Alteplase

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

• Acute Ischemic Stroke
• Cardiac mortality
• Heart Failure
• Pulmonary Embolism Acute Massive
• Central venous access device thrombosis

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

Target	Actions	Organism
APlasminogen	activator	Humans
AFibrinogen alpha chain	binder	Humans
AFibrinogen gamma chain	binder	Humans
UPlasminogen activator inhibitor 1	Not Available	Humans

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

Pathway	Category
Alteplase Action Pathway	Drug 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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abciximab	The risk or severity of bleeding can be increased when Abciximab is combined with Alteplase.
Aceclofenac	The risk or severity of bleeding and hemorrhage can be increased when Aceclofenac is combined with Alteplase.
Acemetacin	The risk or severity of bleeding and hemorrhage can be increased when Alteplase is combined with Acemetacin.
Acenocoumarol	The risk or severity of bleeding can be increased when Alteplase is combined with Acenocoumarol.
Acetylsalicylic acid	Acetylsalicylic acid may increase the anticoagulant activities of Alteplase.
Albutrepenonacog alfa	The therapeutic efficacy of Albutrepenonacog alfa can be decreased when used in combination with Alteplase.
Alclofenac	The risk or severity of bleeding and hemorrhage can be increased when Alclofenac is combined with Alteplase.
Aldesleukin	The risk or severity of bleeding can be increased when Alteplase is combined with Aldesleukin.
Alemtuzumab	The risk or severity of bleeding can be increased when Alteplase is combined with Alemtuzumab.
Alogliptin	The 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

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Activase	Injection, powder, lyophilized, for solution; Kit	100 mg/100mL	Intravenous	Genentech, Inc.	1987-11-13	Not applicable
Activase	Injection, powder, lyophilized, for solution; Kit	50 mg/50mL	Intravenous	Genentech, Inc.	1987-11-13	Not applicable
Activase RT-PA Inj	Powder, for solution	50 mg/50mL	Intravenous	Hoffmann La Roche	1987-12-31	1998-07-31
Activase RT-PA Inj	Powder, for solution	50 mg/50mL	Intravenous	Hoffmann La Roche	1987-12-31	1998-07-31
Activase RT-PA Inj	Powder, for solution	50 mg/50mL	Intravenous	Hoffmann La Roche	1987-12-31	1998-07-31
Cathflo	Powder, for solution	2 mg / vial	Intravenous	Hoffmann La Roche	2002-09-26	Not applicable
Cathflo Activase	Injection, powder, lyophilized, for solution	2.2 mg/2mL	Intravenous	Genentech, Inc.	2001-09-04	Not applicable

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Activase RT-PA	Alteplase (100 mg / kit) + Water (100 mL / kit)	Liquid; Powder, for solution	Intravenous	Hoffmann La Roche	1996-12-31	Not applicable
Activase RT-PA	Alteplase (50 mg / kit) + Water (50 mL / kit)	Liquid; Powder, for solution	Intravenous	Hoffmann La Roche	1998-04-12	Not applicable
Lysatec RT - Pa	Alteplase (50 mg / kit) + Water (50 mL / kit)	Powder, for solution	Intravenous	Genentech, Inc.	1993-12-31	1997-08-26

Categories

ATC Codes

B01AD02 — Alteplase

• B01AD — Enzymes
• B01A — ANTITHROMBOTIC AGENTS
• B01 — ANTITHROMBOTIC AGENTS
• B — BLOOD AND BLOOD FORMING ORGANS

S01XA13 — Alteplase

• S01XA — Other ophthalmologicals
• S01X — OTHER OPHTHALMOLOGICALS
• S01 — OPHTHALMOLOGICALS
• S — SENSORY ORGANS

Drug Categories

• Agents causing angioedema
• Amino Acids, Peptides, and Proteins
• Anticoagulants
• Blood and Blood Forming Organs
• Blood Proteins
• Cardiovascular Agents
• Endopeptidases
• Enzymes
• Enzymes and Coenzymes
• Fibrin Modulating Agents
• Fibrinolytic Agents
• Hematologic Agents
• Hydrolases
• Ophthalmologicals
• Peptide Hydrolases
• Plasminogen Activators
• Proteins
• Sensory Organs
• Serine Endopeptidases
• Serine Proteases
• Tissue Plasminogen Activator
• Tissue Plasminogen Activator, antagonists & inhibitors

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]

External Links

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

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Pulmonary Embolism / Pulmonary Hypertension (PH) / Thromboembolism / Ventricular Dysfunction, Right	1
4	Completed	Treatment	Acute Myocardial Infarction With ST Segment Elevation	2
4	Completed	Treatment	Cerebrovascular Accident	3
4	Completed	Treatment	Deep Vein Thrombosis / Post Thrombotic Syndrome	1
4	Completed	Treatment	Dysfunctional Central Venous Access Devices (CVADS)	1
4	Completed	Treatment	Empyema / Parapneumonic Effusion / Pleural Diseases / Pleural space infections	1
4	Completed	Treatment	Ischemic Stroke	1
4	Completed	Treatment	Ischemic Stroke / Large-Artery Atherosclerosis (Embolus/Thrombosis) / Thrombectomy	1
4	Completed	Treatment	Pleural Diseases	1
4	Completed	Treatment	Pleural Diseases / Pleural Effusions / Pleural Empyema	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

• Genentech Inc.

Dosage Forms

Form	Route	Strength
Injection, powder, for solution
Injection, powder, for solution	Intravenous	2 MG
Injection, powder, for solution	Intravenous	20 MG/20ML
Injection, powder, for solution	Intravenous	50 MG/50ML
Solution	Intravenous	20 MG
Solution	Intravenous	50 MG
Injection, powder, for solution	Parenteral
Injection, powder, lyophilized, for solution	Intravenous
Injection, powder, for solution	Intravenous	50 mg
Solution	Intravenous
Injection, powder, lyophilized, for solution; kit	Intravenous	100 mg/100mL
Injection, powder, lyophilized, for solution; kit	Intravenous	50 mg/50mL
Liquid; powder, for solution	Intravenous
Powder, for solution	Intravenous	50 mg/50mL
Powder, for solution	Intravenous	2 mg / vial
Injection, powder, lyophilized, for solution	Intravenous	2.2 mg/2mL
Powder, for solution	Intravenous
Powder		50 mg/1vial

Prices

Unit description	Cost	Unit
Activase 100 mg vial	4779.71USD	vial
Activase 50 mg vial	2389.85USD	vial
Cathflo activase 2 mg vial	106.33USD	vial

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Not Available

Properties

State

Liquid

Experimental Properties

Property	Value	Source
melting point (°C)	60 °C	Novokhatny, V.V. et al., J. Biol. Chem. 266:12994-123002 (1991)
hydrophobicity	-0.516	Not Available
isoelectric point	7.61	Not Available

Targets

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Details1. Plasminogen

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]

Details2. Fibrinogen alpha chain

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]

Details3. Fibrinogen gamma chain

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]

Details4. Plasminogen activator inhibitor 1

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]

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Drug created at June 13, 2005 13:24 / Updated at September 26, 2022 19:02