrupole mass spectrometry based metabolite identification and semi-quantitative estimation approach in the investigation of in vitro dabigatran etexilate metabolism. Anal Bioanal Chem. 2013 Feb;405(5):1695-704. doi: 10.1007/s00216-012-6576-4. Epub 2012 Dec 14. [Article]
  2. Laizure SC, Parker RB, Herring VL, Hu ZY: Identification of carboxylesterase-dependent dabigatran etexilate hydrolysis. Drug Metab Dispos. 2014 Feb;42(2):201-6. doi: 10.1124/dmd.113.054353. Epub 2013 Nov 8. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Methylumbelliferyl-acetate deacetylase activity
Specific Function
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Shows high catalytic efficiency for hydrolysis of cocaine, 4-methylumbelliferyl acetate, heroin and ...
Gene Name
CES2
Uniprot ID
O00748
Uniprot Name
Cocaine esterase
Molecular Weight
61806.41 Da
References
  1. Hu ZY, Parker RB, Herring VL, Laizure SC: Conventional liquid chromatography/triple quadrupole mass spectrometry based metabolite identification and semi-quantitative estimation approach in the investigation of in vitro dabigatran etexilate metabolism. Anal Bioanal Chem. 2013 Feb;405(5):1695-704. doi: 10.1007/s00216-012-6576-4. Epub 2012 Dec 14. [Article]
  2. Laizure SC, Parker RB, Herring VL, Hu ZY: Identification of carboxylesterase-dependent dabigatran etexilate hydrolysis. Drug Metab Dispos. 2014 Feb;42(2):201-6. doi: 10.1124/dmd.113.054353. Epub 2013 Nov 8. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Glucuronosyltransferase activity
Specific Function
UDPGTs are of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isozyme displays activity toward several classes of xeno...
Gene Name
UGT2B15
Uniprot ID
P54855
Uniprot Name
UDP-glucuronosyltransferase 2B15
Molecular Weight
61035.815 Da
References
  1. Ebner T, Wagner K, Wienen W: Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity. Drug Metab Dispos. 2010 Sep;38(9):1567-75. doi: 10.1124/dmd.110.033696. Epub 2010 Jun 15. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da
References
  1. Ebner T, Wagner K, Wienen W: Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity. Drug Metab Dispos. 2010 Sep;38(9):1567-75. doi: 10.1124/dmd.110.033696. Epub 2010 Jun 15. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Nadph dehydrogenase (quinone) activity
Specific Function
The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinones involved in detoxification pathways as well as in biosynthetic processes such as the vi...
Gene Name
NQO2
Uniprot ID
P16083
Uniprot Name
Ribosyldihydronicotinamide dehydrogenase [quinone]
Molecular Weight
25918.4 Da
References
  1. Michaelis S, Marais A, Schrey AK, Graebner OY, Schaudt C, Sefkow M, Kroll F, Dreger M, Glinski M, Koester H, Metternich R, Fischer JJ: Dabigatran and dabigatran ethyl ester: potent inhibitors of ribosyldihydronicotinamide dehydrogenase (NQO2). J Med Chem. 2012 Apr 26;55(8):3934-44. doi: 10.1021/jm3001339. Epub 2012 Apr 17. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Glucuronosyltransferase activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol su...
Gene Name
UGT2B7
Uniprot ID
P16662
Uniprot Name
UDP-glucuronosyltransferase 2B7
Molecular Weight
60694.12 Da
References
  1. Ebner T, Wagner K, Wienen W: Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity. Drug Metab Dispos. 2010 Sep;38(9):1567-75. doi: 10.1124/dmd.110.033696. Epub 2010 Jun 15. [Article]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. De Simone G, Pasquadibisceglie A, di Masi A, Buzzelli V, Trezza V, Macari G, Polticelli F, Ascenzi P: Binding of direct oral anticoagulants to the FA1 site of human serum albumin. J Mol Recognit. 2021 Mar;34(3):e2877. doi: 10.1002/jmr.2877. Epub 2020 Oct 9. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
Dabigatran etexilate, but not dabigatran itself, is a P-gp substrate.
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Galanis T, Thomson L, Palladino M, Merli GJ: New oral anticoagulants. J Thromb Thrombolysis. 2011 Apr;31(3):310-20. doi: 10.1007/s11239-011-0559-8. [Article]
  2. Scaglione F: New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clin Pharmacokinet. 2013 Feb;52(2):69-82. doi: 10.1007/s40262-012-0030-9. [Article]
  3. Liesenfeld KH, Lehr T, Dansirikul C, Reilly PA, Connolly SJ, Ezekowitz MD, Yusuf S, Wallentin L, Haertter S, Staab A: Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost. 2011 Nov;9(11):2168-75. doi: 10.1111/j.1538-7836.2011.04498.x. [Article]
  4. Hartter S, Koenen-Bergmann M, Sharma A, Nehmiz G, Lemke U, Timmer W, Reilly PA: Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin. Br J Clin Pharmacol. 2012 Sep;74(3):490-500. doi: 10.1111/j.1365-2125.2012.04218.x. [Article]
  5. Hartter S, Sennewald R, Nehmiz G, Reilly P: Oral bioavailability of dabigatran etexilate (Pradaxa((R)) ) after co-medication with verapamil in healthy subjects. Br J Clin Pharmacol. 2013 Apr;75(4):1053-62. doi: 10.1111/j.1365-2125.2012.04453.x. [Article]
  6. Delavenne X, Ollier E, Basset T, Bertoletti L, Accassat S, Garcin A, Laporte S, Zufferey P, Mismetti P: A semi-mechanistic absorption model to evaluate drug-drug interaction with dabigatran: application with clarithromycin. Br J Clin Pharmacol. 2013 Jul;76(1):107-13. doi: 10.1111/bcp.12055. [Article]
  7. Stollberger C, Finsterer J: Relevance of P-glycoprotein in stroke prevention with dabigatran, rivaroxaban, and apixaban. Herz. 2015 Apr;40 Suppl 2:140-5. doi: 10.1007/s00059-014-4188-9. Epub 2015 Jan 25. [Article]
  8. Doki K, Neuhoff S, Rostami-Hodjegan A, Homma M: Assessing Potential Drug-Drug Interactions Between Dabigatran Etexilate and a P-Glycoprotein Inhibitor in Renal Impairment Populations Using Physiologically Based Pharmacokinetic Modeling. CPT Pharmacometrics Syst Pharmacol. 2019 Feb;8(2):118-126. doi: 10.1002/psp4.12382. [Article]
  9. FDA Approved Drug Products: PRADAXA (dabigatran) oral pellets [Link]
  10. FDA Approved Drug Products: PRADAXA (dabigatran) oral capsules [Link]

Drug created on May 03, 2010 18:25 / Updated on July 24, 2021 14:57