Identification

Summary

Alteplase is a recombinant form of human tissue plasminogen activator used in the emergency treatment of myocardial infarction, ischemic stroke, and pulmonary emboli.

Brand Names
Activase, Cathflo, Cathflo Activase
Generic Name
Alteplase
DrugBank Accession Number
DB00009
Background

Alteplase is a recombinant tissue plasminogen activator (rt-PA) used as a thrombolytic agent.6 It cleaves plasminogen to form plasmin, an enzyme involved in the degradation of fibrin clots. In the absence of fibrin, the alteplase-mediated conversion of plasminogen is limited, thanks to the high affinity between alteplase and fibrin.3,6 Alteplase is a purified glycoprotein of 527 amino acids expressed in Chinese hamster ovary (CHO) cells.5,6 It was first approved by the FDA in 1987 for the management of thromboembolic disease, including acute myocardial infarction (AMI).1 The use of alteplase to manage AMI has decreased thanks to the availability of safer treatments such as angioplasty and stenting. However, its use for the treatment of acute ischemic stroke (AIS) has increased over the years.4 New thrombolytic agents derived from tissue plasminogen activator, such as desmoteplase, tenecteplase and reteplase, have also been developed.1,5 Alteplase is also available as Cathflo Activase (intracatheter instillation) for the restoration of function to central venous access devices.8

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Thrombolytic agents
Protein Structure
Protein Chemical Formula
C2569H3928N746O781S40
Protein Average Weight
59000.0 Da (Does not include carboyhydrate moieties)
Sequences
>Alteplase sequence
SYQVICRDEKTQMIYQQHQSWLRPVLRSNRVEYCWCNSGRAQCHSVPVKSCSEPRCFNGG
TCQQALYFSDFVCQCPEGFAGKCCEIDTRATCYEDQGISYRGTWSTAESGAECTNWNSSA
LAQKPYSGRRPDAIRLGLGNHNYCRNPDRDSKPWCYVFKAGKYSSEFCSTPACSEGNSDC
YFGNGSAYRGTHSLTESGASCLPWNSMILIGKVYTAQNPSAQALGLGKHNYCRNPDGDAK
PWCHVLKNRRLTWEYCDVPSCSTCGLRQYSQPQFRIKGGLFADIASHPWQAAIFAKHRRS
PGERFLCGGILISSCWILSAAHCFQERFPPHHLTVILGRTYRVVPGEEEQKFEVEKYIVH
KEFDDDTYDNDIALLQLKSDSSRCAQESSVVRTVCLPPADLQLPDWTECELSGYGKHEAL
SPFYSERLKEAHVRLYPSSRCTSQHLLNRTVTDNMLCAGDTRSGGPQANLHDACQGDSGG
PLVCLNDGRMTLVGIISWGLGCGQKDVPGVYTKVTNYLDWIRDNMRP
References:
  1. Health Canada Product Monograph Including Patient Medication Information: Activase rt-PA (alteplase) lyophilized powder for injection [Link]
Download FASTA Format
Synonyms
  • Alteplasa
  • Alteplase
  • Alteplase (genetical recombination)
  • Alteplase, recombinant
  • Alteplase,recombinant
  • Plasminogen activator (human tissue-type protein moiety)
  • rt-PA
  • t-PA
  • t-plasminogen activator
  • Tissue plasminogen activator
  • Tissue plasminogen activator alteplase
  • Tissue plasminogen activator, recombinant
  • tPA

Pharmacology

Indication

Alteplase is indicated for the treatment of acute ischemic stroke (AIS) and for use in acute myocardial infarction (AMI) for the reduction of mortality and incidence of heart failure. Alteplase is also indicated for the lysis of acute massive pulmonary embolism, defined as acute pulmonary emboli obstructing blood flow to a lobe or multiple lung segments, and acute pulmonary emboli accompanied by unstable hemodynamics.6

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Alteplase binds to fibrin and plasminogen. Alteplase specificity for fibrin is achieved thanks to its high affinity for lysine residues. Also, it can bind plasminogen via loop structures called kringles, stabilized by three disulphide linkages similar to the ones in plasminogen. The specificity of alteplase for plasminogen bound to fibrin allows this drug to act in a clot- or fibrin-specific manner, leading to low concentrations of circulating plasmin and a lower risk of hemorrhagic transformation.1,3

In patients with acute myocardial infarction, alteplase reduces fibrinogen levels 3 to 6 hours after treatment. In patients with acute ischemic stroke, patients treated with alteplase have a significantly higher resolution of hyperdense artery sign, a marker of clot formation in the proximal middle cerebral artery, compared to those treated with placebo.3 The use of alteplase increases the risk of bleeding and thromboembolic events. Rare cases of cholesterol embolism have also been reported.6

Mechanism of action

Alteplase is a recombinant tissue plasminogen activator (rt-PA) that converts plasminogen to plasmin in a fibrin-dependent process. In the absence of fibrin, alteplase converts a limited amount of plasminogen. However, in the presence of fibrin clots, alteplase binds to fibrin and cleaves the arginine-valine bond at positions 560 and 561 of plasminogen, converting it into its active form, plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus and promotes clot dissolution.1 Alteplase initiates local fibrinolysis with limited systemic proteolysis.6

TargetActionsOrganism
APlasminogen
activator
Humans
AFibrinogen alpha chain
binder
Humans
AFibrinogen gamma chain
binder
Humans
UPlasminogen activator inhibitor 1Not AvailableHumans
Absorption

Healthy volunteers with a baseline endogenous tissue plasminogen activator (t-PA) of 3.3 ng/ml had a 290-fold increase in baseline concentrations after receiving alteplase at an infusion rate of 0.25 mg/kg for 30 min; with an infusion rate of 0.5 mg/kg, a 550-fold increase was observed.1 Acute myocardial infarction patients (n=12) given 10 mg of alteplase in a 2-minute infusion reached a peak plasma concentration of 3310 ng/ml. This was followed by 50 mg of alteplase in 1 h and 30 mg in 1.5 h, resulting in steady-state plasma levels of 2210 ng/ml and 930 ng/ml, respectively.2

Volume of distribution

The initial volume of distribution approximates plasma volume.6 The average volume of distribution of the central compartment goes from 3.9 to 4.3 L, and the volume of distribution at steady state goes from 7.2 to 12 L.1

Protein binding

Not available.

Metabolism

Alteplase is mainly metabolized by the liver. The carbohydrate and polypeptide domains of alteplase interact with hepatic glycoprotein receptors, leading to receptor-mediated endocytosis.1 In vivo studies suggest that alteplase follows zero-order kinetics, meaning that its metabolism is saturable at higher plasma concentrations.1

Route of elimination

In healthy volunteers, more than 80% of alteplase is eliminated through urine 18 hours after administration.1

Half-life

Alteplase has an initial half-life of less than 5 minutes in patients with acute myocardial infarction (AMI). The dominant initial plasma half-life of the 3-hour and the accelerated regimens for AMI are similar.6

Clearance

Alteplase has a plasma clearance between 380 and 570 mL/min.6

Adverse Effects
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Toxicity

Toxicity information regarding alteplase is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as risk of bleeding and thromboembolic events.6 Symptomatic and supportive measures are recommended. The carcinogenic potential of alteplase or its effect on fertility have not been evaluated. In vivo studies evaluating tumorigenicity and in vitro studies evaluating mutagenicity were negative.6 It has been estimated that the acute oral and dermal toxicity of alteplase is above 5,000 mg/kg.7

Pathways
PathwayCategory
Alteplase Action PathwayDrug action
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
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Alteplase.
AceclofenacThe risk or severity of bleeding and hemorrhage can be increased when Aceclofenac is combined with Alteplase.
AcemetacinThe risk or severity of bleeding and hemorrhage can be increased when Alteplase is combined with Acemetacin.
AcenocoumarolThe risk or severity of bleeding can be increased when Alteplase is combined with Acenocoumarol.
Acetylsalicylic acidAcetylsalicylic acid may increase the anticoagulant activities of Alteplase.
Albutrepenonacog alfaThe therapeutic efficacy of Albutrepenonacog alfa can be decreased when used in combination with Alteplase.
AlclofenacThe risk or severity of bleeding and hemorrhage can be increased when Alclofenac is combined with Alteplase.
AldesleukinThe risk or severity of bleeding can be increased when Alteplase is combined with Aldesleukin.
AlemtuzumabThe risk or severity of bleeding can be increased when Alteplase is combined with Alemtuzumab.
AlogliptinThe risk or severity of angioedema can be increased when Alteplase is combined with Alogliptin.
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Food Interactions
  • Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ActivaseInjection, powder, lyophilized, for solution; Kit50 mg/50mLIntravenousGenentech, Inc.1987-11-13Not applicableUS flag
ActivaseInjection, powder, lyophilized, for solution; Kit100 mg/100mLIntravenousGenentech, Inc.1987-11-13Not applicableUS flag
Activase RT-PA InjPowder, for solution50 mg/50mLIntravenousHoffmann La Roche1987-12-311998-07-31Canada flag
Activase RT-PA InjPowder, for solution50 mg/50mLIntravenousHoffmann La Roche1987-12-311998-07-31Canada flag
Activase RT-PA InjPowder, for solution50 mg/50mLIntravenousHoffmann La Roche1987-12-311998-07-31Canada flag
CathfloPowder, for solution2 mg / vialIntravenousHoffmann La Roche2002-09-26Not applicableCanada flag
Cathflo ActivaseInjection, powder, lyophilized, for solution2.2 mg/2mLIntravenousGenentech, Inc.2001-09-04Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Activase RT-PAAlteplase (50 mg / kit) + Water (50 mL / kit)Liquid; Powder, for solutionIntravenousHoffmann La Roche1998-04-12Not applicableCanada flag
Activase RT-PAAlteplase (100 mg / kit) + Water (100 mL / kit)Liquid; Powder, for solutionIntravenousHoffmann La Roche1996-12-31Not applicableCanada flag
Lysatec RT - PaAlteplase (50 mg / kit) + Water (50 mL / kit)Powder, for solutionIntravenousGenentech, Inc.1993-12-311997-08-26Canada flag

Categories

ATC Codes
B01AD02 — AlteplaseS01XA13 — Alteplase
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
1RXS4UE564
CAS number
105857-23-6

References

Synthesis Reference

Goeddel, DV., et al. (1988). Human tissue plasminogen activator (U.S. Patent No. 4,766,075 A). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/a7/38/45/ec3813293b05c5/US4766075.pdf

General References
  1. Acheampong P, Ford GA: Pharmacokinetics of alteplase in the treatment of ischaemic stroke. Expert Opin Drug Metab Toxicol. 2012 Feb;8(2):271-81. doi: 10.1517/17425255.2012.652615. Epub 2012 Jan 17. [Article]
  2. Seifried E, Tanswell P, Ellbruck D, Haerer W, Schmidt A: Pharmacokinetics and haemostatic status during consecutive infusions of recombinant tissue-type plasminogen activator in patients with acute myocardial infarction. Thromb Haemost. 1989 Jun 30;61(3):497-501. [Article]
  3. Dhillon S: Alteplase: a review of its use in the management of acute ischaemic stroke. CNS Drugs. 2012 Oct 1;26(10):899-926. doi: 10.2165/11209940-000000000-00000. [Article]
  4. Doggrell SA: Alteplase: descendancy in myocardial infarction, ascendancy in stroke. Expert Opin Investig Drugs. 2001 Nov;10(11):2013-29. doi: 10.1517/13543784.10.11.2013. [Article]
  5. Collen D, Lijnen HR: Tissue-type plasminogen activator: a historical perspective and personal account. J Thromb Haemost. 2004 Apr;2(4):541-6. doi: 10.1111/j.1538-7933.2004.00645.x. [Article]
  6. FDA Approved Drug Products: ACTIVASE (alteplase) injection for intravenous use [Link]
  7. Genentech: ACTIVASE (alteplase) SDS [Link]
  8. FDA Approved Drug Products: Cathflo Activase (alteplase) powder for reconstitution for use in central venous access devices [Link]
UniProt
P00750
Genbank
L00153
KEGG Drug
D02837
PubChem Substance
46507035
RxNav
8410
ChEMBL
CHEMBL1201593
Therapeutic Targets Database
DAP000203
PharmGKB
PA164776730
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Alteplase

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentPulmonary Embolism / Pulmonary Hypertension (PH) / Thromboembolism / Ventricular Dysfunction, Right1
4CompletedTreatmentAcute Myocardial Infarction With ST Segment Elevation2
4CompletedTreatmentCerebrovascular Accident3
4CompletedTreatmentDeep Vein Thrombosis / Post Thrombotic Syndrome1
4CompletedTreatmentDysfunctional Central Venous Access Devices (CVADS)1
4CompletedTreatmentEmpyema / Parapneumonic Effusion / Pleural Diseases / Pleural space infections1
4CompletedTreatmentIschemic Stroke1
4CompletedTreatmentIschemic Stroke / Large-Artery Atherosclerosis (Embolus/Thrombosis) / Thrombectomy1
4CompletedTreatmentPleural Diseases1
4CompletedTreatmentPleural Diseases / Pleural Effusions / Pleural Empyema1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Genentech Inc.
Dosage Forms
FormRouteStrength
Injection, powder, for solution
Injection, powder, for solutionIntravenous2 MG
Injection, powder, for solutionIntravenous20 MG/20ML
Injection, powder, for solutionIntravenous50 MG/50ML
SolutionIntravenous20 MG
SolutionIntravenous50 MG
Injection, powder, for solutionParenteral
Injection, powder, lyophilized, for solutionIntravenous
Injection, powder, for solutionIntravenous50 mg
SolutionIntravenous
Injection, powder, lyophilized, for solution; kitIntravenous100 mg/100mL
Injection, powder, lyophilized, for solution; kitIntravenous50 mg/50mL
Liquid; powder, for solutionIntravenous
Powder, for solutionIntravenous50 mg/50mL
Powder, for solutionIntravenous2 mg / vial
Injection, powder, lyophilized, for solutionIntravenous2.2 mg/2mL
Powder, for solutionIntravenous
Powder50 mg/1vial
Prices
Unit descriptionCostUnit
Activase 100 mg vial4779.71USD vial
Activase 50 mg vial2389.85USD vial
Cathflo activase 2 mg vial106.33USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)60 °CNovokhatny, V.V. et al., J. Biol. Chem. 266:12994-123002 (1991)
hydrophobicity-0.516Not Available
isoelectric point7.61Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Activator
General Function
Serine-type peptidase activity
Specific Function
Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation. In...
Gene Name
PLG
Uniprot ID
P00747
Uniprot Name
Plasminogen
Molecular Weight
90568.415 Da
References
  1. Longstaff C, Williams S, Thelwell C: Fibrin binding and the regulation of plasminogen activators during thrombolytic therapy. Cardiovasc Hematol Agents Med Chem. 2008 Jul;6(3):212-23. [Article]
  2. Hilleman DE, Tsikouris JP, Seals AA, Marmur JD: Fibrinolytic agents for the management of ST-segment elevation myocardial infarction. Pharmacotherapy. 2007 Nov;27(11):1558-70. [Article]
  3. Acheampong P, Ford GA: Pharmacokinetics of alteplase in the treatment of ischaemic stroke. Expert Opin Drug Metab Toxicol. 2012 Feb;8(2):271-81. doi: 10.1517/17425255.2012.652615. Epub 2012 Jan 17. [Article]
  4. FDA Approved Drug Products: ACTIVASE (alteplase) injection for intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
Curator comments
Alteplase binds to fibrin, a molecule formed by the action of the protease thrombin on fibrinogen.
General Function
Structural molecule activity
Specific Function
Cleaved by the protease thrombin to yield monomers which, together with fibrinogen beta (FGB) and fibrinogen gamma (FGG), polymerize to form an insoluble fibrin matrix. Fibrin has a major function ...
Gene Name
FGA
Uniprot ID
P02671
Uniprot Name
Fibrinogen alpha chain
Molecular Weight
94972.455 Da
References
  1. Longstaff C, Williams S, Thelwell C: Fibrin binding and the regulation of plasminogen activators during thrombolytic therapy. Cardiovasc Hematol Agents Med Chem. 2008 Jul;6(3):212-23. [Article]
  2. Hilleman DE, Tsikouris JP, Seals AA, Marmur JD: Fibrinolytic agents for the management of ST-segment elevation myocardial infarction. Pharmacotherapy. 2007 Nov;27(11):1558-70. [Article]
  3. Acheampong P, Ford GA: Pharmacokinetics of alteplase in the treatment of ischaemic stroke. Expert Opin Drug Metab Toxicol. 2012 Feb;8(2):271-81. doi: 10.1517/17425255.2012.652615. Epub 2012 Jan 17. [Article]
  4. FDA Approved Drug Products: ACTIVASE (alteplase) injection for intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
Curator comments
Alteplase binds to fibrin, a molecule formed by the action of the protease thrombin on fibrinogen.
General Function
Structural molecule activity
Specific Function
Together with fibrinogen alpha (FGA) and fibrinogen beta (FGB), polymerizes to form an insoluble fibrin matrix. Has a major function in hemostasis as one of the primary components of blood clots. I...
Gene Name
FGG
Uniprot ID
P02679
Uniprot Name
Fibrinogen gamma chain
Molecular Weight
51511.29 Da
References
  1. Longstaff C, Williams S, Thelwell C: Fibrin binding and the regulation of plasminogen activators during thrombolytic therapy. Cardiovasc Hematol Agents Med Chem. 2008 Jul;6(3):212-23. [Article]
  2. Hilleman DE, Tsikouris JP, Seals AA, Marmur JD: Fibrinolytic agents for the management of ST-segment elevation myocardial infarction. Pharmacotherapy. 2007 Nov;27(11):1558-70. [Article]
  3. Acheampong P, Ford GA: Pharmacokinetics of alteplase in the treatment of ischaemic stroke. Expert Opin Drug Metab Toxicol. 2012 Feb;8(2):271-81. doi: 10.1517/17425255.2012.652615. Epub 2012 Jan 17. [Article]
  4. FDA Approved Drug Products: ACTIVASE (alteplase) injection for intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Serine-type endopeptidase inhibitor activity
Specific Function
Serine protease inhibitor. This inhibitor acts as 'bait' for tissue plasminogen activator, urokinase, protein C and matriptase-3/TMPRSS7. Its rapid interaction with PLAT may function as a major con...
Gene Name
SERPINE1
Uniprot ID
P05121
Uniprot Name
Plasminogen activator inhibitor 1
Molecular Weight
45059.695 Da
References
  1. Hilleman DE, Tsikouris JP, Seals AA, Marmur JD: Fibrinolytic agents for the management of ST-segment elevation myocardial infarction. Pharmacotherapy. 2007 Nov;27(11):1558-70. [Article]

Drug created at June 13, 2005 13:24 / Updated at December 04, 2022 18:48