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Epirubicin
(8S-cis)-10-[(3-Amino-2,3,6-trideoxy-alpha-L-arabino-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxynaphthacene-5,12-dione · imi28 · WP 697 · epi-dx · 4'-Epi-DX · NSC 256942 · EPIRUBICIN · Pidorubicin
Identifikatoren & physikalische Daten
| CAS No. | 56420-45-2 |
|---|---|
| Summenformel | C27H29NO11 |
| Durchschnittliche Molmasse | 543,5 g/mol |
| Monoisotopische Masse | 543,17406075 g/mol |
| SMILES | COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 |
| InChIKey | AOJJSUZBOXZQNB-VTZDEGQISA-N |
| PubChem CID | 41867 |
| ChEMBL | CHEMBL417 |
| ChEBI | CHEBI:47898 |
| DTXSID | DTXSID0022987 |
Chemische & physikalische Eigenschaften
| XLogP | 1,3 |
|---|---|
| Polarare Oberfläche (TPSA) | 206 |
| H-Brücken-Donoren | 6 |
| H-Brücken-Akzeptoren | 12 |
| Frei drehbare Bindungen | 5 |
| Schwere Atome | 39 |
| Formalladung | 0 |
| Komplexität | 977 |
| Arzneimittel | Pharmaceuticals -> AntibioticsPharmaceuticals -> Listed in ZINC15 |
| LogP (Verteilungskoeffizient) | -0.5 |
| Löslichkeit | 1.18e+00 g/LSoluble in DMSO |
| Human Drugs | Breast FeedingLactationMilk, HumanAntineoplastic AgentsAnthracyclinesAntibiotics, AntineoplasticTopoisomerase II Inhibitors |
| Endocrine Disruptors | Potential endocrine disrupting compound |
| Decomposition | When heated to decomposition it emits toxic fumes of /nitrogen oxides/. |
| Schmelzpunkt | 344.53 °C |
| Physical Description | Solid |
| Stability/Shelf Life | Stable under recommended storage conditions. /Epirubicin hydrochloride/The stability of /anthracycline antibiotics/ doxorubicin HCI (Adriblastine), daunorubicin HCI (Cerubidine), 4' epidoxorubicin (epirubicin), 4' deoxydoxorubicin (esorubicin), 4' O methyldoxorubicin and 4 demethoxydaunorubicin (idarubicin) was studied in 5% dextrose, 3.3% dextrose 0.3% sodium chloride solution, lactated Ringer's and 0.9% sodium chloride. All compounds were stable for 28 days at 25 °C in the dark when mixed in the dextrose solutions. Only daunorubicin and idarubicin were stable in lactated Ringer's or normal saline.The stability of epirubicin in sodium chloride 0.9% injection, the degradation kinetics of an epirubicin 1 mg/ml solution and the stability of epirubicin 2 mg/ml in polypropylene syringes stored under hospital conditions were studied at various temperature. The degradation of epirubicin in sodium chloride 0.9% solutions followed first order kinetics. The shelf life was defined as the time by which the epirubicin concentration had decreased by 10% from the initial concentration. Epirubicin was stable in sodium chloride 0.9% injection stored in polypropylene containers for all time periods and all conditions. That resulted in a shelf life of at least 14 and 180 days at 25 °C and 4 °C, respectively. The maximum decrease in epirubicin concentration observed at 25 °C and 14 days was 4%, and at 4 °C and 180 days was 8%. The predicted shelf life obtained from Arrhenius equation was 72. and 3070 days at 25 and 4 °C, respectively, in both dark and illuminated conditions. |
| Collision Cross Section | 215.2 Ų [M+H-H2O]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards] |
| Other Experimental Properties | The carbohydrate C-4 epimer of adriamycin, epirubicin is as potent as its parent molecule, but significantly less toxic.Red-orange crystals. MP: 185 °C (decomposes). Specific optical rotation: +274 deg at 20 °C/D (c = 0.01 in methanol). Solution should be protected from sunlight. /Epirubicin hydrochloride/ |
| Siedepunkt | 617.77°C (rough estimate) |
| Dichte | 1.3783 (rough estimate) |
| Brechungsindex | 1.6400 (estimate) |
| Lagerbedingungen | Store at -20°C |
| Aggregatzustand | Solid |
| pKa (Säurekonstante) | 7.35±0.60(Predicted) |
| Farbe | Orange to red |
Sicherheit & Vorschriften
| GHS-Einstufung | WarningH302: Harmful if swallowed [Warning Acute toxicity, oral]P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement) |
|---|---|
| Regulatorische Informationen | 5,12-Naphthacenedione, 10-(3-amino-2,3,6-trideoxy-.alpha.-L-arabino-hexopyranosyl)oxy-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, (8S,10S)-: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right. |
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including epirubicin hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Epirubicin hydrochloride/ |
| Special Reports | Wadler S et alPhase I and 11 agents in cancer therapy: Part 1. Anthracyclines and related compoundsJ Clin Pharmacol 26 (Sep-Oct): 491-509. /There is/ even modified anthracyclines emerging as investigational antineoplastic agents which are currently undergoing phase I and phase 11 testing in human subjects, epirubicin, idarubicin, esorubicin, aclacinomycin A (aclarubicin), menogaril, mitoxantrone and amsacrine, are reviewed. Preclinical studies, pharmacokinetics, human toxicology, clinical studies and phase I and phase 11 studies where applicable are presented. It was concluded that new anthracycline analogues with up to 100 times the potency of currently available anthracyclines are being developed and that these complex molecules retain a nearly unlimited potential for structural modification.Goodman TLAntibiotics in cancer chemotherapy: anthracyclines, Oncologyernatology Div Genesee Hosp Univ of Rochester Cancer Ctr, Rochester, NY 14607Hosp Formul 21 (Apr): 444-452, 454, 455, (1986). A /study/ of the structure activity relationships, mechanism of action, pharmacokinetics, body distribution, toxicity and clinical application of doxorubicin hydrochloride (Adriamycin), daunorubicin hydrochloride (Cerubidine), aclarubicin, epirubicin hydrochloride (4' epidoxorubicin hydrochloride) and mitoxantrone in the treatment of leukemias, lymphomas and solid tumors is presented.Clinical, studies with new anthracyclines: epirubicin, idarubicin, esorubicin Hurteloup P Ganzina F Drugs Exp Clin Res 12 (1 3): 233 246 (1986). A review o~clinical studies (phase 11 and III) relating to the therapeutic efficacy of epirubicin, idarubicin and esorubicin waspFesemted. |
| Toxic Combustion Products | Special hazards arising from the substance or mixture: Carbon oxides, nitrogen oxides (NOx), Hydrogen chloride gas. /Epirubicin hydrochloride/ |
| Brandbekämpfungsverfahren | Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /Epirubicin hydrochloride/Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Epirubicin hydrochloride/ |
| Lagerbedingungen | Store refrigerated between 2 °C and 8 °C (36 °F and 46 °F). Do not freeze. Protect from light. Storage of the solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15-25 °C). Solution for injection should be used within 24 hours after removal from refrigeration.Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature: -20 °C. /Epirubicin hydrochloride/ |
| Reinigungsverfahren | Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Epirubicin hydrochloride/ |
| Entsorgungsverfahren | SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. 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.Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product. /Epirubicin hydrochloride/The results of a study examining the ability of sodium hypochlorite solution to inactivate hazardous (cytostatic) drug spills were summarized. Solutions of amsacrine, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, methotrexate, mitomycin, and mitoxantrone were reconstituted according to the manufacturers' directions, initial concentrations varying from 0.5 to 25 mg/ml. They were mixed with equivalent amounts of sodium hypochlorite solution providing 2.4% available chlorine. The extent of inactivation of the drugs was determined from decreases in concentration measured 5 minutes (min) later by absorption spectrophotometry. All drugs were significantly degraded within 5 min after sodium hypochlorite treatment. Except for methotrexate, the extent of degradation exceeded 90%. Methotrexate was 88.2% degraded. Doxorubicin and mitoxantrone were degraded by more than 99.9%. The authors conclude that these results indicate that sodium hypochlorite solution may be a good reagent for inactivating hazardous drug spills before cleanup. Mutagenicity studies, however, need to be performed on the degradation products to confirm that the drugs have in fact been inactivated. |
| Preventive Measures | Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Epirubicin hydrochloride/Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.Normal measures for preventive fire protection. /Epirubicin hydrochloride/Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Epirubicin hydrochloride/ |
| Personal Protective Equipment (PPE) | Skin protection: Handle with gloves. /Epirubicin hydrochloride/Eye/face protection: Safety glasses with side-shields conforming to EN166 Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Epirubicin hydrochloride/Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Epirubicin hydrochloride/Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Epirubicin hydrochloride/ |
| Treatment | If an overdose occurs, supportive treatment (including antibiotic therapy, blood and platelet transfusions, colony-stimulating factors, and intensive care as needed) should be provided until the recovery of toxicities. Delayed CHF has been observed months after anthracycline administration. Patients must be observed carefully over time for signs of CHF and provided with appropriate supportive therapy. (L1712) |
| Wechselwirkungen | The methylparaben present in the epirubicin HCl formulation enhances the dissolution rate by disrupting bonding between epirubicin & other components. /Epirubicin HCl/Lleukopenic and/thrombocytopenic effects of epirubicin may be increased with concurrent or recurrent therapy if these medications /blood dyscrasia-causing medications/ cause the same effectsdosage of epirubicin should be based on blood counts in these cases.There are few data regarding the coadministration of radiation therapy and Ellence. In adjuvant trials of Ellence-containing CEF-120 or FEC-100 chemotherapies, breast irradiation was delayed until after chemotherapy was completed. This practice resulted in no apparent increase in local breast cancer recurrence relative to published accounts in the literature. A small number of patients received Ellence-based chemotherapy concomitantly with radiation therapy but had chemotherapy interrupted in order to avoid potential overlapping toxicities. It is likely that use of Ellence with radiotherapy may sensitize tissues to the cytotoxic actions of irradiation. Administration of Ellence after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation.Do not administer epirubicin in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored. Patients receiving epirubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity. Concomitant use of Ellence with other cardioactive compounds that could cause heart failure (e.g., calcium channel blockers), requires close monitoring of cardiac function throughout treatment.For more Interactions (Complete) data for EPIRUBICIN (18 total), please visit the HSDB record page. |
| Umweltverhalten | TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 6000(SRC), determined from a structure estimation method(2), indicates that epirubicin is expected to be immobile in soil(SRC). An estimated pKa of epirubicin is 9.93(3), indicating that this compound will exist almost entirely in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as an cation and cations do not volatilize. Epirubicin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.5X10-23 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2015).AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 6000(SRC), determined from a structure estimation method(2), indicates that epirubicin is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 9.93(3) indicates epirubicin will exist almost entirely in the anion form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(5), an estimated BCF of 1(SRC), from its log Kow of 1.27(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2015).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), epirubicin, which has an estimated vapor pressure of 2.5X10-23 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase epirubicin may be removed from the air by wet and dry deposition(SRC). Epirubicin contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC). |
| Expositionspfade | Intravenous |
| Toxizitätsübersicht | IDENTIFICATION AND USE: Epirubicin is red-orange crystals that are formulated into a solution for intravenous administration. It is used as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer. HUMAN EXPOSURE AND TOXICITY: Instances of administration of doses higher than recommended have been reported at doses ranging from 150 to 250 mg/sq m. The observed adverse events in these patients were qualitatively similar to known toxicities of epirubicin. Most of the patients recovered with appropriate supportive care. Secondary acute myelogenous leukemia (AML) has been reported in patients with breast cancer treated with anthracyclines, including epirubicin. Cardiac toxicity, including fatal congestive heart failure (CHF), may occur either during therapy with epirubicin or months to years after termination of therapy. Epirubicin was clastogenic in vitro (chromosome aberrations in human lymphocytes) both in the presence and absence of metabolic activation. ANIMAL STUDIES: Conventional long-term animal studies to evaluate the carcinogenic potential of epirubicin have not been conducted, but intravenous administration of a single 3.6 mg/kg epirubicin dose to female rats approximately doubled the incidence of mammary tumors (primarily fibroadenomas) observed at 1 year. Administration of 0.5 mg/kg epirubicin intravenously to rats every 3 weeks for ten doses increased the incidence of subcutaneous fibromas in males over an 18-month observation period. In addition, subcutaneous administration of 0.75 or 1.0 mg/kg/day to newborn rats for 4 days on both the first and tenth day after birth for a total of eight doses increased the incidence of animals with tumors compared to controls during a 24-month observation period. Administration of 0.8 mg/kg/day intravenously of epirubicin to rats during days 5 to 15 of gestation was embryotoxic (increased resorptions and post-implantation loss) and caused fetal growth retardation (decreased body weight), but was not teratogenic up to this dose. Administration of 2 mg/kg/day intravenously of epirubicin to rats on days 9 and 10 of gestation was embryotoxic (increased late resorptions, post-implantation losses, and dead fetusesand decreased live fetuses), retarded fetal growth (decreased body weight), and caused decreased placental weight. This dose was also teratogenic, causing numerous external (anal atresia, misshapen tail, abnormal genital tubercle), visceral (primarily gastrointestinal, urinary, and cardiovascular systems), and skeletal (deformed long bones and girdles, rib abnormalities, irregular spinal ossification) malformations. Administration of intravenous epirubicin to rabbits at doses up to 0.2 mg/kg/day during days 6 to 18 of gestation was not embryotoxic or teratogenic, but a maternally toxic dose of 0.32 mg/kg/day increased abortions and delayed ossification. Administration of a maternally toxic intravenous dose of 1 mg/kg/day epirubicin to rabbits on days 10 to 12 of gestation induced abortion, but no other signs of embryofetal toxicity or teratogenicity were observed. When doses up to 0.5 mg/kg/day epirubicin were administered to rat dams from day 17 of gestation to day 21 after delivery, no permanent changes were observed in the development, functional activity, behavior, or reproductive performance of the offspring. In fertility studies in rats, males were given epirubicin daily for 9 weeks and mated with females that were given epirubicin daily for 2 weeks prior to mating and through day 7 of gestation. When dose of 0.3 mg/kg/day was administered to both sexes, no pregnancies resulted. No effects on mating behavior or fertility were observed at 0.1 mg/kg/day, but male rats had atrophy of the testes and epididymis, and reduced spermatogenesis. The 0.1 mg/kg/day dose also caused embryolethality. An increased incidence of fetal growth retardation was observed in these studies at 0.03 mg/kg/day. Multiple daily doses of epirubicin to rabbits and dogs also caused atrophy of male reproductive organs. Single 20.5 and 12 mg/kg doses of intravenous epirubicin caused testicular atrophy in mice and rats, respectively. A single dose of 16.7 mg/kg epirubicin caused uterine atrophy in rats. Epirubicin was mutagenic in vitro to bacteria (Ames test) either in the presence or absence of metabolic activation and to mammalian cells (HGPRT assay in V79 Chinese hamster lung fibroblasts) in the absence but not in the presence of metabolic activation. Epirubicin was clastogenic in vivo (chromosome aberration in mouse bone marrow).Epirubicin has antimitotic and cytotoxic activity. It inhibits nucleic acid (DNA and RNA) and protein synthesis through a number of proposed mechanisms of action: Epirubicin forms complexes with DNA by intercalation between base pairs, and 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. It also interferes with DNA replication and transcription by inhibiting DNA helicase activity. |
| Signs and Symptoms | bone marrow aplasia, grade 4 mucositis, and gastrointestinal bleeding |
| Effluent Concentrations | Epirubicin has been detected in the Thames catchment in the UK. It is estimated that the drug is present in sewage treatment effluent at a concentration of 9.01X10-2 ng/L(1). |
| Soil Adsorption/Mobility | Using a structure estimation method based on molecular connectivity indices(1), the Koc of epirubicin can be estimated to be 6000(SRC). According to a classification scheme(2), this estimated Koc value suggests that epirubicin is expected to be immobile in soil. An estimated pKa of epirubicin is 9.93(3), indicating that this compound will exist almost entirely in the anion form and cations generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Epirubicin was shown to adsorb to suspended solids during treatment of raw wastewater from the oncologic in-patient department of the Vienna University Hospital, sampled for 98 days over 2 years(5). Epirubicin has been detected in the Thames catchment in the UK. It is estimated that the drug is present in sewage treatment effluent at a concentration of 9.01X10-2 ng/L, with a 90% treatment plant removal due to adsorption(6). |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ Secondary acute myelogenous leukemia (AML) has been reported in patients with breast cancer treated with anthracyclines, including epirubicin. The occurrence of refractory secondary leukemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated. The cumulative risk of developing treatment-related AML or myelodysplastic syndrome (MDS), in 7110 patients with breast cancer who received adjuvant treatment with Ellence-containing regimens, was estimated as 0.27% at 3 years, 0.46% at 5 years, and 0.55% at 8 years./SIGNS AND SYMPTOMS/ Cardiac toxicity, including fatal congestive heart failure (CHF), may occur either during therapy with Ellence or months to years after termination of therapy. The probability of developing clinically evident CHF is estimated as approximately 0.9% at a cumulative dose of 550 mg/sq m, 1.6% at 700 mg/sq m, and 3.3% at 900 mg/sq m. In the adjuvant treatment of breast cancer, the maximum cumulative dose used in clinical trials was 720 mg/sq m. The risk of developing CHF increases rapidly with increasing total cumulative doses of Ellence in excess of 900 mg/sq mthis cumulative dose should only be exceeded with extreme caution. Active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with Ellence may occur at lower cumulative doses whether or not cardiac risk factors are present./SIGNS AND SYMPTOMS/ Severe local tissue necrosis will occur if there is extravasation during administration. Ellence must not be given by the intramuscular or subcutaneous route./SIGNS AND SYMPTOMS/ ... Instances of administration of doses higher than recommended have been reported at doses ranging from 150 to 250 mg/sq m. The observed adverse events in these patients were qualitatively similar to known toxicities of epirubicin. Most of the patients recovered with appropriate supportive care.For more Human Toxicity Excerpts (Complete) data for EPIRUBICIN (15 total), please visit the HSDB record page. |
| Artificial Pollution Sources | Epirubicin's production and administration as an antineoplastic(1) may result in its release to the environment through various waste streams(SRC). |
| Carcinogen Classification | No indication of carcinogenicity to humans (not listed by IARC). |
| Drug Induced Liver Injury | Drug-Induced Liver Injury Severity and Toxicity (DILIst)epirubicinDILI NegativeIntravenousDOI:10.1016/j.drudis.2019.09.022 |
| Toxizität | LD50 intravenous in dog: 2mg/kg |
| Gefahrstoffdaten | 56420-45-2(Hazardous Substances Data) |
Anwendungen & Verwendung
Verwenden
Epirubicin is a cell permeable Topo II inhibitor.