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Identification
NameArgatroban
Accession NumberDB00278  (APRD00105)
TypeSmall Molecule
GroupsApproved, Investigational
Description

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.

Structure
Thumb
SynonymsNot Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Argatrobaninjection, solution100 mg/mLintravenousGlaxo Smith Kline Llc2000-11-28Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Argatrobaninjection250 mg/2.5mLintravenousWest ward Pharmaceutical Corp2012-01-05Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Argatrobansolution125 mg/125mLintravenousSandoz Inc2011-05-09Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Argatrobaninjection1 mg/mLintravenousSandoz Inc2011-09-06Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Argatrobaninjection1 mg/mLintravenousSandoz Inc2011-09-06Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Argatrobaninjection1 mg/mLintravenousEagle Pharmaceuticals, Inc.2011-09-06Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Argatrobaninjection1 mg/mLintravenousEagle Pharmaceuticals, Inc.2011-09-06Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Argatrobansolution100 mgintravenousPfizer Canada IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
CategoriesNot Available
CAS number74863-84-6
WeightAverage: 508.634
Monoisotopic: 508.246788982
Chemical FormulaC23H36N6O5S
InChI KeyKXNPVXPOPUZYGB-XYVMCAHJSA-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-[(diaminomethylidene)amino]-2-[(3R)-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](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as peptides. These are compounds containing an amide derived from two or more amino carboxylic acid molecules (the same or different) by formation of a covalent bond from the carbonyl carbon of one to the nitrogen atom of another.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentPeptides
Alternative Parents
Substituents
  • Alpha peptide
  • Alpha-amino acid amide
  • Tetrahydroquinoline
  • Benzenesulfonamide
  • Alpha-amino acid or derivatives
  • Piperidinecarboxylic acid
  • N-acyl-piperidine
  • Aralkylamine
  • Secondary aliphatic/aromatic amine
  • Benzenoid
  • Piperidine
  • Aminosulfonyl compound
  • Tertiary carboxylic acid amide
  • Sulfonyl
  • Sulfonic acid derivative
  • Sulfonamide
  • Tertiary amine
  • Guanidine
  • Carboxamide group
  • Azacycle
  • Organoheterocyclic compound
  • Organic 1,3-dipolar compound
  • Propargyl-type 1,3-dipolar organic compound
  • Carboximidamide
  • Secondary amine
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Hydrocarbon derivative
  • Organosulfur compound
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationArgatroban 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.
PharmacodynamicsArgatroban 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 actionArgatroban 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.
AbsorptionBioavailability is 100% (intravenous).
Volume of distribution
  • 174 mL/kg
  • 12.18 L [70-kg adult]
Protein binding54%
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 eliminationArgatroban is excreted primarily in the feces (65%), presumably through biliary secretion; 22% is eliminated via urine.
Half life39 and 51 minutes
Clearance
  • 5.1 L/kg/hr [infusion doses up to 40 mcg/kg/min]
ToxicityExcessive bleeding
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Argatroban Action PathwayDrug actionSMP00276
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 substrateNon-inhibitor0.662
CYP450 2D6 substrateNon-inhibitor0.8789
CYP450 2C19 substrateNon-inhibitor0.7706
CYP450 3A4 substrateNon-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
Pharmacoeconomics
Manufacturers
Packagers
Dosage forms
FormRouteStrength
Injectionintravenous1 mg/mL
Injectionintravenous250 mg/2.5mL
Injection, solutionintravenous100 mg/mL
Solutionintravenous100 mg
Solutionintravenous125 mg/125mL
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
CountryPatent NumberApprovedExpires (estimated)
United States52140521994-06-302014-06-30
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP1Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.221 mg/mLALOGPS
logP0.19ALOGPS
logP-0.97ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)3.07ChemAxon
pKa (Strongest Basic)10.91ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area180.21 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity133.54 m3·mol-1ChemAxon
Polarizability53.9 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

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

US5506241
General Reference
  1. Di Nisio M, Middeldorp S, Buller HR: Direct thrombin inhibitors. N Engl J Med. 2005 Sep 8;353(10):1028-40. Pubmed
External Links
ATC CodesB01AE03
AHFS Codes
  • 20:12.04.12
PDB EntriesNot Available
FDA labelDownload (83.7 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AbciximabMay enhance the anticoagulant effect of other Anticoagulants.
AcenocoumarolMay enhance the anticoagulant effect of other Anticoagulants.
Acetylsalicylic acidMay enhance the anticoagulant effect of Anticoagulants.
AlteplaseMay enhance the anticoagulant effect of Anticoagulants.
AnistreplaseMay enhance the anticoagulant effect of Anticoagulants.
ApixabanMay enhance the anticoagulant effect of Anticoagulants.
Citric AcidMay enhance the anticoagulant effect of other Anticoagulants.
Dabigatran etexilateMay enhance the anticoagulant effect of Anticoagulants.
DalteparinMay enhance the anticoagulant effect of other Anticoagulants.
DasatinibMay enhance the anticoagulant effect of Anticoagulants.
DeferasiroxAnticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased.
Deoxycholic AcidAnticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased.
DesogestrelMay diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects.
DicoumarolMay enhance the anticoagulant effect of other Anticoagulants.
DydrogesteroneMay diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects.
Edetic AcidMay enhance the anticoagulant effect of other Anticoagulants.
EnoxaparinMay enhance the anticoagulant effect of other Anticoagulants.
Ethyl biscoumacetateMay enhance the anticoagulant effect of other Anticoagulants.
Fondaparinux sodiumMay enhance the anticoagulant effect of other Anticoagulants.
GestodeneMay diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects.
HeparinMay enhance the anticoagulant effect of other Anticoagulants.
IbritumomabAnticoagulants may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to an increased risk of bleeding.
ObinutuzumabAnticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased.
PhenindioneMay enhance the anticoagulant effect of other Anticoagulants.
PhenprocoumonMay enhance the anticoagulant effect of other Anticoagulants.
ProgesteroneMay diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects.
ReteplaseMay enhance the anticoagulant effect of Anticoagulants.
RidogrelMay enhance the anticoagulant effect of Anticoagulants.
RivaroxabanAnticoagulants may enhance the anticoagulant effect of Rivaroxaban.
Salicylate-sodiumMay enhance the anticoagulant effect of Anticoagulants.
StreptokinaseMay enhance the anticoagulant effect of Anticoagulants.
SugammadexMay enhance the anticoagulant effect of Anticoagulants.
SulodexideMay enhance the anticoagulant effect of other Anticoagulants.
TenecteplaseMay enhance the anticoagulant effect of Anticoagulants.
TipranavirMay enhance the anticoagulant effect of Anticoagulants.
TreprostinilMay enhance the anticoagulant effect of other Anticoagulants.
UrokinaseMay enhance the anticoagulant effect of Anticoagulants.
Vitamin EMay enhance the anticoagulant effect of Anticoagulants. Vitamin E may also increase the overall risk for bleeding.
VorapaxarMay enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding.
WarfarinMay enhance the anticoagulant effect of other Anticoagulants.
Food Interactions
  • Herbs and food with anticoagulant/antiplatelet activity. Major interactions may occur with danshen, dong quai, evening primrose oil, gingko, policosanol, willow bark

Targets

1. Prothrombin

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Prothrombin P00734 Details

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. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  5. Serebruany VL, Jang IK, Giugliano RP, Massey TJ, Schwarz Jr RP: A Randomized, Blinded Study of Two Doses of Novastan® (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® and T-PA (MINT) Study. J Thromb Thrombolysis. 1998;5(1):49-52. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:09