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Identification
NameDexrazoxane
Accession NumberDB00380  (APRD00090, DB02444)
TypeSmall Molecule
GroupsApproved, Withdrawn
Description

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.

Structure
Thumb
Synonyms
SynonymLanguageCode
(+)-(S)-4,4'-Propylenedi-2,6-piperazinedioneNot AvailableWHO
(+)-1,2-Bis(3,5-dioxo-1-piperazinyl)propaneNot AvailableNot Available
4-[(2S)-2-(3,5-dioxopiperazin-1-yl)propyl]piperazine-2,6-dioneNot AvailableIUPAC
DexrazoxanGermanINN
DexrazoxaneNot AvailableUSAN, DCF, BAN
DexrazoxanoSpanishINN
DexrazoxanumLatinINN
DextrorazoxaneNot AvailableNot Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Zinecardinjection, powder, lyophilized, for solution250 mg/25mLintravenousPharmacia and Upjohn Company1995-05-26Not AvailableUs
Zinecardinjection, powder, lyophilized, for solution500 mg/50mLintravenousPharmacia and Upjohn Company1995-05-26Not AvailableUs
Zinecardpowder for solution250 mgintravenousPfizer Canada IncNot AvailableNot AvailableCanada
Zinecardpowder for solution500 mgintravenousPfizer Canada IncNot AvailableNot AvailableCanada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Dexrazoxane HydrochloridekitMylan Institutional LLC2011-11-18Not AvailableUs
Dexrazoxane HydrochloridekitMylan Institutional LLC2011-11-18Not AvailableUs
Over the Counter ProductsNot Available
International Brands
NameCompany
Ao Nuo XianAosaiKang Pharmaceutical
CardioxaneNovartis
DexrazoxaneRaffo
SaveneTopoTarget
TotectTopoTarget
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Dexrazoxane hydrochloride
ThumbNot applicableDBSALT001028
Categories
CAS number24584-09-6
WeightAverage: 268.2691
Monoisotopic: 268.11715502
Chemical FormulaC11H16N4O4
InChI KeyBMKDZUISNHGIBY-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)-2-(3,5-dioxopiperazin-1-yl)propyl]piperazine-2,6-dione
SMILES
C[C@@H](CN1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentAlpha amino acids and derivatives
Alternative Parents
Substituents
  • Alpha-amino acid or derivatives
  • Dioxopiperazine
  • N-alkylpiperazine
  • Dicarboximide
  • Piperazine
  • 1,4-diazinane
  • Carboxylic acid imide, n-unsubstituted
  • Carboxylic acid imide
  • Tertiary aliphatic amine
  • Tertiary amine
  • Carboxamide group
  • Azacycle
  • Organoheterocyclic compound
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aliphatic heteromonocyclic compound
Molecular FrameworkAliphatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationFor 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.
PharmacodynamicsDexrazoxane 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 actionThe 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.
AbsorptionIV administration results in complete bioavailability.
Volume of distribution
  • 9 to 22.6 L/m^2
Protein bindingVery 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 eliminationUrinary 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 life2.5 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]
ToxicityIntraperitoneal, mouse LD10 = 500 mg/kg. Intravenous, dog LD10 = 2 gm/kg.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 substrateNon-inhibitor0.8828
CYP450 2D6 substrateNon-inhibitor0.9348
CYP450 2C19 substrateNon-inhibitor0.7777
CYP450 3A4 substrateNon-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
Pharmacoeconomics
Manufacturers
  • Bedford laboratories div ben venue laboratories inc
  • Topotarget as
  • Pharmacia and upjohn co
Packagers
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionintravenous250 mg/25mL
Injection, powder, lyophilized, for solutionintravenous500 mg/50mL
Kit
Powder for solutionintravenous250 mg
Powder for solutionintravenous500 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
CountryPatent NumberApprovedExpires (estimated)
United States52429011993-09-072010-09-07
United States67272532000-03-132020-03-13
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point191-197 °CNot Available
water solubilitySparingly solubleNot Available
logP-2.6Not Available
pKa2.1Not Available
Predicted Properties
PropertyValueSource
Water Solubility10.4 mg/mLALOGPS
logP-1.1ALOGPS
logP-2.7ChemAxon
logS-1.4ALOGPS
pKa (Strongest Acidic)11.2ChemAxon
pKa (Strongest Basic)3.6ChemAxon
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 FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  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. Pubmed
  2. Hasinoff BB: The use of dexrazoxane for the prevention of anthracycline extravasation injury. Expert Opin Investig Drugs. 2008 Feb;17(2):217-23. Pubmed
  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. Pubmed
  4. Weiss G, Loyevsky M, Gordeuk VR: Dexrazoxane (ICRF-187). Gen Pharmacol. 1999 Jan;32(1):155-8. Pubmed
  5. Langer SW: Dexrazoxane for anthracycline extravasation. Expert Rev Anticancer Ther. 2007 Aug;7(8):1081-8. Pubmed
External Links
ATC CodesV03AF02
AHFS CodesNot Available
PDB Entries
FDA labelDownload (162 KB)
MSDSDownload (161 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. DNA topoisomerase 2-alpha

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
DNA topoisomerase 2-alpha P11388 Details

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

2. DNA topoisomerase 2-beta

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
DNA topoisomerase 2-beta Q02880 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
  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. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on March 15, 2014 16:59