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Identification
NameDrotrecogin alfa
Accession NumberDB00055  (BIOD00068, BTD00068)
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GroupsApproved, Investigational, Withdrawn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 Drotrecogin alfa was withdrawn from the market after a major study indicated that it was not effective in improving outcomes in patients with sepsis.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
Protein chemical formulaC1786H2779N509O519S29
Protein average weight55000.0000
Sequences
>Heavy chain
LIDGKMTRRGDSPWQVVLLDSKKKLACGAVLIHPSWVLTAAHCMDESKKLLVRLGEYDLR
RWEKWELDLDIKEVFVHPNYSKSTTDNDIALLHLAQPATLSQTIVPICLPDSGLAERELN
QAGQETLVTGWGYHSSREKEAKRNRTFVLNFIKIPVVPHNECSEVMSNMVSENMLCAGIL
GDRQDACEGDSGGPMVASFHGTWFLVGLVSWGEGCGLLHNYGVYTKVSRYLDWIHGHIRD
KEAPQKSWAP
>Light chain
SKHVDGDQCLVLPLEHPCASLCCGHGTCIXGIGSFSCDCRSGWEGRFCQREVSFLNCSLD
NGGCTHYCLEEVGWRRCSCAPGYKLGDDLLQCHPAVKFPCGRPWKRMEKKRSHL
Download FASTA Format
Synonyms
SynonymLanguageCode
Anticoagulant protein CNot AvailableNot Available
Autoprothrombin IIANot AvailableNot Available
Blood coagulation factor XIVNot AvailableNot Available
Vitamin K-dependent protein C precursorNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
XigrisEli Lilly & Co
Brand mixturesNot Available
Categories
CAS number60202-16-6
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentPeptides
Alternative parentsNot Available
SubstituentsNot Available
Classification descriptionNot 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.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism
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 solutionIntravenous
Prices
Unit descriptionCostUnit
Xigris 20 mg vial1481.66USDvial
Xigris 5 mg vial370.42USDvial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
Canada21394682007-08-212015-01-03
Canada20368942002-01-152011-02-22
Properties
Stateliquid
Experimental Properties
PropertyValueSource
hydrophobicity-0.291Not Available
isoelectric point6.78Not Available
References
Synthesis ReferenceNot Available
General ReferenceNot Available
External Links
ResourceLink
UniProtP04070
GenbankM11228
PharmGKBPA131548935
Drug Product Database2247130
RxListhttp://www.rxlist.com/cgi/generic/drotrecogin.htm
Drugs.comhttp://www.drugs.com/cdi/drotrecogin-alfa.html
WikipediaDrotrecogin_alfa
ATC CodesB01AD10
AHFS Codes
  • 20:12.20
PDB Entries
FDA labelshow(241 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
ClopidogrelAntiplatelet agents such as clopidogrel may enhance the adverse/toxic effect of Drotrecogin Alfa. Bleeding may occur. Increase monitoring for signs/symptoms of bleeding during concomitant therapy. If possible, avoid use of drotrecogin within 7 days of use of any IIb/IIIa antagonists, higher dose aspirin (more than 650 mg/day), or use of other antiplatelet agents.
DalteparinLow molecular weight heparin (LMWH) such as dalteparin may enhance the adverse/toxic effect of drotrecogin alfa. Bleeding may occur.
EnoxaparinCombination should be used with caution after weighing advantages and disadvantages. Low molecular weight heparins such as enoxaparin may increase the adverse effects of drotrecogin. Monitor for bleeding if used concomitantly.
Fondaparinux sodiumDrotrecogin alfa may increase the adverse effects of fondaparinux, resulting in excessive bleeding. Concomitant use should be avoided.
HeparinThe potential benefits of drotrecogin alfa should be weighed against an increased risk of bleeding in patients receiving therapeutic doses of heparin. Monitor for bleeding during concomitant therapy, and immediately stop infusion of drotrecogin if clinically important bleeding occurs. In patients receiving prophylactic heparin doses, consider continuing this during drotrecogin.
KetoprofenThe antiplatelet effect of ketoprofen may increase the bleed risk associated with drotrecogin alfa. Consider spacing use of the two agents by at least 7 days. Increase monitoring for signs and symptoms of bleeding during concomitant therapy.
NadroparinThe potential benefits of drotrecogin alfa should be weighed against an increased risk of bleeding in patients receiving therapeutic doses of low molecular weight heparins such as nadroparin. Monitor for bleeding during concomitant therapy, and immediately stop infusion of drotrecogin if clinically important bleeding occurs. In patients receiving prophylactic heparin doses, consider continuing this during drotrecogin.
TenecteplaseIncreased risk of bleeding.
TinzaparinLow molecular weight heparins (LMWHs) such as tinzaparin may enhance the adverse/toxic effects of drotrecogin alfa. Bleeding may occur. The potential benefits of drotrecogin alfa should be weighed against the increased risk of bleeding in patients on therapeutic doses of LMWHs.
TolmetinIncreased risk of bleeding. Monitor for increased bleeding during concomitant therapy.
TreprostinilThe prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the anticoagulant, Drotrecogin alfa. Monitor for increased bleeding during concomitant thearpy.
UrokinaseIncreased risk of bleeding.
VilazodoneIncrease monitoring for signs/symptoms of bleeding during concomitant therapy. If possible, avoid use of drotrecogin within 7 days of use of any IIb/IIIa antagonists, higher dose aspirin (more than 650 mg/day), or use of other antiplatelet agents.
WarfarinIncreased risk of bleeding.
Food InteractionsNot Available

Targets

1. Coagulation factor VIII

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: multitarget

Components

Name UniProt ID Details
Coagulation factor VIII P00451 Details

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
  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. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Coagulation factor V

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: multitarget

Components

Name UniProt ID Details
Coagulation factor V P12259 Details

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
  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
  3. Lyseng-Williamson KA, Perry CM: Drotrecogin alfa (activated). Drugs. 2002;62(4):617-30; discussion 631-2. Pubmed
  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
  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
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

3. Plasminogen activator inhibitor 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Plasminogen activator inhibitor 1 P05121 Details

References:

  1. Carr ME: Diabetes mellitus: a hypercoagulable state. J Diabetes Complications. 2001 Jan-Feb;15(1):44-54. Pubmed
  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
  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
  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

4. Thrombomodulin

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Thrombomodulin P07204 Details

References:

  1. Gresele P, Agnelli G: Novel approaches to the treatment of thrombosis. Trends Pharmacol Sci. 2002 Jan;23(1):25-32. Pubmed
  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
  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
  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 (Tokyo). 1988 Feb;103(2):281-5. Pubmed
  5. Boffa MC, Burke B, Haudenschild C: [Different localization of thrombomodulin] Ann Biol Clin (Paris). 1987;45(2):191-7. Pubmed

5. Vitamin K-dependent protein S

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Vitamin K-dependent protein S P07225 Details

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
  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
  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

6. Ceruloplasmin

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Ceruloplasmin P00450 Details

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
  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

7. Prothrombin

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Prothrombin P00734 Details

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
  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
  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
  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
  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

8. Platelet factor 4

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Platelet factor 4 P02776 Details

References:

  1. Carr ME: Diabetes mellitus: a hypercoagulable state. J Diabetes Complications. 2001 Jan-Feb;15(1):44-54. Pubmed

9. Plasma serine protease inhibitor

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Plasma serine protease inhibitor P05154 Details

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
  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
  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
  4. Hayashi T, Suzuki K: [Molecular biology of protein C-thrombomodulin pathway. Structure and function, and basic studies on its clinical application] Nippon Rinsho. 1993 Jun;51(6):1610-9. Pubmed
  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

10. Serpin B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Serpin B6 P35237 Details

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
  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

11. Vitamin K-dependent gamma-carboxylase

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Vitamin K-dependent gamma-carboxylase P38435 Details

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
  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

12. Endothelial protein C receptor

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Endothelial protein C receptor Q9UNN8 Details

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
  2. Ruf W, Dorfleutner A, Riewald M: Specificity of coagulation factor signaling. J Thromb Haemost. 2003 Jul;1(7):1495-503. Pubmed
  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
  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
  5. Liaw PC: Endogenous protein C activation in patients with severe sepsis. Crit Care Med. 2004 May;32(5 Suppl):S214-8. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on January 29, 2014 09:39