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Identification
Name Epirubicin
Accession Number DB00445 (APRD00361)
Type small molecule
Groups approved
Description

An anthracycline which is the 4'-epi-isomer of doxorubicin. The compound exerts its antitumor effects by interference with the synthesis and function of DNA. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Synonyms Not Available
Salts Not Available
Brand names
Name Company
4'-Epiadriamycin
4'-Epidoxorubicin
Ellence
Epi-Dx
Epiadriamycin
Epidoxorubicin
Epirubicina [INN-Spanish]
Epirubicina [Spanish]
Epirubicine [French]
Epirubicine [INN-French]
Epirubicinum [INN-Latin]
Epirubicinum [Latin]
IMI 28
Pharmorubicin Pfs
Pidorubicina [INN-Spanish]
Pidorubicine [INN-French]
Pidorubicinum [INN-Latin]
Ridorubicin
First Prev Next Last
Brand mixtures Not Available
Categories
  • Antineoplastic Agents
  • Antibiotics, Antineoplastic
CAS number 56420-45-2
Weight Average: 543.5193
Monoisotopic: 543.174060775
Chemical Formula C27H29NO11
InChI Key InChIKey=AOJJSUZBOXZQNB-VTZDEGQISA-N
InChI
InChI=1S/C27H29NO11/c1-10-22(31)13(28)6-17(38-10)39-15-8-27(36,16(30)9-29)7-12-19(15)26(35)21-20(24(12)33)23(32)11-4-3-5-14(37-2)18(11)25(21)34/h3-5,10,13,15,17,22,29,31,33,35-36H,6-9,28H2,1-2H3/t10-,13-,15-,17-,22-,27-/m0/s1
Plain Text
IUPAC Name
(8S,10S)-10-{[(2R,4S,5R,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy}-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-5,7,8,9,10,12-hexahydrotetracene-5,12-dione
SMILES
COC1=CC=CC2=C1C(=O)C1=C(O)C3=C(C[C@](O)(C[C@@H]3O[C@H]3C[C@H](N)[C@@H](O)[C@H](C)O3)C(=O)CO)C(O)=C1C2=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Anthracyclines
Substructures
  • Anthracyclines
  • Hydroxy Compounds
  • Pyrans
  • Benzyl Alcohols and Derivatives
  • Naphthalenes
  • Acetals and Derivatives
  • Phenols and Derivatives
  • Benzoquinones
  • Aliphatic and Aryl Amines
  • Ethers
  • Benzene and Derivatives
  • Naphthoquinones
  • Anthraquinones
  • Anthracenes
  • Hydroquinones
  • Alcohols and Polyols
  • Amino Alcohols
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Benzoyl Derivatives
  • Cyclohexenes and Derivatives
  • Phenyl Esters
  • Ketones
Pharmacology
Indication For use as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer.
Pharmacodynamics Epirubicin is an antineoplastic in the anthracycline class. General properties of drugs in this class include: interaction with DNA in a variety of different ways including intercalation (squeezing between the base pairs), DNA strand breakage and inhibition with the enzyme topoisomerase II. Most of these compounds have been isolated from natural sources and antibiotics. However, they lack the specificity of the antimicrobial antibiotics and thus produce significant toxicity. The anthracyclines are among the most important antitumor drugs available. Doxorubicin is widely used for the treatment of several solid tumors while daunorubicin and idarubicin are used exclusively for the treatment of leukemia. Epirubicin may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA. Epirubicin possesses an antitumor effect against a wide spectrum of tumors, either grafted or spontaneous. The anthracyclines are cell cycle-nonspecific.
Mechanism of action Epirubicin has antimitotic and cytotoxic activity. It inhibits nucleic acid (DNA and RNA) and protein synthesis through a number of proposed mechanisms of action: Epirubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. It also interferes with DNA replication and transcription by inhibiting DNA helicase activity.
Absorption 100%
Volume of distribution
  • 21 ± 2 L/kg [60 mg/m2 Dose]
  • 27 ± 11 L/kg [75 mg/m2 Dose]
  • 23 ± 7 L/kg [120 mg/m2 Dose]
  • 21 ± 7 L/kg [150 mg/m2 Dose]
Protein binding 77%
Metabolism Extensively and rapidly metabolized in the liver. Epirubicin is also metabolized by other organs and cells, including red blood cells. The four main metabolic routes are: (1) reduction of the C-13 keto-group with the formation of the 13(S)-dihydro derivative, epirubicinol; (2) conjugation of both the unchanged drug and epirubicinol with glucuronic acid; (3) loss of the amino sugar moiety through a hydrolytic process with the formation of the doxorubicin and doxorubicinol aglycones; and (4) loss of the amino sugar moiety through a redox process with the formation of the 7-deoxy-doxorubicin aglycone and 7-deoxy-doxorubicinol aglycone. Epirubicinol exhibits in vitro cytoxic activity (~10% that of epirubicin), but it is unlikely to reach sufficient concentrations in vivo to produce cytotoxic effects.
Route of elimination Epirubicin and its major metabolites are eliminated through biliary excretion and, to a lesser extent, by urinary excretion.
Half life Half-lives for the alpha, beta, and gamma phases of about 3 minutes, 2.5 hours and 33 hours, respectively
Clearance
  • 65 +/- 8 L/hour [Patients1 with Solid Tumors Receiving Intravenous Epirubicin 60 mg/m2]
  • 83 +/- 14 L/hour [Patients1 with Solid Tumors Receiving Intravenous Epirubicin 75 mg/m2]
  • 65 +/- 13 L/hour [Patients1 with Solid Tumors Receiving Intravenous Epirubicin 120 mg/m2]
  • 69 +/- 13 L/hour [Patients1 with Solid Tumors Receiving Intravenous Epirubicin 150 mg/m2]
Toxicity bone marrow aplasia, grade 4 mucositis, and gastrointestinal bleeding
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Pfizer inc
  • Actavis totowa llc
  • Akorn inc
  • App pharmaceuticals llc
  • Bedford laboratories div ben venue laboratories inc
  • Bioniche pharma usa llc
  • Ebewe pharma ges mbh nfg kg
  • Fresenius kabi oncology plc
  • Hospira inc
  • Teva parenteral medicines inc
  • Watson laboratories inc
  • X gen pharmaceuticals inc
Packagers
Dosage forms
Form Route Strength
Solution Intravenous 200 mg/100 ml
Solution Intravenous 50 mg/25 ml
Prices
Unit description Cost Unit
Epirubicin hcl 200 mg vial 2845.85 USD vial
Epirubicin hcl 50 mg vial 69.54 USD vial
Ellence 2 mg/ml vial 5.38 USD ml
Patents Not Available
Properties
State solid
Melting point 344.53oC
Experimental Properties
Property Value Source
water solubility 0.093 mg/ml PhysProp
logP -0.5 PhysProp
Predicted Properties
Property Value Source
water solubility 1.18e+00 g/l ALOGPS
logP 1.41 ALOGPS
logP 0.92 ChemAxon Molconvert
logS -2.7 ALOGPS
pKa 11.02 ChemAxon Molconvert
hydrogen acceptor count 12 ChemAxon Molconvert
hydrogen donor count 6 ChemAxon Molconvert
polar surface area 206.07 ChemAxon Molconvert
rotatable bond count 5 ChemAxon Molconvert
refractivity 134.59 ChemAxon Molconvert
polarizability 53.88 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Pharmacia. Ellence® (epirubicin hydrochloride injection) full prescribing information. New York, NY; 2007 Feb.
External Links
Resource Link
KEGG Compound C11230 Link_out
PubChem Compound 41867 Link_out
PubChem Substance 46507282 Link_out
ChemSpider 38201 Link_out
ChEBI 47898 Link_out
ChEMBL 47898 Link_out
Therapeutic Targets Database DAP000193 Link_out
PharmGKB PA449476 Link_out
Drug Product Database 2069512 Link_out
RxList http://www.rxlist.com/cgi/generic2/epirub.htm Link_out
Drugs.com http://www.drugs.com/cdi/epirubicin.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Epirubicin Link_out
ATC Codes
  • L01DB03
AHFS Codes
  • 10:00.00
PDB Entries Not Available
FDA label show (92.7 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Cimetidine Cimetidine can increase epirubicin levels
Trastuzumab Trastuzumab may increase the cardiotoxicity of Epirubicin. Signs and symptoms of cardiac dysfunction should be monitored for frequently. Increased risk of heart failure. Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food Interactions
  • Liberal fluid intake to increase urine output and help the excretion of uric acid.
Targets

1. Chromodomain-helicase-DNA-binding protein 1

Pharmacological action: yes
Actions: antagonist

Sequence-selective DNA-binding protein. Could play an important role in gene regulation

Organism class: human
UniProt ID: O14646 Link_out
Gene: CHD1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

2. DNA topoisomerase 2-alpha

Pharmacological action: unknown
Actions: inhibitor

Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks

Organism class: human
UniProt ID: P11388 Link_out
Gene: TOP2A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Petit T, Wilt M, Velten M, Millon R, Rodier JF, Borel C, Mors R, Haegele P, Eber M, Ghnassia JP: Comparative value of tumour grade, hormonal receptors, Ki-67, HER-2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. Eur J Cancer. 2004 Jan;40(2):205-11. Pubmed
  2. Knoop AS, Knudsen H, Balslev E, Rasmussen BB, Overgaard J, Nielsen KV, Schonau A, Gunnarsdottir K, Olsen KE, Mouridsen H, Ejlertsen B: retrospective analysis of topoisomerase IIa amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil: Danish Breast Cancer Cooperative Group. J Clin Oncol. 2005 Oct 20;23(30):7483-90. Pubmed
  3. Liang CH, Shiu LY, Chang LC, Sheu HM, Kuo KW: Solamargine upregulation of Fas, downregulation of HER2, and enhancement of cytotoxicity using epirubicin in NSCLC cells. Mol Nutr Food Res. 2007 Aug;51(8):999-1005. Pubmed

3. DNA

Pharmacological action: unknown
Actions: intercalation

DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.

Gene Sequence: FASTA

References:
  1. Ganzina F: 4’-epi-doxorubicin, a new analogue of doxorubicin: a preliminary overview of preclinical and clinical data. Cancer Treat Rev. 1983 Mar;10(1):1-22. Pubmed
  2. Williams LD, Frederick CA, Ughetto G, Rich A: Ternary interactions of spermine with DNA: 4’-epiadriamycin and other DNA: anthracycline complexes. Nucleic Acids Res. 1990 Sep 25;18(18):5533-41. Pubmed
  3. Podell ER, Harrington DJ, Taatjes DJ, Koch TH: Crystal structure of epidoxorubicin-formaldehyde virtual crosslink of DNA and evidence for its formation in human breast-cancer cells. Acta Crystallogr D Biol Crystallogr. 1999 Sep;55(Pt 9):1516-23. Pubmed
Transporters

1. Multidrug resistance-associated protein 1

Actions: substrate

May participate directly in the active transport of drugs into subcellular organelles or influence drug distribution indirectly. Confers resistance to anticancer drugs. Transports LTC4. May protect milk against xenobiotics

UniProt ID: P33527 Link_out
Gene: ABCC1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Godinot N, Iversen PW, Tabas L, Xia X, Williams DC, Dantzig AH, Perry WL 3rd: Cloning and functional characterization of the multidrug resistance-associated protein (MRP1/ABCC1) from the cynomolgus monkey. Mol Cancer Ther. 2003 Mar;2(3):307-16. Pubmed
  2. Nunoya K, Grant CE, Zhang D, Cole SP, Deeley RG: Molecular cloning and pharmacological characterization of rat multidrug resistance protein 1 (mrp1). Drug Metab Dispos. 2003 Aug;31(8):1016-26. Pubmed
  3. Stride BD, Grant CE, Loe DW, Hipfner DR, Cole SP, Deeley RG: Pharmacological characterization of the murine and human orthologs of multidrug-resistance protein in transfected human embryonic kidney cells. Mol Pharmacol. 1997 Sep;52(3):344-53. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 14, 2012 11:41