Identification

Name
Argatroban
Accession Number
DB00278  (APRD00105)
Type
Small Molecule
Groups
Approved, 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
Synonyms
  • Argatroban anhydrous
Product Ingredients
IngredientUNIICASInChI Key
Argatroban monohydrateIY90U61Z3S141396-28-3AIEZTKLTLCMZIA-CZSXTPSTSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ArgatrobanInjection250 mg/2.5mLIntravenousWest-Ward Pharmaceuticals Corp2012-01-05Not applicableUs
ArgatrobanInjection, solution100 mg/1mLIntravenousNovartis Pharmaceuticals Corporation2018-02-02Not applicableUs
ArgatrobanSolution100 mgIntravenousNovartis2002-06-13Not applicableCanada
ArgatrobanInjection1 mg/1mLIntravenousSandoz2011-09-06Not applicableUs
ArgatrobanInjection1 mg/1mLIntravenousEagle Pharmaceuticals, Inc.2011-09-06Not applicableUs
ArgatrobanInjection250 mg/2.5mLIntravenousWest-Ward Pharmaceuticals Corp2012-01-05Not applicableUs
ArgatrobanInjection50 mg/50mLIntravenousWest-Ward Pharmaceuticals Corp2016-11-01Not applicableUs
ArgatrobanInjection1 mg/1mLIntravenousSandoz2011-09-06Not applicableUs
ArgatrobanInjection, solution100 mg/1mLIntravenousGlaxosmithkline Inc2000-11-282018-08-31Us
ArgatrobanInjection, solution100 mg/1mLIntravenousFresenius Kabi2015-03-23Not applicableUs
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ArgatrobanInjection, solution100 mg/1mLIntravenousHospira, Inc.2017-03-06Not applicableUs
ArgatrobanInjection250 mg/2.5mLIntravenousPar Pharmaceutical2015-06-01Not applicableUs
ArgatrobanInjection, solution100 mg/1mLIntravenousAmneal Biosciences Llc2018-01-26Not applicableUs
ArgatrobanInjection, solution250 mg/2.5mLIntravenousMylan Institutional LLC2017-11-14Not applicableUs
ArgatrobanSolution125 mg/125mLIntravenousGland Pharma Limited2017-05-26Not applicableUs
Categories
UNII
OCY3U280Y3
CAS number
74863-84-6
Weight
Average: 508.64
Monoisotopic: 508.246789457
Chemical Formula
C23H36N6O5S
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

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.

Associated Conditions
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
Human
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]
Toxicity

Excessive bleeding

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Argatroban Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(1,2,6,7-3H)TestosteroneThe therapeutic efficacy of Argatroban can be increased when used in combination with (1,2,6,7-3H)Testosterone.
(R)-warfarinThe risk or severity of bleeding can be increased when Argatroban is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Argatroban is combined with (S)-Warfarin.
1-TestosteroneThe therapeutic efficacy of Argatroban can be increased when used in combination with 1-Testosterone.
18-methyl-19-nortestosteroneThe therapeutic efficacy of Argatroban can be increased when used in combination with 18-methyl-19-nortestosterone.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Argatroban is combined with 4-hydroxycoumarin.
4-HydroxytestosteroneThe therapeutic efficacy of Argatroban can be increased when used in combination with 4-Hydroxytestosterone.
5beta-dihydrotestosteroneThe therapeutic efficacy of Argatroban can be increased when used in combination with 5beta-dihydrotestosterone.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Argatroban.
AcalabrutinibThe metabolism of Argatroban can be decreased when combined with Acalabrutinib.
Food Interactions
  • Herbs and food with anticoagulant/antiplatelet activity. Major interactions may occur with danshen, dong quai, evening primrose oil, gingko, policosanol, willow bark

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. [PubMed:16148288]
External Links
Human Metabolome Database
HMDB0014423
KEGG Compound
C04931
PubChem Compound
152951
PubChem Substance
46507650
ChemSpider
83702
BindingDB
50038001
ChEBI
94385
ChEMBL
CHEMBL1166
Therapeutic Targets Database
DAP000758
PharmGKB
PA164745516
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Argatroban
ATC Codes
B01AE03 — Argatroban
AHFS Codes
  • 20:12.04.12 — Direct Thrombin Inhibitors
FDA label
Download (83.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentStroke, Ischemic1
2CompletedNot AvailableStaphylococcus Aureus Bacteraemia1
2CompletedTreatmentAchievement of a Sufficient Thrombosis Prohpylaxis in Clitically Ill Patients With Heparin Resistance1
2CompletedTreatmentCoronary Artery Disease / Unstable Angina (UA)1
2CompletedTreatmentHeparin-induced Thrombocytopenia Type II1
2CompletedTreatmentIschemia, Cerebral / Strokes1
2TerminatedTreatmentStroke, Ischemic1
3CompletedTreatmentCardiac surgery, heparin-induced thrombocytopenia and thrombosis syndrome1
3RecruitingTreatmentArgatroban / Low Molecular Weight Heparin / Neoplasms, Gynecologic / Venous Thromboembolism (VTE)1
4CompletedTreatmentCVD2
4CompletedTreatmentChronic Renal Failure (CRF) / Renal Disease, End-Stage1
4CompletedTreatmentThrombocytopenias / Thrombotic events1
4TerminatedOtherCoronary Artery Bypass Graft Surgery Patients / Presence of Heparin/Platelet Factor 4 Antibody1
4TerminatedTreatmentCardiac surgery, heparin-induced thrombocytopenia and thrombosis syndrome1
Not AvailableCompletedNot AvailableAcute HIT II (Heparin-induced Thrombocytopenia Type II)1

Pharmacoeconomics

Manufacturers
  • Pfizer inc
Packagers
  • GlaxoSmithKline Inc.
Dosage forms
FormRouteStrength
InjectionIntravenous1 mg/1mL
InjectionIntravenous250 mg/2.5mL
InjectionIntravenous50 mg/50mL
Injection, solutionIntravenous1 mg/1mL
Injection, solutionIntravenous100 mg/1mL
Injection, solutionIntravenous250 mg/2.5mL
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
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5214052No1994-06-302014-06-30Us
US7589106No2007-09-262027-09-26Us
US7687516No2007-09-262027-09-26Us

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
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Human
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. [PubMed:10226408]
  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:10353669]
  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:10362188]
  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:10608016]
  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. [PubMed:10608050]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Enzymes

Kind
Protein
Organism
Human
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. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
Kind
Protein
Organism
Human
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. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. 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. [PubMed:10234600]

Drug created on June 13, 2005 07:24 / Updated on November 14, 2018 12:40