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25316-40-9

Supplier Related Products Identification Chemical Properties Safety Data Raw materials And Preparation Products Hazard Information Material Safety Data Sheet(MSDS) Questions And Answer

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Identification

Name
Doxorubicin hydrochloride
CAS
25316-40-9
Synonyms
14-HYDROXYDAUNOMYCIN HCL
14-HYDROXYDAUNOMYCIN HYDROCHLORIDE
(8s-cis)-10-[(3-amino-2,3,6-trideoxy-alpha-l-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxynaphthacene-5,12-dione hydrochloride
ADRIACIN
ADRIAMYCIN
ADRIAMYCIN HCL
ADRIAMYCIN HYDROCHLORIDE
ADRIBLASTINA
ADRIBLASTINA HYDROCHLORIDE
CAELYX
DOX HYDROCHLORIDE
DOXORUBICIN HCL
DOXORUBICIN HYDROCHLORIDE
HYDROXYDAUNORUBICIN HYDROCHLORIDE
(8s-cis)-hlorid
10-((3-amino-2,3,6-trideoxy-alpha-l-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-12-naphthacenedione
8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-xy)-hydroc
admhydrochloride
Ardriamycin
fi6804
EINECS(EC#)
246-818-3
Molecular Formula
C27H30ClNO11
MDL Number
MFCD00077757
Molecular Weight
579.98
MOL File
25316-40-9.mol

Chemical Properties

Appearance
Adriamycin is an orange to red cake-like or needle-like crystalline solid.
Appearance
Orange-Red Crystalline Solid
mp 
216 °C (dec.)(lit.)

storage temp. 
2-8°C

solubility 
H2O: 10 mg/mL, clear, red-orange

Usage
Used as an antineoplastic
Merck 
13,3473
CAS DataBase Reference
25316-40-9(CAS DataBase Reference)
EPA Substance Registry System
25316-40-9(EPA Substance)

Safety Data

Hazard Codes 
T,T+
Risk Statements 
R45:May cause cancer.
R22:Harmful if swallowed.
R40:Limited evidence of a carcinogenic effect.
R26/27/28:Very Toxic by inhalation, in contact with skin and if swallowed .
Safety Statements 
S53:Avoid exposure-obtain special instruction before use .
S45:In case of accident or if you feel unwell, seek medical advice immediately (show label where possible) .
S36/37/39:Wear suitable protective clothing, gloves and eye/face protection .
S22:Do not breathe dust .
S7/9:Keep container tightly closed and in a well-ventilated place .
WGK Germany 
3

RTECS 
QI9295900


10-21
HS Code 
29419000

Raw materials And Preparation Products

Raw materials
Daunorubicin
Preparation Products
Pirarubicin

Hazard Information

General Description
Orange-red thin needles. Aqueous solutions yellow-orange at acid pHs, orange-red at neutral pHs, and violet blue over pH 9.
Reactivity Profile
Amines, like ADRIAMYCIN HYDROCHLORIDE(25316-40-9), are weak chemical bases. They neutralize acids to form salts plus water. These acid-base reactions are exothermic. Amines may be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated by amines in combination with strong reducing agents, such as hydrides.
Air & Water Reactions
Water soluble.
Potential Exposure
An antibiotic product from streptomyces, used as anticancer drug
First aid
Move victim to fresh air. Call 911 or emergency medical service. Give artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; give artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involvedand take precautions to protect themselves. Medical observation is recommended for 24 to 48 hours after breathing overexposure, as pulmonary edema may be delayed. As first aid for pulmonary edema, a doctor or authorized paramedic may consider administering a drug or other inhalation therapy.
Fire Hazard
This compound is probably combustible.
Shipping
UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required.
Incompatibilities
Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides
Waste Disposal
It is inappropriate and possibly dangerous to the environment to dispose of expired or waste pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Material Safety Data Sheet(MSDS)

Questions And Answer

Overview
Doxorubicin (DXR) is a clinically important cancer chemotherapeutic agent and, in spite of undesirable acute and long-term toxic effects, DXR remains one of the most widely used antitumor drugs because of its broad spectrum of activity[1]. DXR was first isolated in 1969[1] from Streptomyces peucetius subsp caesius ATCC 27952, a higher DXR-producing mutant strain derived from the wild-type S. peucetius ATCC 29050 strain, and is formed by C-14 hydroxylation of its immediate precursor, DNR. Although a number of organisms (including the 29050 strain) are known to produce DNR [2], S. peucetius subsp caesius is the only organism reported to produce DXR. The current production of DXR is over 225 kilograms annually due to its wide use and the fact that it is the starting point for the synthesis of numerous analogs and derivatives aimed at improving clinical cancer treatment[1]. Although DXR was discovered as a microbial metabolite, it is produced commercially by semi-synthesis from the more abundant DNR instead of by fermentation. High-DNR producing strains are available worldwide yet apparently lack the ability to make useful amounts of DXR or the DXR produced cannot easily be separated from the DNR that also is present. Consequently, the development of improved strains for DXR production is a beneficial goal since this drug is an expensive product.

Figure 1 the chemical structure of DXR

Much effort has been devoted to unraveling the mechanism of antitumor action of doxorubicin. Currently the belief is widespread that free radical formation is critically involved in the mechanism of cytotoxicity of doxorubicin against tumor cells. However, most of the evidence favoring a free radical-dependent model has been obtained by studying subcellular fractions, often in combination with extremely high concentrations of doxorubicin that are not encountered in clinical practice.
Indications
Doxorubicin is a potent antitumour agent active against a wide spectrum of malignancies, including leukaemias, sarcomas, breast cancer, small cell lung cancer and ovarian cancer. Doxorubicin is used to produce regression in disseminated neoplastic conditions like acute lymphoblastic leukemia, acute myeloblastic leukemia, Wilms’ tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin's disease, malignant lymphoma and bronchogenic carcinoma in which the small cell histologic type is the most responsive compared to other cell types. Doxorubicin is also indicated for use as a component of adjuvant therapy in women with evidence of axillary lymph node involvement following resection of primary breast cancer. Doxorubicin does not playa crucial role in the treatment of tumours that can be cured with chemotherapy, such as testicular carcinoma, nephroblastoma, Burkitt's tumour and choriocarcinoma[3]. Like most other cytostatic agents, doxorubicin is not effective in the most frequently occurring malignancies such as colorectal cancer and non-small cell lung cancer.
Mechanism of action
Doxorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action, however, remaining not fully understood: Data pointing to the role of free radicals, and to damage of mitochondria and membranes, have modified the original hypothesis that DNA-intercalation was the sole cytotoxic mechanism. Meanwhile, the focus on plasma pharmacokinetics has been shifted towards pharmacodynamic studies, with emphasis on cellular doxorubicin concentrations in haematopoietic tissues[4], in solid tumours[5], and in cell constituents. Doxorubicin forms complexes with DNA by intercalation between base pairs. In addition, doxorubicin-iron complexes bind tightly to DNA[6]. However, contrary to intercalated doxorubicin, the doxorubicin-iron complex preserves its ability to catalyze the formation of oxygen free radicals in the presence of double-stranded DNA[6]. Thus, the doxorubicin-iron complex-driven hydroxyl radical formation can proceed in close proximity to DNA and has therefore the potential to damage DNA efficiently, especially since DNA seems to catalyze hydroxyl radical formation by this complex[7]. Hydroxyl radicals are probably involved in damaging of DNA since the generation of hydroxyl radicals by the Dox-iron complex correlates with its ability to cleave DNA[7] and also since catalase, iron chelates and hydroxyl radical scavengers are protective in this system[6]. Relatively high concentrations of hydroxyl radical scavengers were required for protection, indicating that these radicals were indeed generated in a site-specific way.
Moreover, 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. Topoisomerase II causes transient double-strand breaks during the twisting of 2 double-stranded DNA helices. Singleand double-stranded DNA breaks have been documented after in vivo and in vitro treatment with doxorubicin of P388 leukaemia cells in mice[8].
Special reference must be made to observations that interference with the cell membrane alone may lead to cell death [9]. Doxorubicin binding to membranes, and particularly its covalent binding to cardiolipin, a phospholipid with 2 negatively charged phosphate head groups, has received much attention[10]. Cardiolipin is found in the inner leaflet of the mitochondrial membrane and is closely associated with electron transport mechanisms. Goormaghtigh et al. (1983) [10] have shown that doxorubicin bound to cardiolipin undergoes redox cycling, producing covalent binding of doxorubicin to cardiolipin in mitochondrial membranes. The hydrophobic nature of the chromophore of anthracyclines allows partitioning into the lipid phase, resulting in changed fluidity of the membrane. Diminished membrane fluidity is related to doxorubicin resistance. A detailed study of the mechanisms involved in doxorubicin-induced changes in membrane structure and function has not been undertaken. However, doxorubicin binds to the epidermal growth factor receptor at clinically relevant drug concentrations, and alters its function.
Administration and formulation
Doxorubicin is available as a dry powder; reconstituted in water, it is most stable at a mildly acidic pH of 4, and unstable at a very acidic or basic pH[11]. When diluted in 0.9% sodium chloride or dextrose 5%, less than 5% decomposition occurred over 7 to 30 days[12]. It is stable in light at room temperature for at least 24 hours [12], although stability may be shorter in plasma and culture media[11].
Doxorubicin has been administered intravenously, intra-arterially, intraperitoneally, intrapleurally and intravesically. A bioavailability of 5% prohibits oral administration[13]. Subcutaneous, intramuscular and intrathecal application cannot be used, as severe tissue necrosis results, as in extravasation.
Pharmacokinetics
Absorption
An intravenous bolus injection of doxorubicin produces high plasma concentrations, which fall quickly due to rapid and extensive distribution into tissues. 50 to 85% of plasma doxorubicin is bound to protein[13], independent of the absolute drug concentration in plasma, leaving 15 to 50% of the total doxorubicin and doxorubicinol as free drug. After repeated injections no accumulation in plasma occurs. Apparent volumes of distribution are in the range of 20 to 30 L/kg (1400 to 3000L)[14].
Doxorubicin does not cross the blood-brain barrier and is therefore inactive against tumours in the central nervous system[15]. Some transplacental passage has been observed, although healthy children have been born after pregnancies during which doxorubicin was administered from the first to the third trimester[16]. Negligible doxorubicin concentrations have been found in breast milk. Salivary doxorubicin concentrations are 6 to 26% of plasma concentrations during the first 75 minutes after administration[17].

Metabolism
Doxorubicin is rapidly metabolized into the hydrophilic 13-hydoxy1 metabolite, doxorubicinol, and the poorly water-soluble aglycones, doxorubicinone and 7-deoxydoxorubicinone. Like doxorubicin, doxorubicinol is cytotoxic, but doxorubicinone is not[18]. Metabolism to doxorubicino1 occurs by cytoplasmatic NADPH-dependent aldoketoreductases, present in all cells, but particularly in red cells, and liver and kidney cells[18]. The non-cytotoxic aglycones are formed by an NADPH-dependent, cytochrome reductase-mediated cleavage of the amino sugar moiety in microsomes. This enzymatic reduction of doxorubicin is of paramount importance, as it finally produces the OH•-radicals, which cause extensive cell damage and cell death[19].

Elimination
Doxorubicin and its catabolites are primarily excreted in the bile[20]. Over 50% is eliminated during the first transit through the liver. Cumulative faecal excretion over 7 days has been estimated at 25 to 45%[21]; no evidence for enterohepatic recirculation has been observed. Although patients often notice a reddish coloration of the urine during the first hours to days after doxorubicin administration, only 0.7 to 23% (on average, approximately 5%) of a dose has been recovered in the urine[20, 21], of which approximately two-thirds is unaltered drug. Nevertheless, doxorubicin-induced nephrotoxicity has been noted only in mice, rats, rabbits and dogs, and not in humans. The reason for this interspecies difference has not been explained, although stimulated lipid peroxidation may play a role[22]. The doxorubicin plasma concentration-time curve can be best described by a biexponentia1 model, which is characterized by a distribution half-life of less than 5 to 10 minutes, and a terminal phase elimination half-life of 30 ± 8 hours[14]. A triphasic curve with half-lives of 12 ± 8 minutes, 3.3 ± 2.2 hours and 30 ± 14 hours has also been proposed[23].
Side effects
Doxorubicin is a carcinogenic and mutagenic substance. Phlebitis is frequently observed after long-term intravenous infusion[24]. Paravasal leakage causes severe necrosis of skin and adjacent tissues, the extent of which depends on the degree of extravasation[25]. An appropriate antidote is not available. A number of agents injected locally may even worsen the necrosis; however, ice packs and 48 hours' rest may be beneficial[25]. Acute doxorubicin toxicity consists of gastrointestinal complaints and cardiac arrhythmias. Nausea and vomiting occur within 4 to 8 hours of doxorubicin administration and can only be partially controlled by antiemetic drugs. Arrhythmias and electrocardiographic changes are transient. Anaphylactoid and hypersensitivity reactions ('flare') may occur during injection, thus mimicking extravasation, but discontinuation of therapy is not necessary[26]. In long term, infusion the occurrence of acute side effects is almost completely abolished. Repeated administrations of doxorubicin bolus injections, and the resultant high doxorubicin plasma concentrations, have been associated with an increased risk of acute and late-onset cardiotoxicity.
Delayed toxicity consists mainly of myelosuppression, alopecia and cardiomyopathy. At approximately 16 days after a single dose of doxorubicin the white blood cell and platelet counts reach their lowest point. Myelosuppression and alopecia are dose related, but independent of the mode of administration (i.e. peak plasma concentration). The onset of myelosuppression occurs after 7 to 10 days, and recovery at 19 to 24 days after doxorubicin administration. This side effect, although reversible, is dose limiting. Hair loss starts approximately 3 weeks after the first administration of doxorubicin; however, hair growth resumes a few weeks after the last therapy[26]. Local application of ice-packs to prevent hair loss have been of limited value. Mucositis and/or diarrhoea are noticed especially during long-term infusion regimens[24].
References
  1. Arcamone F, et al 1998. Pharmacol Ther 76: 117–124.
  2. Grein A. 1987. Adv Appl Microbiol 32: 203–214
  3. Zubrod CG. Historic milestones in curative chemotherapy. Seminars in Oncology 6: 490-505, 1979
  4. Speth PAJ, et al Clinical Pharmacology and Therapeutics 41: 661-665, 1987
  5. Cummings J, et al Cancer Chemotherapy and Pharmacology 17: 80-84, 1986
  6. ELIOT, H., et al (1984) Biochemistry 23: 928-936.
  7. MUINDI, J. R. F., et al FEBS Lett. 172: 226-230.
  8. Russo P, et al Anticancer Research 6: 1297-1304, 1986
  9. Tritton TR, et al Science 217: 248-250, 1982
  10. Goormaghtigh E, et al Biochemical Pharmacology 32: 889-893, 1983
  11. Bouma J, et al Pharmaceutisch Weekblad, Scientific Edition 8: 109-133, 1986
  12. Benvenuto JA, et al Cancer chemotherapy by infusion, pp. 100-113, Precept Press, Chicago, 1987
  13. Harris PA, et al Cancer Chemotherapy Reports 59: 819-825, 1975
  14. Greene RF, et al Cancer Research 43: 3417-3421, 1983
  15. Mooney C, et al European Journal of Cancer and Oinical Oncology 19: 1037-1038, 1983
  16. Fassas A, et al Nouvelle Revue Fran~ise Hematologique 26: 19-24, 1984
  17. Celio LA, et al European Journal of Clinical Pharmacology 24: 261-266, 1983
  18. Bachur NR, et al Journal of Medicinal Chemistry 19: 651-654, 1976
  19. Myers CE, et al In Lawn (Ed.) Anthracyclines in press, 1988
  20. Takanashi S, et al Drug Metabolism and Disposition 4: 79-87, 1976
  21. DiFronzo G, et al Biomedicine 19: 169-171, 1973
  22. Mimnaugh EG, et al Biochemical Pharmacology 35: 4327-4335, 1986
  23. Benjamin RS, et al Cancer Research 37: 1416-1420, 1977
  24. Legha SS, Hortobagyi GN, benjamin RS. Anthracyclines. In Lokich JJ (Ed) Cancer chemotherapy by infusion, pp. 100-113, Precept Press, Chicago, 1987
  25. Rudolph R, Journal of Clinical Oncology 5: 1116-1126, 1987
  26. Maral RJ, et al Cancer Treatment Reports 65 (Suppl. 4): 9-18, 1981

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