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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Groupsapproved, withdrawn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
Salts
Name/CAS Structure Properties
Dexrazoxane hydrochloride
Thumb Not applicable DBSALT001028
Brand names
NameCompany
Ao Nuo XianAosaiKang Pharmaceutical
CardioxaneNovartis
DexrazoxaneRaffo
SaveneTopoTarget
TotectTopoTarget
ZinecardPfizer
Brand mixturesNot Available
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)-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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassPiperazines
SubclassDioxopiperazines
Direct parentDioxopiperazines
Alternative parentsDiazinanes; N-unsubstituted Carboxylic Acid Imides; Secondary Carboxylic Acid Amides; Tertiary Amines; Polyamines; Carboxylic Acids
Substituents1,4-diazinane; carboxylic acid imide; carboxylic acid imide, n-unsubstituted; secondary carboxylic acid amide; carboxamide group; tertiary amine; polyamine; carboxylic acid derivative; carboxylic acid; amine; organonitrogen compound
Classification descriptionThis compound belongs to the dioxopiperazines. These are compounds containing a piperazine ring bearing two ketone groups.
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
Property Value Probability
Human Intestinal Absorption + 0.8518
Blood Brain Barrier + 0.6387
Caco-2 permeable - 0.6144
P-glycoprotein substrate Substrate 0.8766
P-glycoprotein inhibitor I Inhibitor 0.6576
P-glycoprotein inhibitor II Non-inhibitor 0.9653
Renal organic cation transporter Non-inhibitor 0.7348
CYP450 2C9 substrate Non-substrate 0.8399
CYP450 2D6 substrate Non-substrate 0.7872
CYP450 3A4 substrate Substrate 0.5139
CYP450 1A2 substrate Non-inhibitor 0.9458
CYP450 2C9 substrate Non-inhibitor 0.8828
CYP450 2D6 substrate Non-inhibitor 0.9348
CYP450 2C19 substrate Non-inhibitor 0.7777
CYP450 3A4 substrate Non-inhibitor 0.9666
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9741
Ames test Non AMES toxic 0.9132
Carcinogenicity Non-carcinogens 0.9077
Biodegradation Not ready biodegradable 0.991
Rat acute toxicity 2.4267 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.941
hERG inhibition (predictor II) Non-inhibitor 0.8929
Pharmacoeconomics
Manufacturers
  • Bedford laboratories div ben venue laboratories inc
  • Topotarget as
  • Pharmacia and upjohn co
Packagers
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous
Prices
Unit descriptionCostUnit
Zinecard 500 mg vial517.18USDvial
Dexrazoxane 500 mg vial492.55USDvial
Zinecard 250 mg vial258.59USDvial
Dexrazoxane 250 mg vial246.28USDvial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States67272532000-03-132020-03-13
United States52429011993-09-072010-09-07
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 solubility1.04e+01 g/lALOGPS
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 area98.82ChemAxon
rotatable bond count3ChemAxon
refractivity64.25ChemAxon
polarizability26.12ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
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
ResourceLink
PubChem Compound71384
PubChem Substance46505982
ChemSpider64479
ChEBI50223
ChEMBLCHEMBL1738
Therapeutic Targets DatabaseDAP000649
PharmGKBPA449259
HETCDX
Drug Product Database2153440
RxListhttp://www.rxlist.com/cgi/generic2/dexrazoxane.htm
Drugs.comhttp://www.drugs.com/cdi/dexrazoxane.html
WikipediaDexrazoxane
ATC CodesV03AF02
AHFS CodesNot Available
PDB Entries
FDA labelshow(162 KB)
MSDSshow(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