Argatroban

Identification

Summary

Argatroban is a synthetic direct thrombin inhibitor used for the prevention and treatment of thrombosis related to heparin use.

Generic Name
Argatroban
DrugBank Accession Number
DB00278
Background

Argatroban is a direct, selective thrombin inhibitor. The American College of Cardiologists (ACC) recommend using bivalirudin or argatroban in patients who have had, or at risk for, heparin induced thrombocytopenia (HIT) and are undergoing percutaneous coronary intervention. Argatroban is a non-heparin anticoagulant shown to both normalize platelet count in patients with HIT and prevent the formation of thrombi. Parental anticoagulants must be stopped and a baseline activated partial thromboplastin time must be obtained prior to administering argatroban.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 508.64
Monoisotopic: 508.246789457
Chemical Formula
C23H36N6O5S
Synonyms
  • Argatroban
  • Argatroban anhydrous

Pharmacology

Indication

Argatroban is indicated for prevention and treatment of thrombosis caused by heparin-induced thrombocytopenia (HIT). It is also indicated for use in patients with, or at risk for, HIT who are undergoing percutaneous coronary intervention.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Prophylaxis ofThrombosis••••••••••••••••••••••••••••• •••••••• •••••••••••• •••••
Treatment ofThrombosis••••••••••••••••••
Prophylaxis ofThrombosis•••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Argatroban is a synthetic direct thrombin inhibitor derived from L-arginine indicated as an anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia. Argatroban is a direct thrombin inhibitor that reversibly binds to the thrombin active site. Argatroban does not require the co-factor antithrombin III for antithrombotic activity. Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation; activation of coagulation factors V, VIII, and XIII; protein C; and platelet aggregation. Argatroban is highly selective for thrombin with an inhibitory constant (Ki) of 0.04 µM. At therapeutic concentrations, Argatroban has little or no effect on related serine proteases (trypsin, factor Xa, plasmin, and kallikrein). Argatroban is capable of inhibiting the action of both free and clot-associated thrombin.

Mechanism of action

Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation; activation of coagulation factors V, VIII, and XIII; protein C; and platelet aggregation.

TargetActionsOrganism
AProthrombin
inhibitor
Humans
Absorption

Bioavailability is 100% (intravenous).

Volume of distribution
  • 174 mL/kg
  • 12.18 L [70-kg adult]
Protein binding

54%

Metabolism

Liver via hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring. Age and gender do not substantially affect the pharmacodynamic or pharmacokinetic profile of argatroban.

Route of elimination

Argatroban is excreted primarily in the feces (65%), presumably through biliary secretion; 22% is eliminated via urine.

Half-life

39 and 51 minutes

Clearance
  • 5.1 L/kg/hr [infusion doses up to 40 mcg/kg/min]
Adverse Effects
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Toxicity

Excessive bleeding

Pathways
PathwayCategory
Argatroban Action PathwayDrug action
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
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
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Argatroban.
AceclofenacThe risk or severity of bleeding and hemorrhage can be increased when Aceclofenac is combined with Argatroban.
AcemetacinThe risk or severity of bleeding and hemorrhage can be increased when Argatroban is combined with Acemetacin.
AcenocoumarolThe risk or severity of bleeding can be increased when Argatroban is combined with Acenocoumarol.
Acetylsalicylic acidAcetylsalicylic acid may increase the anticoagulant activities of Argatroban.
Food Interactions
  • Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.
  • Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of argatroban; however, the evidence is conflicting.
  • Exercise caution with St. John's Wort.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Argatroban monohydrateIY90U61Z3S141396-28-3AIEZTKLTLCMZIA-CZSXTPSTSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ArgatrobanSolution100 mg / mLIntravenousSandoz Canada Incorporated2002-06-13Not applicableCanada flag
ArgatrobanInjection, solution1 mg/1mLIntravenousTeva Parenteral Medicines, Inc.2015-04-272017-03-31US flag
ArgatrobanInjection250 mg/2.5mLIntravenousHikma Pharmaceuticals USA Inc.2012-01-05Not applicableUS flag
ArgatrobanInjection1 mg/1mLIntravenousSandoz Inc2011-09-06Not applicableUS flag
ArgatrobanInjection1 mg/1mLIntravenousEagle Pharmaceuticals, Inc.2011-09-06Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ArgatrobanInjection50 mg/50mLIntravenousFresenius Kabi USA, LLC2021-05-24Not applicableUS flag
ArgatrobanInjection, solution250 mg/2.5mLIntravenousMylan Institutional LLC2017-11-14Not applicableUS flag
ArgatrobanInjection250 mg/2.5mLIntravenousPar Pharmaceutical, Inc.2015-06-01Not applicableUS flag
ArgatrobanInjection, solution1 mg/1mLIntravenousSagent Pharmaceuticals2021-04-15Not applicableUS flag
ArgatrobanInjection, solution100 mg/1mLIntravenousHospira, Inc.2017-03-06Not applicableUS flag

Categories

ATC Codes
B01AE03 — Argatroban
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as dipeptides. These are organic compounds containing a sequence of exactly two alpha-amino acids joined by a peptide bond.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Dipeptides
Alternative Parents
Alpha amino acid amides / Hydroquinolines / Piperidinecarboxylic acids / N-acylpiperidines / Secondary alkylarylamines / Aralkylamines / Organosulfonamides / Benzenoids / Tertiary carboxylic acid amides / Aminosulfonyl compounds
show 11 more
Substituents
Alpha-amino acid amide / Alpha-amino acid or derivatives / Alpha-dipeptide / Amine / Amino acid / Amino acid or derivatives / Aminosulfonyl compound / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle
show 28 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
OCY3U280Y3
CAS number
74863-84-6
InChI Key
KXNPVXPOPUZYGB-IOVMHBDKSA-N
InChI
InChI=1S/C23H36N6O5S/c1-14-8-10-29(18(12-14)22(31)32)21(30)17(6-4-9-26-23(24)25)28-35(33,34)19-7-3-5-16-11-15(2)13-27-20(16)19/h3,5,7,14-15,17-18,27-28H,4,6,8-13H2,1-2H3,(H,31,32)(H4,24,25,26)/t14-,15?,17+,18-/m1/s1
IUPAC Name
(2R,4R)-1-[(2S)-5-carbamimidamido-2-(3-methyl-1,2,3,4-tetrahydroquinoline-8-sulfonamido)pentanoyl]-4-methylpiperidine-2-carboxylic acid
SMILES
C[C@@H]1CCN([C@H](C1)C(O)=O)C(=O)[C@H](CCCNC(N)=N)NS(=O)(=O)C1=CC=CC2=C1NCC(C)C2

References

Synthesis Reference

Tomiya Mano, Jin Shiomura, "Argatroban preparations for ophthalmic use." U.S. Patent US5506241, issued October, 1986.

US5506241
General References
  1. Di Nisio M, Middeldorp S, Buller HR: Direct thrombin inhibitors. N Engl J Med. 2005 Sep 8;353(10):1028-40. [Article]
Human Metabolome Database
HMDB0014423
KEGG Compound
C04931
PubChem Compound
152951
PubChem Substance
46507650
ChemSpider
83702
BindingDB
50038001
RxNav
15202
ChEBI
94385
ChEMBL
CHEMBL1166
Therapeutic Targets Database
DAP000758
PharmGKB
PA164745516
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Argatroban
FDA label
Download (83.7 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
4CompletedTreatmentAcute Progressive Ischemic Stroke1
4CompletedTreatmentCVD2
4CompletedTreatmentEnd Stage Renal Disease (ESRD) / Renal Failure, Chronic Renal Failure1
4CompletedTreatmentIschemic Stroke1
4CompletedTreatmentStable Coronary Artery Disease (CAD) / Unstable Angina (Troponin Negative)1

Pharmacoeconomics

Manufacturers
  • Pfizer inc
Packagers
  • GlaxoSmithKline Inc.
Dosage Forms
FormRouteStrength
SolutionParenteral1 mg/ml
Injection, solution, concentrateIntravenous100 mg/ml
InjectionIntravenous1 mg/1mL
InjectionIntravenous250 mg/2.5mL
InjectionIntravenous50 mg/50mL
Injection, solutionIntravenous1 mg/1mL
Injection, solutionIntravenous100 mg/1mL
Injection, solutionIntravenous250 mg/2.5mL
Injection, solutionIntravenous50 mg/50mL
SolutionIntravenous100 mg / mL
SolutionIntravenous125 mg/125mL
SolutionParenteral
Injection, solution, concentrateIntravenous; Parenteral100 MG/ML
Prices
Unit descriptionCostUnit
Argatroban 100 mg/ml Solution 2.5ml Vial1546.46USD vial
Argatroban 100 mg/ml vial743.49USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5214052No1993-05-252014-06-30US flag
US7589106No2009-09-152027-09-26US flag
US7687516No2010-03-302027-09-26US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP1Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.168 mg/mLALOGPS
logP0.04ALOGPS
logP-0.92Chemaxon
logS-3.5ALOGPS
pKa (Strongest Acidic)3.06Chemaxon
pKa (Strongest Basic)11.8Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count9Chemaxon
Hydrogen Donor Count6Chemaxon
Polar Surface Area177.71 Å2Chemaxon
Rotatable Bond Count8Chemaxon
Refractivity143.83 m3·mol-1Chemaxon
Polarizability53.77 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.6195
Blood Brain Barrier-0.8933
Caco-2 permeable-0.7293
P-glycoprotein substrateSubstrate0.8193
P-glycoprotein inhibitor INon-inhibitor0.6701
P-glycoprotein inhibitor IINon-inhibitor0.6802
Renal organic cation transporterNon-inhibitor0.8147
CYP450 2C9 substrateNon-substrate0.5571
CYP450 2D6 substrateNon-substrate0.8861
CYP450 3A4 substrateNon-substrate0.5477
CYP450 1A2 substrateNon-inhibitor0.8849
CYP450 2C9 inhibitorNon-inhibitor0.662
CYP450 2D6 inhibitorNon-inhibitor0.8789
CYP450 2C19 inhibitorNon-inhibitor0.7706
CYP450 3A4 inhibitorNon-inhibitor0.8316
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9636
Ames testNon AMES toxic0.6238
CarcinogenicityNon-carcinogens0.7551
BiodegradationNot ready biodegradable0.9966
Rat acute toxicity1.5767 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9833
hERG inhibition (predictor II)Non-inhibitor0.6071
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 MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4l-0510390000-53aeab384ddd34d47532
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4i-0010190000-afb6403a6e4cdfb5fc65
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4j-1821890000-e4264c44306f132f66e0
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4l-0292860000-de017279329746917cd8
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-01wb-2980110000-f7f6a41333ce5422da4e
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0gy5-2093000000-2d4691952334215a383f
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
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. Kawada T, Okada Y, Hoson M, Endo S, Yokoyama M, Kitanaka Y, Kimura K, Abe H, Yamate N: Argatroban, an attractive anticoagulant, for left heart bypass with centrifugal pump for repair of traumatic aortic rupture. Jpn J Thorac Cardiovasc Surg. 1999 Mar;47(3):104-9. [Article]
  2. Sakai M, Ohteki H, Narita Y, Naitoh K, Natsuaki M, Itoh T: Argatroban as a potential anticoagulant in cardiopulmonary bypass-studies in a dog model. Cardiovasc Surg. 1999 Mar;7(2):187-94. [Article]
  3. Jang IK, Brown DF, Giugliano RP, Anderson HV, Losordo D, Nicolau JC, Dutra OP, Bazzino O, Viamonte VM, Norbady R, Liprandi AS, Massey TJ, Dinsmore R, Schwarz RP Jr: A multicenter, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: myocardial infarction with novastan and TPA (MINT) study. J Am Coll Cardiol. 1999 Jun;33(7):1879-85. [Article]
  4. Matsuo T, Kario K, Matsuda S, Yamaguchi N, Kakishita E: Effect of Thrombin Inhibition on Patients with Peripheral Arterial Obstructive Disease: A Multicenter Clinical Trial of Argatroban. J Thromb Thrombolysis. 1995;2(2):131-136. [Article]
  5. Serebruany VL, Jang IK, Giugliano RP, Massey TJ, Schwarz Jr RP: A Randomized, Blinded Study of Two Doses of Novastan(R) (Brand of Argatroban) Versus Heparin as Adjunctive Therapy to Recombinant Tissue Plasminogen Activator (Accelerated Administration) in Acute Myocardial Infarction: Rationale and Design of the Myocardial Infarction using Novastan(R) and T-PA (MINT) Study. J Thromb Thrombolysis. 1998;5(1):49-52. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Tran JQ, Di Cicco RA, Sheth SB, Tucci M, Peng L, Jorkasky DK, Hursting MJ, Benincosa LJ: Assessment of the potential pharmacokinetic and pharmacodynamic interactions between erythromycin and argatroban. J Clin Pharmacol. 1999 May;39(5):513-9. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Tran JQ, Di Cicco RA, Sheth SB, Tucci M, Peng L, Jorkasky DK, Hursting MJ, Benincosa LJ: Assessment of the potential pharmacokinetic and pharmacodynamic interactions between erythromycin and argatroban. J Clin Pharmacol. 1999 May;39(5):513-9. [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
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...

Components:

Drug created at June 13, 2005 13:24 / Updated at February 20, 2024 23:54