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Identification
NameDrotrecogin alfa
Accession NumberDB00055  (BTD00068, BIOD00068)
TypeBiotech
GroupsApproved, Investigational, Withdrawn
Description

Drotrecogin alfa is activated human protein C that is synthesized by recombinant DNA technology. It is a glycoprotein of approximately 55 kilodalton molecular weight, consisting of a heavy chain and a light chain linked by a disulfide bond. Drotrecogin alfa was withdrawn from the market after a major study indicated that it was not effective in improving outcomes in patients with sepsis.

Protein structureDb00055
Related Articles
Protein chemical formulaC1786H2779N509O519S29
Protein average weight55000.0 Da
Sequences
>Heavy chain
LIDGKMTRRGDSPWQVVLLDSKKKLACGAVLIHPSWVLTAAHCMDESKKLLVRLGEYDLR
RWEKWELDLDIKEVFVHPNYSKSTTDNDIALLHLAQPATLSQTIVPICLPDSGLAERELN
QAGQETLVTGWGYHSSREKEAKRNRTFVLNFIKIPVVPHNECSEVMSNMVSENMLCAGIL
GDRQDACEGDSGGPMVASFHGTWFLVGLVSWGEGCGLLHNYGVYTKVSRYLDWIHGHIRD
KEAPQKSWAP
>Light chain
SKHVDGDQCLVLPLEHPCASLCCGHGTCIXGIGSFSCDCRSGWEGRFCQREVSFLNCSLD
NGGCTHYCLEEVGWRRCSCAPGYKLGDDLLQCHPAVKFPCGRPWKRMEKKRSHL
Download FASTA Format
Synonyms
Activated protein C
Blood coagulation factor XIV (human)
Drotrecogin alfa (activated)
Drotrecogin alfa (activated), lyophilized
Drotrecogin alfa activated
Drotrecogin alfa, activated
Drotrecogin-alfa
Recombinant human activated protein C (rH-APC)
External Identifiers
  • LY203638
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Xigris (20mg/vial)powder for solution20 mgintravenousEli Lilly Canada Inc2003-03-252011-11-14Canada
Xigris (5mg/vial)powder for solution5 mgintravenousEli Lilly Canada Inc2003-02-202011-11-14Canada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
XigrisEli Lilly & Co
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIJGH8MYC891
CAS number98530-76-8
Taxonomy
DescriptionNot Available
KingdomOrganic Compounds
Super ClassOrganic Acids
ClassCarboxylic Acids and Derivatives
Sub ClassAmino Acids, Peptides, and Analogues
Direct ParentPeptides
Alternative ParentsNot Available
SubstituentsNot Available
Molecular FrameworkNot Available
External DescriptorsNot Available
Pharmacology
IndicationFor reduction of mortality in patients with severe sepsis.
PharmacodynamicsDrotrecogin alfa is activated human protein C that is synthesized by recombinant DNA technology. It is a glycoprotein of approximately 55 kilodalton molecular weight, consisting of a heavy chain and a light chain linked by a disulfide bond. Drotrecogin alfa inhibits factor Va and VIIIa, thereby reducing the coagulability of blood.
Mechanism of actionActivated protein C combines with protein S on platelet surfaces and then degrades factor Va and factor VIIIa, thereby reducing blood coagulability.
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half life5.5 hours (mammalian reticulocytes, in vitro).
Clearance
  • 40 L/hr [severe sepsis adults]
  • 30 +/- 8 L/hr [patients without sepsis undergoing hemodialysis]
  • 28 +/- 9 L/hr [heathy]
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Powder for solutionintravenous20 mg
Powder for solutionintravenous5 mg
Prices
Unit descriptionCostUnit
Xigris 20 mg vial1481.66USD vial
Xigris 5 mg vial370.42USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2036894 No2002-01-152011-02-22Canada
CA2139468 No2007-08-212015-01-03Canada
Properties
StateLiquid
Experimental Properties
PropertyValueSource
hydrophobicity-0.291Not Available
isoelectric point6.78Not Available
References
Synthesis ReferenceNot Available
General ReferencesNot Available
External Links
ATC CodesB01AD10
AHFS Codes
  • 20:12.20
PDB Entries
FDA labelDownload (241 KB)
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
multitarget
General Function:
Oxidoreductase activity
Specific Function:
Factor VIII, along with calcium and phospholipid, acts as a cofactor for factor IXa when it converts factor X to the activated form, factor Xa.
Gene Name:
F8
Uniprot ID:
P00451
Molecular Weight:
267007.42 Da
References
  1. Geng JP, Castellino FJ: Properties of a recombinant chimeric protein in which the gamma-carboxyglutamic acid and helical stack domains of human anticoagulant protein C are replaced by those of human coagulation factor VII. Thromb Haemost. 1997 May;77(5):926-33. [PubMed:9184404 ]
  2. Colin G, Annane D: Corticosteroids and human recombinant activated protein C for septic shock. Clin Chest Med. 2008 Dec;29(4):705-12, x. doi: 10.1016/j.ccm.2008.06.009. [PubMed:18954704 ]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
multitarget
General Function:
Copper ion binding
Specific Function:
Central regulator of hemostasis. It serves as a critical cofactor for the prothrombinase activity of factor Xa that results in the activation of prothrombin to thrombin.
Gene Name:
F5
Uniprot ID:
P12259
Molecular Weight:
251701.245 Da
References
  1. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001 Mar 8;344(10):699-709. [PubMed:11236773 ]
  2. Kanji S, Devlin JW, Piekos KA, Racine E: Recombinant human activated protein C, drotrecogin alfa (activated): a novel therapy for severe sepsis. Pharmacotherapy. 2001 Nov;21(11):1389-402. [PubMed:11714212 ]
  3. Lyseng-Williamson KA, Perry CM: Drotrecogin alfa (activated). Drugs. 2002;62(4):617-30; discussion 631-2. [PubMed:11893230 ]
  4. Joyce DE, Grinnell BW: Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-kappaB. Crit Care Med. 2002 May;30(5 Suppl):S288-93. [PubMed:12004250 ]
  5. Poe K: Drotrecogin alfa (activated) approved for treatment of severe sepsis. J Am Pharm Assoc (Wash). 2002 May-Jun;42(3):520-2. [PubMed:12030642 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Kind
Protein
Organism
Human
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 control point in the regulation of fibrinolysis.
Gene Name:
SERPINE1
Uniprot ID:
P05121
Molecular Weight:
45059.695 Da
References
  1. Carr ME: Diabetes mellitus: a hypercoagulable state. J Diabetes Complications. 2001 Jan-Feb;15(1):44-54. [PubMed:11259926 ]
  2. Cerchiara E, Tirindelli MC, Giannetti B, Dicuonzo G, Avvisati G: [The numerous properties of the anticoagulant protein C]. Clin Ter. 2007 Mar-Apr;158(2):181-7. [PubMed:17566522 ]
  3. Idell S: Endothelium and disordered fibrin turnover in the injured lung: newly recognized pathways. Crit Care Med. 2002 May;30(5 Suppl):S274-80. [PubMed:12004248 ]
  4. Dhainaut JF, Yan SB, Margolis BD, Lorente JA, Russell JA, Freebairn RC, Spapen HD, Riess H, Basson B, Johnson G 3rd, Kinasewitz GT: Drotrecogin alfa (activated) (recombinant human activated protein C) reduces host coagulopathy response in patients with severe sepsis. Thromb Haemost. 2003 Oct;90(4):642-53. [PubMed:14515185 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Transmembrane signaling receptor activity
Specific Function:
Thrombomodulin is a specific endothelial cell receptor that forms a 1:1 stoichiometric complex with thrombin. This complex is responsible for the conversion of protein C to the activated protein C (protein Ca). Once evolved, protein Ca scissions the activated cofactors of the coagulation mechanism, factor Va and factor VIIIa, and thereby reduces the amount of thrombin generated.
Gene Name:
THBD
Uniprot ID:
P07204
Molecular Weight:
60328.72 Da
References
  1. Gresele P, Agnelli G: Novel approaches to the treatment of thrombosis. Trends Pharmacol Sci. 2002 Jan;23(1):25-32. [PubMed:11804648 ]
  2. Pineda AO, Chen ZW, Caccia S, Cantwell AM, Savvides SN, Waksman G, Mathews FS, Di Cera E: The anticoagulant thrombin mutant W215A/E217A has a collapsed primary specificity pocket. J Biol Chem. 2004 Sep 17;279(38):39824-8. Epub 2004 Jul 13. [PubMed:15252033 ]
  3. McCachren SS, Diggs J, Weinberg JB, Dittman WA: Thrombomodulin expression by human blood monocytes and by human synovial tissue lining macrophages. Blood. 1991 Dec 15;78(12):3128-32. [PubMed:1660324 ]
  4. Shirai T, Shiojiri S, Ito H, Yamamoto S, Kusumoto H, Deyashiki Y, Maruyama I, Suzuki K: Gene structure of human thrombomodulin, a cofactor for thrombin-catalyzed activation of protein C. J Biochem. 1988 Feb;103(2):281-5. [PubMed:2836377 ]
  5. Boffa MC, Burke B, Haudenschild C: [Different localization of thrombomodulin]. Ann Biol Clin (Paris). 1987;45(2):191-7. [PubMed:3039877 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Endopeptidase inhibitor activity
Specific Function:
Anticoagulant plasma protein; it is a cofactor to activated protein C in the degradation of coagulation factors Va and VIIIa. It helps to prevent coagulation and stimulating fibrinolysis.
Gene Name:
PROS1
Uniprot ID:
P07225
Molecular Weight:
75121.905 Da
References
  1. Cvirn G, Gallistl S, Koestenberger M, Kutschera J, Leschnik B, Muntean W: Alpha 2-macroglobulin enhances prothrombin activation and thrombin potential by inhibiting the anticoagulant protein C/protein S system in cord and adult plasma. Thromb Res. 2002 Mar 1;105(5):433-9. [PubMed:12062545 ]
  2. Hesselvik JF, Malm J, Dahlback B, Blomback M: Protein C, protein S and C4b-binding protein in severe infection and septic shock. Thromb Haemost. 1991 Feb 12;65(2):126-9. [PubMed:1828915 ]
  3. Cosio FG, Harker C, Batard MA, Brandt JT, Griffin JH: Plasma concentrations of the natural anticoagulants protein C and protein S in patients with proteinuria. J Lab Clin Med. 1985 Aug;106(2):218-22. [PubMed:3160800 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Ferroxidase activity
Specific Function:
Ceruloplasmin is a blue, copper-binding (6-7 atoms per molecule) glycoprotein. It has ferroxidase activity oxidizing Fe(2+) to Fe(3+) without releasing radical oxygen species. It is involved in iron transport across the cell membrane. Provides Cu(2+) ions for the ascorbate-mediated deaminase degradation of the heparan sulfate chains of GPC1. May also play a role in fetal lung development or pul...
Gene Name:
CP
Uniprot ID:
P00450
Molecular Weight:
122204.45 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
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 homeostasis, inflammation and wound healing.
Gene Name:
F2
Uniprot ID:
P00734
Molecular Weight:
70036.295 Da
References
  1. Omar MN, Shouk TA, Khaleq MA: Activity of blood coagulation and fibrinolysis during and after hydroxyethyl starch (HES) colloidal volume replacement. Clin Biochem. 1999 Jun;32(4):269-74. [PubMed:10463819 ]
  2. Cvirn G, Gallistl S, Koestenberger M, Kutschera J, Leschnik B, Muntean W: Alpha 2-macroglobulin enhances prothrombin activation and thrombin potential by inhibiting the anticoagulant protein C/protein S system in cord and adult plasma. Thromb Res. 2002 Mar 1;105(5):433-9. [PubMed:12062545 ]
  3. Gruber A, Cantwell AM, Di Cera E, Hanson SR: The thrombin mutant W215A/E217A shows safe and potent anticoagulant and antithrombotic effects in vivo. J Biol Chem. 2002 Aug 2;277(31):27581-4. Epub 2002 Jun 17. [PubMed:12070133 ]
  4. Conway EM, Van de Wouwer M, Pollefeyt S, Jurk K, Van Aken H, De Vriese A, Weitz JI, Weiler H, Hellings PW, Schaeffer P, Herbert JM, Collen D, Theilmeier G: The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen-activated protein kinase pathways. J Exp Med. 2002 Sep 2;196(5):565-77. [PubMed:12208873 ]
  5. Levi M, De Jonge E, van der Poll T: Recombinant human activated protein C (Xigris). Int J Clin Pract. 2002 Sep;56(7):542-5. [PubMed:12296618 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Heparin binding
Specific Function:
Released during platelet aggregation. Neutralizes the anticoagulant effect of heparin because it binds more strongly to heparin than to the chondroitin-4-sulfate chains of the carrier molecule. Chemotactic for neutrophils and monocytes. Inhibits endothelial cell proliferation, the short form is a more potent inhibitor than the longer form.
Gene Name:
PF4
Uniprot ID:
P02776
Molecular Weight:
10844.78 Da
References
  1. Carr ME: Diabetes mellitus: a hypercoagulable state. J Diabetes Complications. 2001 Jan-Feb;15(1):44-54. [PubMed:11259926 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Serine-type endopeptidase inhibitor activity
Specific Function:
Heparin-dependent serine protease inhibitor acting in body fluids and secretions. Inactivates serine proteases by binding irreversibly to their serine activation site. Involved in the regulation of intravascular and extravascular proteolytic activities. Plays hemostatic roles in the blood plasma. Acts as a procoagulant and proinflammatory factor by inhibiting the anticoagulant activated protein...
Gene Name:
SERPINA5
Uniprot ID:
P05154
Molecular Weight:
45674.315 Da
References
  1. Shen L, Villoutreix BO, Dahlback B: Involvement of Lys 62(217) and Lys 63(218) of human anticoagulant protein C in heparin stimulation of inhibition by the protein C inhibitor. Thromb Haemost. 1999 Jul;82(1):72-9. [PubMed:10456457 ]
  2. He X, Shen L, Bjartell A, Malm J, Lilja H, Dahlback B: The gene encoding vitamin K-dependent anticoagulant protein C is expressed in human male reproductive tissues. J Histochem Cytochem. 1995 Jun;43(6):563-70. [PubMed:7769227 ]
  3. Kobayashi H, Gabazza EC, Taguchi O, Wada H, Takeya H, Nishioka J, Yasui H, Kobayashi T, Hataji O, Suzuki K, Adachi Y: Protein C anticoagulant system in patients with interstitial lung disease. Am J Respir Crit Care Med. 1998 Jun;157(6 Pt 1):1850-4. [PubMed:9620917 ]
  4. Hayashi T, Suzuki K: [Molecular biology of protein C-thrombomodulin pathway. Structure and function, and basic studies on its clinical application]. Nihon Rinsho. 1993 Jun;51(6):1610-9. [PubMed:8391599 ]
  5. Berg DT, Gerlitz B, Shang J, Smith T, Santa P, Richardson MA, Kurz KD, Grinnell BW, Mace K, Jones BE: Engineering the proteolytic specificity of activated protein C improves its pharmacological properties. Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4423-8. Epub 2003 Apr 1. [PubMed:12671072 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Serine-type endopeptidase inhibitor activity
Specific Function:
May be involved in the regulation of serine proteinases present in the brain or extravasated from the blood (By similarity). Inhibitor of cathepsin G, kallikrein-8 and thrombin. May play an important role in the inner ear in the protection against leakage of lysosomal content during stress and loss of this protection results in cell death and sensorineural hearing loss.
Gene Name:
SERPINB6
Uniprot ID:
P35237
Molecular Weight:
42621.575 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Gamma-glutamyl carboxylase activity
Specific Function:
Mediates the vitamin K-dependent carboxylation of glutamate residues to calcium-binding gamma-carboxyglutamate (Gla) residues with the concomitant conversion of the reduced hydroquinone form of vitamin K to vitamin K epoxide.
Gene Name:
GGCX
Uniprot ID:
P38435
Molecular Weight:
87560.065 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Receptor activity
Specific Function:
Binds activated protein C. Enhances protein C activation by the thrombin-thrombomodulin complex; plays a role in the protein C pathway controlling blood coagulation.
Gene Name:
PROCR
Uniprot ID:
Q9UNN8
Molecular Weight:
26671.245 Da
References
  1. Fukudome K, Ye X, Tsuneyoshi N, Tokunaga O, Sugawara K, Mizokami H, Kimoto M: Activation mechanism of anticoagulant protein C in large blood vessels involving the endothelial cell protein C receptor. J Exp Med. 1998 Apr 6;187(7):1029-35. [PubMed:9529319 ]
  2. Ruf W, Dorfleutner A, Riewald M: Specificity of coagulation factor signaling. J Thromb Haemost. 2003 Jul;1(7):1495-503. [PubMed:12871285 ]
  3. Castellino FJ, Liang Z, Volkir SP, Haalboom E, Martin JA, Sandoval-Cooper MJ, Rosen ED: Mice with a severe deficiency of the endothelial protein C receptor gene develop, survive, and reproduce normally, and do not present with enhanced arterial thrombosis after challenge. Thromb Haemost. 2002 Sep;88(3):462-72. [PubMed:12353077 ]
  4. Cerchiara E, Tirindelli MC, Giannetti B, Dicuonzo G, Avvisati G: [The numerous properties of the anticoagulant protein C]. Clin Ter. 2007 Mar-Apr;158(2):181-7. [PubMed:17566522 ]
  5. Liaw PC: Endogenous protein C activation in patients with severe sepsis. Crit Care Med. 2004 May;32(5 Suppl):S214-8. [PubMed:15118520 ]
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Drug created on June 13, 2005 07:24 / Updated on May 03, 2016 11:03