Dexrazoxane

Identification

Summary

Dexrazoxane is a cytoprotective drug used to prevent and improve cardiomyopathy associated with doxorubicin treatment for metastatic breast cancer.

Brand Names
Cardioxane, Savene, Totect, Zinecard
Generic Name
Dexrazoxane
DrugBank Accession Number
DB00380
Background

An antimitotic agent with immunosuppressive properties. Dexrazoxane, the (+)-enantiomorph of razoxane, provides cardioprotection against anthracycline toxicity. It appears to inhibit formation of a toxic iron-anthracycline complex. [PubChem] The Food and Drug Administration has designated dexrazoxane as an orphan drug for use in the prevention or reduction in the incidence and severity of anthracycline-induced cardiomyopathy.

Type
Small Molecule
Groups
Approved, Withdrawn
Structure
Weight
Average: 268.2691
Monoisotopic: 268.11715502
Chemical Formula
C11H16N4O4
Synonyms
  • (+)-(S)-4,4'-Propylenedi-2,6-piperazinedione
  • (+)-1,2-Bis(3,5-dioxo-1-piperazinyl)propane
  • 4-[(2S)-2-(3,5-dioxopiperazin-1-yl)propyl]piperazine-2,6-dione
  • Dexrazoxan
  • Dexrazoxane
  • Dexrazoxano
  • Dexrazoxanum
  • Dextrorazoxane
External IDs
  • ADR 529
  • ADR-529
  • ICRF-187
  • NSC 169780
  • NSC-169780

Pharmacology

Indication

For reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin hydrochloride dose of 300 mg/m^2 and would benefit from continued doxorubicin therapy. Also approved for the treatment of extravasation from intravenous anthracyclines.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Prophylaxis ofDoxorubicin induced cardiomyopathy•••••••••••••••••••••• •••••• ••••••
Treatment ofDrug extravasation••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Dexrazoxane is a cardioprotective agent for use in conjunction with doxorubicin indicated for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose. Patients receiving anthracycline-derivative antineoplastic agents may experience three types of cardiotoxicity: acute transient type; chronic, subacute type (related to cumulative dose and has a more indolent onset later on); and a late-onset type that manifests years after therapy, mainly in patients that have been exposed to the drug as a child. Although the exact mechanism of anthracycline-induced cardiotoxicity is not known, it has shown to exert a variety of actions that may result in the development of cardiotoxicity. In animals, anthracyclines cause a selective inhibition of cardiac muscle gene expression for α-actin, troponin, myosin light-chain 2, and the M isoform of creatine kinase. This may lead to myofibrillar loss associated with anthracycline-induced cardiotoxicity. Anthracyclines may also cause myocyte damage via calcium overload, altered myocardial adrenergic function, release of vasoactive amines, and proinflammatory cytokines. Furthermore, it has been suggested that the main cause of anthracycline-induced cardiotoxicity is associated with free-radical damage to DNA. The drugs intercalate DNA, chelate metal ions to produce drug-metal complexes, and generate superoxide radicals via oxidation-reduction reactions. Anthracyclines also contain a quinone structure that can undergo reduction via NADPH-dependent reactions to produce a semiquinone free radical that initiates a cascade of superoxide and hydroxide radical generation. Chelation of metal ions, particularly iron, by anthracyclines results in an anthracycline-metal complex that catalyzes the generation of reactive oxygen free radicals. This complex is a powerful oxidant that can initiate lipid peroxidation in the absence of oxygen free radicals. The toxicity induced by antrhacyclines may be exacerbated in cardiac cells, as these cells do not possess sufficient amounts of certain enzymes (e.g., superoxide dismutase, catalase, glutathione peroxidase) involved in detoxifying free radicals and protecting the cells from subsequent damage.

Mechanism of action

The mechanism by which dexrazoxane exerts its cardioprotective activity is not fully understood. Dexrazoxane is a cyclic derivative of EDTA that readily penetrates cell membranes. Results of laboratory studies suggest that dexrazoxane (a prodrug) is converted intracellularly to a ring-opened bidentate chelating agent that chelates to free iron and interferes with iron-mediated free radical generation thought to be responsible, in part, for anthracycline-induced cardiomyopathy. It should be noted that dexrazoxane may also be protective through its inhibitory effect on topoisomerase II.

TargetActionsOrganism
ADNA topoisomerase 2-alpha
inhibitor
Humans
UDNA topoisomerase 2-betaNot AvailableHumans
Absorption

IV administration results in complete bioavailability.

Volume of distribution
  • 9 to 22.6 L/m^2
Protein binding

Very low (< 2%)

Metabolism

Dexrazoxane is hydrolysed by the enzyme dihydropyrimidine amidohydrolase in the liver and kidney to active metabolites that are capable of binding to metal ions.

Route of elimination

Urinary excretion plays an important role in the elimination of dexrazoxane. Forty-two percent of the 500 mg/m2 dose of dexrazoxane was excreted in the urine.

Half-life

2.5 hours

Clearance
  • 7.88 L/h/m2 [dose of 50 mg/m2 Doxorubicin and 500 mg/m2 Dexrazoxane]
  • 6.25 L/h/m2 [dose of 60 mg/m2 Doxorubicin and 600 mg/m2 Dexrazoxane]
Adverse Effects
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Toxicity

Intraperitoneal, mouse LD10 = 500 mg/kg. Intravenous, dog LD10 = 2 gm/kg.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirDexrazoxane may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbataceptThe risk or severity of adverse effects can be increased when Dexrazoxane is combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Dexrazoxane.
AceclofenacAceclofenac may decrease the excretion rate of Dexrazoxane which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Dexrazoxane which could result in a higher serum level.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Dexrazoxane hydrochloride5346058Q7S149003-01-0BIFMNMPSIYHKDN-FJXQXJEOSA-N
International/Other Brands
Ao Nuo Xian (AosaiKang Pharmaceutical) / Cardioxane (Novartis)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
CardioxaneInjection, powder, for solution500 mg/1IntravenousClinigen Healthcare Ltd2017-07-28Not applicableUS flag
Dexrazoxane for InjectionPowder, for solution250 mg / vialIntravenousJuno Pharmaceuticals Corp.Not applicableNot applicableCanada flag
Dexrazoxane for InjectionPowder, for solution500 mg / vialIntravenousJuno Pharmaceuticals Corp.Not applicableNot applicableCanada flag
SaveneInjection, solution, concentrate20 mg/mlIntravenousClinigen Healthcare B.V.2016-09-08Not applicableEU flag
TotectInjection, powder, lyophilized, for solution500 mg/1IntravenousClinigen Limited2020-01-012022-11-30US flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DexrazoxaneInjection, powder, lyophilized, for solution10 mg/1mLIntravenousHikma Pharmaceuticals USA Inc.2005-03-31Not applicableUS flag
DexrazoxaneKit10 mg/1mLIntravenousBedford Pharmaceuticals2005-03-312013-05-31US flag
DexrazoxaneInjection, powder, lyophilized, for solution; Kit500 mg/50mLIntravenousEugia US LLC2016-05-12Not applicableUS flag
DexrazoxaneInjection, powder, lyophilized, for solution500 mg/50mLIntravenousAlmaject, Inc.2022-06-01Not applicableUS flag
DexrazoxaneInjection, powder, lyophilized, for solution500 mg/50mLIntravenousAlvogen Inc.2017-09-012021-12-01US flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
CardioxaneDexrazoxane hydrochloride (500 mg/1)Injection, powder, for solutionIntravenousClinigen Healthcare Ltd2017-07-28Not applicableUS flag

Categories

ATC Codes
V03AF02 — Dexrazoxane
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as alpha amino acids and derivatives. These are amino acids in which the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (alpha carbon), or a derivative thereof.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Alpha amino acids and derivatives
Alternative Parents
Dioxopiperazines / N-alkylpiperazines / N-unsubstituted carboxylic acid imides / Dicarboximides / Trialkylamines / Azacyclic compounds / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
1,4-diazinane / Aliphatic heteromonocyclic compound / Alpha-amino acid or derivatives / Amine / Azacycle / Carbonyl group / Carboxylic acid imide / Carboxylic acid imide, n-unsubstituted / Dicarboximide / Dioxopiperazine
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
razoxane (CHEBI:50223)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
048L81261F
CAS number
24584-09-6
InChI Key
BMKDZUISNHGIBY-ZETCQYMHSA-N
InChI
InChI=1S/C11H16N4O4/c1-7(15-5-10(18)13-11(19)6-15)2-14-3-8(16)12-9(17)4-14/h7H,2-6H2,1H3,(H,12,16,17)(H,13,18,19)/t7-/m0/s1
IUPAC Name
4-[(2S)-1-(3,5-dioxopiperazin-1-yl)propan-2-yl]piperazine-2,6-dione
SMILES
C[C@@H](CN1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1

References

General References
  1. Hasinoff BB, Herman EH: Dexrazoxane: how it works in cardiac and tumor cells. Is it a prodrug or is it a drug? Cardiovasc Toxicol. 2007;7(2):140-4. [Article]
  2. Hasinoff BB: The use of dexrazoxane for the prevention of anthracycline extravasation injury. Expert Opin Investig Drugs. 2008 Feb;17(2):217-23. doi: 10.1517/13543784.17.2.217. [Article]
  3. Kik K, Szmigiero L: [Dexrazoxane (ICRF-187)--a cardioprotectant and modulator of action of some anticancer drugs]. Postepy Hig Med Dosw (Online). 2006;60:584-90. [Article]
  4. Weiss G, Loyevsky M, Gordeuk VR: Dexrazoxane (ICRF-187). Gen Pharmacol. 1999 Jan;32(1):155-8. [Article]
  5. Langer SW: Dexrazoxane for anthracycline extravasation. Expert Rev Anticancer Ther. 2007 Aug;7(8):1081-8. [Article]
Human Metabolome Database
HMDB0014524
KEGG Drug
D03730
PubChem Compound
71384
PubChem Substance
46505982
ChemSpider
64479
RxNav
42736
ChEBI
50223
ChEMBL
CHEMBL1738
ZINC
ZINC000087515509
Therapeutic Targets Database
DAP000649
PharmGKB
PA449259
PDBe Ligand
CDX
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Dexrazoxane
FDA label
Download (162 KB)
MSDS
Download (161 KB)

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
  • Bedford laboratories div ben venue laboratories inc
  • Topotarget as
  • Pharmacia and upjohn co
Packagers
  • Bedford Labs
  • Cardinal Health
  • Catalent Pharma Solutions
  • Oso Biopharmaceuticals Manufacturing LLC
  • Pharmacia Inc.
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous500 mg/1
Powder, for solutionParenteral500 MG
Injection, powder, lyophilized, for solutionIntravenous500 mg
Powder, for solution
Injection, powder, for solutionParenteral20 mg/ml
SolutionIntravenous567.954 mg
Injection, powder, lyophilized, for solutionIntravenous10 mg/1mL
Injection, powder, lyophilized, for solutionIntravenous500 mg/50mL
Injection, powder, lyophilized, for solution; kitIntravenous250 mg/25mL
Injection, powder, lyophilized, for solution; kitIntravenous500 mg/50mL
Injection, solutionIntravenous500 mg/50mL
KitIntravenous10 mg/1mL
KitIntravenous250 mg/25mL
KitIntravenous500 mg/50mL
SolutionIntravenous500.000 mg
InjectionIntravenous
Injection, solution, concentrateIntravenous20 mg/ml
Injection, powder, lyophilized, for solutionIntravenous500 mg/1
KitIntravenous500 mg/1
Injection, powder, lyophilized, for solutionIntravenous250 mg/25mL
KitIntravenous
Powder, for solutionIntravenous250 mg / vial
Powder, for solutionIntravenous500 mg / vial
SolutionParenteral500.00 mg
Prices
Unit descriptionCostUnit
Zinecard 500 mg vial517.18USD vial
Dexrazoxane 500 mg vial492.55USD vial
Zinecard 250 mg vial258.59USD vial
Dexrazoxane 250 mg vial246.28USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5242901No1993-09-072010-09-07US flag
US6727253No2004-04-272020-03-13US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)191-197 °CNot Available
water solubilitySparingly solubleNot Available
logP-2.6Not Available
pKa2.1Not Available
Predicted Properties
PropertyValueSource
Water Solubility10.4 mg/mLALOGPS
logP-1ALOGPS
logP-2.7Chemaxon
logS-1.4ALOGPS
pKa (Strongest Acidic)11.2Chemaxon
pKa (Strongest Basic)3.2Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area98.82 Å2Chemaxon
Rotatable Bond Count3Chemaxon
Refractivity64.25 m3·mol-1Chemaxon
Polarizability26.12 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.8518
Blood Brain Barrier+0.6387
Caco-2 permeable-0.6144
P-glycoprotein substrateSubstrate0.8766
P-glycoprotein inhibitor IInhibitor0.6576
P-glycoprotein inhibitor IINon-inhibitor0.9653
Renal organic cation transporterNon-inhibitor0.7348
CYP450 2C9 substrateNon-substrate0.8399
CYP450 2D6 substrateNon-substrate0.7872
CYP450 3A4 substrateSubstrate0.5139
CYP450 1A2 substrateNon-inhibitor0.9458
CYP450 2C9 inhibitorNon-inhibitor0.8828
CYP450 2D6 inhibitorNon-inhibitor0.9348
CYP450 2C19 inhibitorNon-inhibitor0.7777
CYP450 3A4 inhibitorNon-inhibitor0.9666
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9741
Ames testNon AMES toxic0.9132
CarcinogenicityNon-carcinogens0.9077
BiodegradationNot ready biodegradable0.991
Rat acute toxicity2.4267 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.941
hERG inhibition (predictor II)Non-inhibitor0.8929
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0m2c-4910000000-46d13032d5f2c6472d9b
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-0900000000-9e1b04817c90f98306f4
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-0090000000-afb87782d39b2c50eaf1
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-3970000000-10b9a5dbbecd6fd7d882
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0q4r-2890000000-2b7449d1e888abd162f6
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0abc-6930000000-a32ad929c662f0dbf311
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-02ec-5940000000-a28bf93c039c3a0189b7
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-170.0846928
predicted
DarkChem Lite v0.1.0
[M-H]-168.2896928
predicted
DarkChem Lite v0.1.0
[M-H]-155.53235
predicted
DeepCCS 1.0 (2019)
[M+H]+171.1213928
predicted
DarkChem Lite v0.1.0
[M+H]+168.5235928
predicted
DarkChem Lite v0.1.0
[M+H]+157.8925
predicted
DeepCCS 1.0 (2019)
[M+Na]+170.5930928
predicted
DarkChem Lite v0.1.0
[M+Na]+168.1259928
predicted
DarkChem Lite v0.1.0
[M+Na]+164.0317
predicted
DeepCCS 1.0 (2019)

Targets

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Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Ubiquitin binding
Specific Function
Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segr...
Gene Name
TOP2A
Uniprot ID
P11388
Uniprot Name
DNA topoisomerase 2-alpha
Molecular Weight
174383.88 Da
References
  1. Hasinoff BB, Chee GL, Thampatty P, Allan WP, Yalowich JC: The cardioprotective and DNA topoisomerase II inhibitory agent dexrazoxane (ICRF-187) antagonizes camptothecin-mediated growth inhibition of Chinese hamster ovary cells by inhibition of DNA synthesis. Anticancer Drugs. 1999 Jan;10(1):47-54. [Article]
  2. Hasinoff BB, Abram ME, Barnabe N, Khelifa T, Allan WP, Yalowich JC: The catalytic DNA topoisomerase II inhibitor dexrazoxane (ICRF-187) induces differentiation and apoptosis in human leukemia K562 cells. Mol Pharmacol. 2001 Mar;59(3):453-61. [Article]
  3. Langer SW, Sehested M, Jensen PB: Dexrazoxane is a potent and specific inhibitor of anthracycline induced subcutaneous lesions in mice. Ann Oncol. 2001 Mar;12(3):405-10. [Article]
  4. Hasinoff BB, Takeda K, Ferrans VJ, Yu ZX: The doxorubicin cardioprotective agent dexrazoxane (ICRF-187) induces endopolyploidy in rat neonatal myocytes through inhibition of DNA topoisomerase II. Anticancer Drugs. 2002 Mar;13(3):255-8. [Article]
  5. Renodon-Corniere A, Jensen LH, Nitiss JL, Jensen PB, Sehested M: Analysis of bisdioxopiperazine dexrazoxane binding to human DNA topoisomerase II alpha: decreased binding as a mechanism of drug resistance. Biochemistry. 2003 Aug 19;42(32):9749-54. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  7. Hasinoff BB, Herman EH: Dexrazoxane: how it works in cardiac and tumor cells. Is it a prodrug or is it a drug? Cardiovasc Toxicol. 2007;7(2):140-4. [Article]
  8. Kik K, Szmigiero L: [Dexrazoxane (ICRF-187)--a cardioprotectant and modulator of action of some anticancer drugs]. Postepy Hig Med Dosw (Online). 2006;60:584-90. [Article]
  9. Hasinoff BB, Abram ME, Chee GL, Huebner E, Byard EH, Barnabe N, Ferrans VJ, Yu ZX, Yalowich JC: The catalytic DNA topoisomerase II inhibitor dexrazoxane (ICRF-187) induces endopolyploidy in Chinese hamster ovary cells. J Pharmacol Exp Ther. 2000 Nov;295(2):474-83. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Protein kinase c binding
Specific Function
Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks.
Gene Name
TOP2B
Uniprot ID
Q02880
Uniprot Name
DNA topoisomerase 2-beta
Molecular Weight
183265.825 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. [Article]
  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. [Article]
  3. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [Article]

Drug created at June 13, 2005 13:24 / Updated at March 02, 2024 03:15