Dexrazoxane combined with doxorubicin, daunorubicin, or idarubicin reduces the tissue lesions in B6D2F1 mice (expressed as area under the curve of wound size times duration) by 96%, 70%, and 87%, respectively. Dexrazoxane combined with doxorubicin, daunorubicin, or idarubicin results in a statistically significant reduction in the fraction of mice with wounds as well as the duration of wounds.

Absorption, Distribution and Excretion
IV administration results in complete bioavailability.
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.
9 to 22.6 L/m^2
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]
After intravenous administration, the drug is rapidly distributed into tissue fluids, the highest concentrations of the parent drug and its hydrolysis product being found in hepatic and renal tissues.
The mean peak plasma concentration of dexrazoxane was 36.5 mcg/mL at the end of the 15-minute infusion of a 500 mg/sq m doxorubicin dose. Following a rapid distributive phase, dexrazoxane reaches post-distributive equilibrium within 2 to 4 hours.
The estimated steady-state volume of distribution of dexrazoxane suggests its distribution primarily in the total body water (25 L/sq m ).
In vitro studies have shown that /dexrazoxane/ is not bound to plasma proteins.
For more Absorption, Distribution and Excretion (Complete) data for DEXRAZOXANE (9 total), please visit the HSDB record page.

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Metabolism / Metabolites
Dexrazoxane is hydrolysed by the enzyme dihydropyrimidine amidohydrolase in the liver and kidney to active metabolites that are capable of binding to metal ions.
Metabolic products include the unchanged drug, a diacid-diamide cleavage product, and two monoacid-monoamide ring products of unknown concentrations.
In vitro studies have shown dexrazoxane to be hydrolysed by DHPase in liver and kidney, but not heart extracts.
/This/ study was undertaken to determine the metabolism of dexrazoxane (ICRF-187) to its one-ring open hydrolysis products and its two-rings opened metal-chelating product ADR-925 in cancer patients with brain metastases treated with high-dose etoposide. In this phase I/II trial dexrazoxane was used as a rescue agent to reduce the extracerebral toxicity of etoposide. Dexrazoxane and its one-ring open hydrolysis products were determined by HPLC and ADR-925 was determined by a fluorescence flow injection assay. The two one-ring open hydrolysis intermediates of dexrazoxane appeared in the plasma at low levels upon completion of dexrazoxane infusion and then rapidly decreased with half-lives of 0.6 and 2.5 hr. A plasma concentration of 10 micro M ADR-925 was also detected at the completion of the dexrazoxane i.v. infusion period, indicating that dexrazoxane was rapidly metabolized in vivo. A plateau level of 30 micro M ADR-925 was maintained for 4 hr and then slowly decreased. The pharmacokinetics of dexrazoxane were found to be similar to other reported data in other settings and at lower doses. The rapid appearance of ADR-925 in plasma may make ADR-925 available to be taken up by heart tissue and bind free iron. These results suggest that the dexrazoxane intermediates are enzymatically metabolized to ADR-925 and provide a pharmacodynamic basis for the antioxidant cardioprotective activity of dexrazoxane.
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

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Biological Half-Life
2.5 hours
The distribution half-life has ranged from about 12 to 60 minutes ...
Elimination - 2.5 hours.

Toxicity Summary
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.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of dexrazoxane during breastfeeding. The manufacturer recommends that women not breastfeed during treatment and for 2 weeks following the final dose of dexrazoxane. However, because dexrazoxane is used with doxorubicin, the abstinence period might be longer, depending on the doxorubicin dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Very low (< 2%)

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Toxicity Data
Man(iv): TDLo: 383 mg/kg
Mouse(ip): LDLo 800 mg/kg
Dog(iv): LDLo: 2 gm/kg
Intraperitoneal, mouse LD₁₀ = 500 mg/kg. Intravenous, dog LD₁₀ = 2 gm/kg.

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Interactions
There was no significant change in the pharmacokinetics of doxorubicin (50 mg/sq m ) and its predominant metabolite, doxorubicinol, in the presence of dexrazoxane (500 mg/sq m ) in a crossover study in cancer patients.

Circ Res.1999 Feb 19;84(3):257-65;Cancer Res.2007 Sep 15;67(18):8839-46.

(+)-dexrazoxane is a razoxane. It has a role as a chelator, an antineoplastic agent, a cardiovascular drug and an immunosuppressive agent.
Dexrazoxane is a Cytoprotective Agent.
Dexrazoxane is a bisdioxopiperazine with iron-chelating, chemoprotective, cardioprotective, and antineoplastic activities. After hydrolysis to an active form that is similar to ethylenediaminetetraacetic acid (EDTA), dexrazoxane chelates iron, limiting the formation of free radical-generating anthracycline-iron complexes, which may minimize anthracycline-iron complex-mediated oxidative damage to cardiac and soft tissues. This agent also inhibits the catalytic activity of topoisomerase II, which may result in tumor cell growth inhibition.
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. 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.
The (+)-enantiomorph of razoxane.
See also: Dexrazoxane Hydrochloride (has salt form).

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Drug 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.
FDA Label
Savene is indicated for the treatment of anthracycline extravasation.

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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.
The mechanism of action of dexrazoxane's cardioprotective activity is not fully understood. Dexrazoxane is a cyclic derivative of ethylenediamine tetra-acetic acid (EDTA) that readily penetrates cell membranes. Laboratory studies suggest that dexrazoxane is converted intracellularly to a ring-opened chelating agent that interferes with iron-mediated free radical generation thought to be responsible, in part, for anthracycline-induced cardiomyopathy.

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Therapeutic Uses
Cardioprotectant
Dexrazoxane is indicated for reducing the incidence and severity of cardiomyopathy associated with the administration of doxorubicin in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/sq m of body surface and who would benefit from continued therapy with doxorubicin. /Included in US product labeling/
/Exptl Ther:/ Accidental extravasation of chemotherapy containing anthracycline often causes mutilating complications as a result of extensive tissue necrosis. Treatment therefore consists of extensive surgical debridement. We present the case of a 41-year-old woman with breast cancer who experienced extravasation of epirubicin. She was treated with an intravenous infusion of dexrazoxane for three successive days and recovered without surgical treatment and only slightly dysaesthesia in the surrounding tissue. Although infusion of dexrazoxane for this indication is still experimental we consider it a promising treatment for patients who have accidental extravasation of anthracyclines.

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Drug Warnings
Dexrazoxane is not indicated for use at the time of initiation of doxorubicin therapy. Cconcurrent use of dexrazoxane with the initiation of fluorouracil, doxorubicin, and cyclophosphamide (FAC) therapy is not recommended because of possible interference with the antitumor efficacy of the regimen.
FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
Dexrazoxane may add to the myelosuppression caused by chemotherapeutic agents.
Do not use with chemotherapy regimens that do not contain anthracycline.
For more Drug Warnings (Complete) data for DEXRAZOXANE (8 total), please visit the HSDB record page.

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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.

C11H16N4O4

268.27

268.117

24584-09-6

Dexrazoxane hydrochloride;149003-01-0

71384

White to light yellow solid powder

1.3±0.1 g/cm3

531.5±50.0 °C at 760 mmHg

194-196ºC

275.3±30.1 °C

0.0±1.4 mmHg at 25°C

1.540

-0.37

2

6

3

19

404

1

C[C@@H](CN1CC(=O)NC(=O)C1)N2CC(=O)NC(=O)C2

BMKDZUISNHGIBY-ZETCQYMHSA-N

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

(S)-4,4-(propane-1,2-diyl)bis(piperazine-2,6-dione)

ICRF-187 (ADR-529) HCl; (+)-Razoxane hydrochloride, ADR-529 hydrochloride, Cardioxan, Dexrazoxane HCl, Dexrazoxane hydrochloride, ICRF-187 hydrochloride, Savene; ADR529; ADR-529; ADR 529; ICRF-187; ICRF187; ICRF 187; NSC169780; NSC-169780; NSC 169780; Cardioxan; Cardioxane; US brand names: Totect; Zinecard. Foreign brand names: Cardioxane Savene.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.32 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (9.32 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (9.32 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)