DB00001

BIOD00024

BTD00024

Lepirudin Lepirudin is identical to natural hirudin except for substitution of leucine for isoleucine at the N-terminal end of the molecule and the absence of a sulfate group on the tyrosine at position 63. It is produced via yeast cells. Bayer ceased the production of lepirudin (Refludan) effective May 31, 2012.

120993-53-5

approved

# Smythe MA, Stephens JL, Koerber JM, Mattson JC: A comparison of lepirudin and argatroban outcomes. Clin Appl Thromb Hemost. 2005 Oct;11(4):371-4. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/16244762 # Tardy B, Lecompte T, Boelhen F, Tardy-Poncet B, Elalamy I, Morange P, Gruel Y, Wolf M, Francois D, Racadot E, Camarasa P, Blouch MT, Nguyen F, Doubine S, Dutrillaux F, Alhenc-Gelas M, Martin-Toutain I, Bauters A, Ffrench P, de Maistre E, Grunebaum L, Mouton C, Huisse MG, Gouault-Heilmann M, Lucke V: Predictive factors for thrombosis and major bleeding in an observational study in 181 patients with heparin-induced thrombocytopenia treated with lepirudin. Blood. 2006 Sep 1;108(5):1492-6. Epub 2006 May 11. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/16690967 # Lubenow N, Eichler P, Lietz T, Greinacher A: Lepirudin in patients with heparin-induced thrombocytopenia - results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3. J Thromb Haemost. 2005 Nov;3(11):2428-36. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/16241940 # Askari AT, Lincoff AM: Antithrombotic Drug Therapy in Cardiovascular Disease. 2009 Oct; pp. 440–. ISBN 9781603272346. "Google books":http://books.google.com/books?id=iadLoXoQkWEC&pg=PA440.

For the treatment of heparin-induced thrombocytopenia Lepirudin is used to break up clots and to reduce thrombocytopenia. It binds to thrombin and prevents thrombus or clot formation. It is a highly potent, selective, and essentially irreversible inhibitor of thrombin and clot-bond thrombin. Lepirudin requires no cofactor for its anticoagulant action. Lepirudin is a recombinant form of hirudin, an endogenous anticoagulant found in medicinal leeches.

Lepirudin forms a stable non-covalent complex with alpha-thrombin, thereby abolishing its ability to cleave fibrinogen and initiate the clotting cascade. The inhibition of thrombin prevents the blood clotting cascade.

In case of overdose (eg, suggested by excessively high aPTT values) the risk of bleeding is increased. Lepirudin is thought to be metabolized by release of amino acids via catabolic hydrolysis of the parent drug. However, con-clusive data are not available. About 48% of the administration dose is excreted in the urine which consists of unchanged drug (35%) and other fragments of the parent drug. Bioavailability is 100% following injection.

Approximately 1.3 hours

Lepirudin is thought to be metabolized by release of amino acids via catabolic hydrolysis of the parent drug. About 48% of the administration dose is excreted in the urine which consists of unchanged drug (35%) and other fragments of the parent drug.

* 12.2 L [Healthy young subjects (n = 18, age 18-60 years)] * 18.7 L [Healthy elderly subjects (n = 10, age 65-80 years)] * 18 L [Renally impaired patients (n = 16, creatinine clearance below 80 mL/min)] * 32.1 L [HIT patients (n = 73)]

* 164 ml/min [Healthy 18-60 yrs] * 139 ml/min [Healthy 65-80 yrs] * 61 ml/min [renal impaired] * 114 ml/min [HIT (Heparin-induced thrombocytopenia)]

Peptides

Organic Compounds Organic Acids Carboxylic Acids and Derivatives Amino Acids, Peptides, and Analogues Hirudin variant-1

Refludan Berlex Labs

Bayer Healthcare http://www.bayerhealthcare.com Berlex Labs http://www.berlex.com Bayer healthcare pharmaceuticals inc Refludan 50 mg vial 273.19 vial Antithrombins

Fibrinolytic Agents

Humans and other mammals

BLOOD AND BLOOD FORMING ORGANS ANTITHROMBOTIC AGENTS ANTITHROMBOTIC AGENTS Direct thrombin inhibitors

20:12.04.12

1339104 Canada 1997-07-29 2014-07-29 5180668 United States 1993-01-19 2010-01-19

>DB00001 sequence LVYTDCTESGQNLCLCEGSNVCGQGNKCILGSDGEKNQCVTGEGTPKPQSHNDGDFEEIP EEYLQ

Melting Point 65 °C Otto, A. & Seckler, R. Eur. J. Biochem. 202:67-73 (1991) Hydrophobicity -0.777 Isoelectric Point 4.04 Molecular Weight 6963.4250 Molecular Formula C287H440N80O110S6

KEGG Drug D06880

National Drug Code Directory 50419-150-57

PharmGKB PA450195

UniProtKB P01050

Wikipedia Lepirudin

RxList http://www.rxlist.com/cgi/generic/lepirudin.htm

Drugs.com http://www.drugs.com/cdi/lepirudin.html

SMP00278

Lepirudin Action Pathway

DB00001

Lepirudin

DB01022

Phylloquinone

DB01373

Calcium

P00734

P00748

P02452

P03952

P03951

P00740

P00451

P12259

P00742

P02671

P02675

P02679

P00488

P05160

P00747

P00750

P08709

P13726

Q9BQB6

P38435

BE0000048 Prothrombin Human inhibitor # Turpie AG: Anticoagulants in acute coronary syndromes. Am J Cardiol. 1999 Sep 2;84(5A):2M-6M. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/10505536 # Warkentin TE: Venous thromboembolism in heparin-induced thrombocytopenia. Curr Opin Pulm Med. 2000 Jul;6(4):343-51. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/10912644 # Eriksson BI: New therapeutic options in deep vein thrombosis prophylaxis. Semin Hematol. 2000 Jul;37(3 Suppl 5):7-9. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/11055889 # Fabrizio MC: Use of ecarin clotting time (ECT) with lepirudin therapy in heparin-induced thrombocytopenia and cardiopulmonary bypass. J Extra Corpor Technol. 2001 May;33(2):117-25. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/11467439 # Szaba FM, Smiley ST: Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo. Blood. 2002 Feb 1;99(3):1053-9. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/11807012 # Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/11752352

yes

Prothrombin

Involved in blood clotting cascade

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

11p11-q12

Secreted protein; extracellular space

None

5.7

70037.0

Human

HUGO Gene Nomenclature Committee (HGNC) HGNC:3535

GenAtlas F2

GeneCards F2

GenBank Gene Database M17262

GenBank Protein Database 339641

UniProtKB P00734

UniProt Accession THRB_HUMAN

Activated Factor II [IIa] Coagulation factor II EC 3.4.21.5 Prothrombin precursor Thrombin

>Prothrombin precursor MAHVRGLQLPGCLALAALCSLVHSQHVFLAPQQARSLLQRVRRANTFLEEVRKGNLEREC VEETCSYEEAFEALESSTATDVFWAKYTACETARTPRDKLAACLEGNCAEGLGTNYRGHV NITRSGIECQLWRSRYPHKPEINSTTHPGADLQENFCRNPDSSTTGPWCYTTDPTVRRQE CSIPVCGQDQVTVAMTPRSEGSSVNLSPPLEQCVPDRGQQYQGRLAVTTHGLPCLAWASA QAKALSKHQDFNSAVQLVENFCRNPDGDEEGVWCYVAGKPGDFGYCDLNYCEEAVEEETG DGLDEDSDRAIEGRTATSEYQTFFNPRTFGSGEADCGLRPLFEKKSLEDKTERELLESYI DGRIVEGSDAEIGMSPWQVMLFRKSPQELLCGASLISDRWVLTAAHCLLYPPWDKNFTEN DLLVRIGKHSRTRYERNIEKISMLEKIYIHPRYNWRENLDRDIALMKLKKPVAFSDYIHP VCLPDRETAASLLQAGYKGRVTGWGNLKETWTANVGKGQPSVLQVVNLPIVERPVCKDST RIRITDNMFCAGYKPDEGKRGDACEGDSGGPFVMKSPFNNRWYQMGIVSWGEGCDRDGKY GFYTHVFRLKKWIQKVIDQFGE

>1869 bp ATGGCGCACGTCCGAGGCTTGCAGCTGCCTGGCTGCCTGGCCCTGGCTGCCCTGTGTAGC CTTGTGCACAGCCAGCATGTGTTCCTGGCTCCTCAGCAAGCACGGTCGCTGCTCCAGCGG GTCCGGCGAGCCAACACCTTCTTGGAGGAGGTGCGCAAGGGCAACCTAGAGCGAGAGTGC GTGGAGGAGACGTGCAGCTACGAGGAGGCCTTCGAGGCTCTGGAGTCCTCCACGGCTACG GATGTGTTCTGGGCCAAGTACACAGCTTGTGAGACAGCGAGGACGCCTCGAGATAAGCTT GCTGCATGTCTGGAAGGTAACTGTGCTGAGGGTCTGGGTACGAACTACCGAGGGCATGTG AACATCACCCGGTCAGGCATTGAGTGCCAGCTATGGAGGAGTCGCTACCCACATAAGCCT GAAATCAACTCCACTACCCATCCTGGGGCCGACCTACAGGAGAATTTCTGCCGCAACCCC GACAGCAGCACCACGGGACCCTGGTGCTACACTACAGACCCCACCGTGAGGAGGCAGGAA TGCAGCATCCCTGTCTGTGGCCAGGATCAAGTCACTGTAGCGATGACTCCACGCTCCGAA GGCTCCAGTGTGAATCTGTCACCTCCATTGGAGCAGTGTGTCCCTGATCGGGGGCAGCAG TACCAGGGGCGCCTGGCGGTGACCACACATGGGCTCCCCTGCCTGGCCTGGGCCAGCGCA CAGGCCAAGGCCCTGAGCAAGCACCAGGACTTCAACTCAGCTGTGCAGCTGGTGGAGAAC TTCTGCCGCAACCCAGACGGGGATGAGGAGGGCGTGTGGTGCTATGTGGCCGGGAAGCCT GGCGACTTTGGGTACTGCGACCTCAACTATTGTGAGGAGGCCGTGGAGGAGGAGACAGGA GATGGGCTGGATGAGGACTCAGACAGGGCCATCGAAGGGCGTACCGCCACCAGTGAGTAC CAGACTTTCTTCAATCCGAGGACCTTTGGCTCGGGAGAGGCAGACTGTGGGCTGCGACCT CTGTTCGAGAAGAAGTCGCTGGAGGACAAAACCGAAAGAGAGCTCCTGGAATCCTACATC GACGGGCGCATTGTGGAGGGCTCGGATGCAGAGATCGGCATGTCACCTTGGCAGGTGATG CTTTTCCGGAAGAGTCCCCAGGAGCTGCTGTGTGGGGCCAGCCTCATCAGTGACCGCTGG GTCCTCACCGCCGCCCACTGCCTCCTGTACCCGCCCTGGGACAAGAACTTCACCGAGAAT GACCTTCTGGTGCGCATTGGCAAGCACTCCCGCACAAGGTACGAGCGAAACATTGAAAAG ATATCCATGTTGGAAAAGATCTACATCCACCCCAGGTACAACTGGCGGGAGAACCTGGAC CGGGACATTGCCCTGATGAAGCTGAAGAAGCCTGTTGCCTTCAGTGACTACATTCACCCT GTGTGTCTGCCCGACAGGGAGACGGCAGCCAGCTTGCTCCAGGCTGGATACAAGGGGCGG GTGACAGGCTGGGGCAACCTGAAGGAGACGTGGACAGCCAACGTTGGTAAGGGGCAGCCC AGTGTCCTGCAGGTGGTGAACCTGCCCATTGTGGAGCGGCCGGTCTGCAAGGACTCCACC CGGATCCGCATCACTGACAACATGTTCTGTGCTGGTTACAAGCCTGATGAAGGGAAACGA GGGGATGCCTGTGAAGGTGACAGTGGGGGACCCTTTGTCATGAAGAGCCCCTTTAACAAC CGCTGGTATCAAATGGGCATCGTCTCATGGGGTGAAGGCTGTGACCGGGATGGGAAATAT GGCTTCTACACACATGTGTTCCGCCTGAAGAAGTGGATACAGAAGGTCATTGATCAGTTT GGAGAGTAG

PF00594 Gla PF00051 Kringle PF00089 Trypsin

component extracellular region

function binding

function catalytic activity

function thrombin activity

function hydrolase activity

function calcium ion binding

function peptidase activity

function ion binding

function endopeptidase activity

function cation binding

function serine-type endopeptidase activity

process cellular protein metabolism

process organismal physiological process

process regulation of body fluids

process physiological process

process hemostasis

process blood coagulation

process metabolism

process macromolecule metabolism

process protein metabolism

process proteolysis