Identification

Name
Aprotinin
Accession Number
DB06692
Type
Biotech
Groups
Approved, Investigational, Withdrawn
Biologic Classification
Protein Based Therapies
Other protein based therapies
Description

Aprotinin, also known as bovine pancreatic trypsin inhibitor, BPTI (Trasylol, Bayer) is a protein, that is used as medication administered by injection to reduce bleeding during complex surgery, such as heart and liver surgery. Its main effect is the slowing down of fibrinolysis, the process that leads to the breakdown of blood clots. The aim in its use is to decrease the need for blood transfusions during surgery, as well as end-organ damage due to hypotension (low blood pressure) as a result of marked blood loss. The drug was temporarily withdrawn worldwide in 2007 after studies suggested that its use increased the risk of complications or death; after this was confirmed by follow-up studies, Trasylol was entirely and permanently withdrawn in May 2008, except - at least for the time being - for very restricted research use. [Wikipedia]

Protein structure
Db06692
Protein chemical formula
C284H432N84O79S7
Protein average weight
6511.439 Da
Sequences
>Aprotinin (bovine pancreatic trypsin inhibitor)
RPDFCLEPPYTGPCKARIIRYFYNAKAGLCQTFVYGGCRAKRNNFKSAEDCMRTCGGA
Download FASTA Format
Synonyms
  • Aprotinin (bovine)
  • Aprotinin Biosynthetic
  • Aprotinin Bovine
  • Aprotinin Concentrated Solution
  • Aprotinina
  • Bovine Aprotinin
  • Bovine Pancreatic Trypsin Inhibitor
  • BPTI
  • Fibrinolysis Inhibitor
  • Trypsin Inhibitor, Pancreatic Basic
External IDs
232-994-9 / Bayer A 128 / Bayer-A-128 / Riker-52G / RP-9921
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TrasylolSolution1000000IntravenousBayer Pharmaceuticals Corporation2007-01-092018-08-02Us
TrasylolSolution10000 unitIntravenousNordic Group Bv1997-12-15Not applicableCanada
TrasylolSolution2000000IntravenousBayer Pharmaceuticals Corporation2007-01-092018-08-02Us
Trasylol Inj 10000 Kiu/mlLiquid100000 unitIntravenousMiles Inc. Pharmaceutical Division1981-12-311998-09-25Canada
Categories
UNII
04XPW8C0FL
CAS number
9087-70-1

Pharmacology

Indication

For prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery who are at an increased risk for blood loss and blood transfusion.

Associated Therapies
Pharmacodynamics

Aprotinin is a broad spectrum protease inhibitor which modulates the systemic inflammatory response (SIR) associated with cardiopulmonary bypass (CPB) surgery. SIR results in the interrelated activation of the hemostatic, fibrinolytic, cellular and humoral inflammatory systems. Aprotinin, through its inhibition of multiple mediators [e.g., kallikrein, plasmin] results in the attenuation of inflammatory responses, fibrinolysis, and thrombin generation. Aprotinin inhibits pro-inflammatory cytokine release and maintains glycoprotein homeostasis. In platelets, aprotinin reduces glycoprotein loss (e.g., GpIb, GpIIb/IIIa), while in granulocytes it prevents the expression of pro-inflammatory adhesive glycoproteins (e.g., CD11b). The effects of aprotinin use in CPB involves a reduction in inflammatory response which translates into a decreased need for allogeneic blood transfusions, reduced bleeding, and decreased mediastinal re-exploration for bleeding.

Mechanism of action

Aprotinin inhibits several serine proteases, specifically trypsin, chymotrypsin and plasmin at a concentration of about 125,000 IU/ml, and kallikrein at 300,000 IU/ml. Its action on kallikrein leads to the inhibition of the formation of factor XIIa. As a result, both the intrinsic pathway of coagulation and fibrinolysis are inhibited. Its action on plasmin independently slows fibrinolysis.

TargetActionsOrganism
UTrypsin-1Not AvailableHuman
UChymotrypsinogen BNot AvailableHuman
UPlasminogenNot AvailableHuman
UKallikrein-1Not AvailableHuman
Absorption

100% (IV)

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Aprotinin is slowly degraded by lysosomal enzymes.

Route of elimination

Following a single IV dose of radiolabelled aprotinin, approximately 25-40% of the radioactivity is excreted in the urine over 48 hours. After a 30 minute infusion of 1 million KIU, about 2% is excreted as unchanged drug. After a larger dose of 2 million KIU infused over 30 minutes, urinary excretion of unchanged aprotinin accounts for approximately 9% of the dose.

Half life

Following this distribution phase, a plasma half-life of about 150 minutes is observed. At later time points, (i.e., beyond 5 hours after dosing) there is a terminal elimination phase with a half-life of about 10 hours.

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

Interactions

Drug Interactions
DrugInteraction
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidAprotinin may decrease the antihypertensive activities of 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid.
AbciximabThe therapeutic efficacy of Abciximab can be decreased when used in combination with Aprotinin.
AcebutololAprotinin may increase the bradycardic activities of Acebutolol.
AcetylcholineThe risk or severity of adverse effects can be increased when Aprotinin is combined with Acetylcholine.
Acetylsalicylic acidThe therapeutic efficacy of Acetylsalicylic acid can be decreased when used in combination with Aprotinin.
AclidiniumThe therapeutic efficacy of Aclidinium can be decreased when used in combination with Aprotinin.
AgmatineThe therapeutic efficacy of Agmatine can be decreased when used in combination with Aprotinin.
AlcuroniumThe therapeutic efficacy of Alcuronium can be decreased when used in combination with Aprotinin.
AldosteroneThe therapeutic efficacy of Aprotinin can be decreased when used in combination with Aldosterone.
Alpha-1-proteinase inhibitorAlpha-1-proteinase inhibitor may increase the thrombogenic activities of Aprotinin.
Food Interactions
Not Available

References

Synthesis Reference

Marion Steinbuch, Jacques Chabbat, Olivier Taby, "Process for preparation of activated protein C by immobilized aprotinin chromatography." U.S. Patent US5198534, issued February, 1985.

US5198534
General References
  1. Mahdy AM, Webster NR: Perioperative systemic haemostatic agents. Br J Anaesth. 2004 Dec;93(6):842-58. Epub 2004 Jul 26. [PubMed:15277296]
External Links
KEGG Drug
D02971
PubChem Substance
347910361
ChEMBL
CHEMBL1201619
Therapeutic Targets Database
DAP000185
PharmGKB
PA448472
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Aprotinin
ATC Codes
B02AB01 — Aprotinin
AHFS Codes
  • 20:28.16 — Hemostatics
FDA label
Download (108 KB)
MSDS
Download (19.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedPreventionPancreatitis1
1TerminatedTreatmentMetastatic Breast Cancer (MBC)1
2RecruitingTreatmentBile Leak / Common Bile Duct Gall Stones / Infection NOS1
3CompletedPreventionBlood Loss,Surgical1
3CompletedPreventionBlood Loss,Surgical / Postoperative Hemorrhages1
3TerminatedTreatmentBlood Loss,Surgical1
3TerminatedTreatmentBlood Loss,Surgical / Postoperative Hemorrhages1
4CompletedTreatmentControl of Local Bleeding in Patients Undergoing Prostatectomy1
Not AvailableCompletedNot AvailableSurgery, Cardiac1
Not AvailableCompletedTreatmentAngina Pectoris / Ischaemic Heart Diseases1
Not AvailableNo Longer AvailableNot AvailablePostoperative Hemorrhages1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Baxter International Inc.
  • Bayer Healthcare
Dosage forms
FormRouteStrength
SolutionIntravenous10000 unit
SolutionIntravenous1000000
SolutionIntravenous2000000
LiquidIntravenous100000 unit
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)>100 °CNot Available

Taxonomy

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

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Serine-type endopeptidase activity
Specific Function
Has activity against the synthetic substrates Boc-Phe-Ser-Arg-Mec, Boc-Leu-Thr-Arg-Mec, Boc-Gln-Ala-Arg-Mec and Boc-Val-Pro-Arg-Mec. The single-chain form is more active than the two-chain form aga...
Gene Name
PRSS1
Uniprot ID
P07477
Uniprot Name
Trypsin-1
Molecular Weight
26557.88 Da
References
  1. Mahdy AM, Webster NR: Perioperative systemic haemostatic agents. Br J Anaesth. 2004 Dec;93(6):842-58. Epub 2004 Jul 26. [PubMed:15277296]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Serine-type endopeptidase activity
Specific Function
Not Available
Gene Name
CTRB1
Uniprot ID
P17538
Uniprot Name
Chymotrypsinogen B
Molecular Weight
27869.74 Da
References
  1. Mahdy AM, Webster NR: Perioperative systemic haemostatic agents. Br J Anaesth. 2004 Dec;93(6):842-58. Epub 2004 Jul 26. [PubMed:15277296]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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. Mahdy AM, Webster NR: Perioperative systemic haemostatic agents. Br J Anaesth. 2004 Dec;93(6):842-58. Epub 2004 Jul 26. [PubMed:15277296]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Serine-type endopeptidase activity
Specific Function
Glandular kallikreins cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin.
Gene Name
KLK1
Uniprot ID
P06870
Uniprot Name
Kallikrein-1
Molecular Weight
28889.425 Da
References
  1. Mahdy AM, Webster NR: Perioperative systemic haemostatic agents. Br J Anaesth. 2004 Dec;93(6):842-58. Epub 2004 Jul 26. [PubMed:15277296]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Identical protein binding
Specific Function
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Gene Name
BCHE
Uniprot ID
P06276
Uniprot Name
Cholinesterase
Molecular Weight
68417.575 Da
References
  1. Jeffrey K. Aronson (2015). Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions (16th ed.). Elsevier. [ISBN:0444537163]

Drug created on February 12, 2009 09:44 / Updated on December 16, 2018 23:30