Epirubicin

Pharmaceuticals -> Antibiotics

Pharmaceuticals -> Listed in ZINC15

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.

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/

Warning

H302: Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)

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.

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/

Wadler S et al; Phase I and 11 agents in cancer therapy: Part 1. Anthracyclines and related compounds; J 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 TL; Antibiotics in cancer chemotherapy: anthracyclines, Oncologyernatology Div Genesee Hosp Univ of Rochester Cancer Ctr, Rochester, NY 14607; Hosp 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.

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/

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/

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/

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.

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/

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/

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)

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 effects; dosage 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.

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).

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 fetuses; and 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.

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).

/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 m; this 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.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

epirubicin

DILI Negative

Intravenous

DOI:10.1016/j.drudis.2019.09.022

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/

L01DB03

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Epirubicin is an antineoplastic in the anthracycline class. General properties of drugs in this class include: interaction with DNA in a variety of different ways including intercalation (squeezing between the base pairs), DNA strand breakage and inhibition with the enzyme topoisomerase II. Most of these compounds have been isolated from natural sources and antibiotics. However, they lack the specificity of the antimicrobial antibiotics and thus produce significant toxicity. The anthracyclines are among the most important antitumor drugs available. Doxorubicin is widely used for the treatment of several solid tumors while daunorubicin and idarubicin are used exclusively for the treatment of leukemia. Epirubicin may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA. Epirubicin possesses an antitumor effect against a wide spectrum of tumors, either grafted or spontaneous. The anthracyclines are cell cycle-nonspecific.

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.

Epirubicin is an anthracycline cytotoxic agent. Although it is known that anthracyclines can interfere with a number of biochemical and biological functions within eukaryotic cells, the precise mechanisms of epirubicin's cytotoxic and/or antiproliferative properties have not been completely elucidated. Epirubicin forms a complex with DNA by intercalation of its planar rings between nucleotide base pairs, with consequent inhibition of nucleic acid (DNA and RNA) and protein synthesis. Such intercalation triggers DNA cleavage by topoisomerase II, resulting in cytocidal activity. Epirubicin also inhibits DNA helicase activity, preventing the enzymatic separation of double-stranded DNA and interfering with replication and transcription. Epirubicin is also involved in oxidation/reduction reactions by generating cytotoxic free radicals. The antiproliferative and cytotoxic activity of epirubicin is thought to result from these or other possible mechanisms.

Epirubicin fights cancer through topoisomerase II inhibition, hence producing DNA strand breaks that finally lead to cell apoptosis. But anthracyclines produce free radicals that may explain their adverse effects. Dexrazoxane--an iron chelator--was proven to decrease free radical production and anthracycline cardiotoxicity. In this article, we report the concentrations of cellular 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo) relative to 2'-deoxyguanosine (dGuo), and comet assay results from a study including 20 cancer patients treated with epirubicin. Plasma concentrations of vitamins A, E, C and carotenoids are also reported. All data were obtained before and immediately after epirubicin infusion. The ratios of 8-Oxo-dGuo to dGuo were measured in leukocyte DNA by HPLC-coulometry after NaI extraction of nucleic acids. Vitamins A and E and carotenoids were measured by HPLC-spectrophotometry. Vitamin C was measured by HPLC-spectrofluorimetry. Median 8-oxo-dGuo/dGuo ratios increased significantly from 0.34 to 0.48 lesions per 100,000 bases while per cent of tail DNA increased from 3.47 to 3.94 after chemotherapy 8-Oxo-dGuo/dGuo and per cent of tail DNA medians remained in the normal range. Only vitamin C decreased significantly from 55.4 to 50.3 microM Decreases in vitamins A, E, lutein and zeaxanthin were not significant, but concentrations were below the lower limit of the normal range both before and after chemotherapy. Only the correlation between comet assay results and vitamin C concentrations was significant (rho =-0.517, p = 0.023). This study shows that cellular DNA is damaged by epirubicin-generated free radicals which produce the mutagenic modified base 8-oxo-dGuo and are responsible for strand breaks. However, strand breaks are created not only by free radicals but also by topoisomerase II inhibition. In a previous study we did not find any significant change in urinary 8-oxo-dGuo excretion after adriamycin treatment. However, 8-oxo-dGuo may have increased at the end of urine collection as DNA repair and subsequent kidney elimination are relatively slow processes. In another study, authors used GC-MS to detect 8-oxo-dGuo in DNA and did not find any change after prolonged adriamycin infusion. Reasons for these apparent discrepancies are discussed.

Half-lives for the alpha, beta, and gamma phases of about 3 minutes, 2.5 hours and 33 hours, respectively

... Epirubicin pharmacokinetics may be described by a 3-compartment model, with median half-life values of 3.2 minutes, 1.2 and 32 hours for each phase. ...

Extensively and rapidly metabolized in the liver. Epirubicin is also metabolized by other organs and cells, including red blood cells. The four main metabolic routes are: (1) reduction of the C-13 keto-group with the formation of the 13(S)-dihydro derivative, epirubicinol; (2) conjugation of both the unchanged drug and epirubicinol with glucuronic acid; (3) loss of the amino sugar moiety through a hydrolytic process with the formation of the doxorubicin and doxorubicinol aglycones; and (4) loss of the amino sugar moiety through a redox process with the formation of the 7-deoxy-doxorubicin aglycone and 7-deoxy-doxorubicinol aglycone. Epirubicinol exhibits in vitro cytoxic activity (~10% that of epirubicin), but it is unlikely to reach sufficient concentrations in vivo to produce cytotoxic effects.

Epirubicin is extensively and rapidly metabolized by the liver and is also metabolized by other organs and cells, including red blood cells. Four main metabolic routes have been identified: (1) reduction of the C-13 keto-group with the formation of the 13(S)-dihydro derivative, epirubicinol; (2) conjugation of both the unchanged drug and epirubicinol with glucuronic acid; (3) loss of the amino sugar moiety through a hydrolytic process with the formation of the doxorubicin and doxorubicinol aglycones; and (4) loss of the amino sugar moiety through a redox process with the formation of the 7-deoxy-doxorubicin aglycone and 7-deoxy-doxorubicinol aglycone. Epirubicinol has in vitro cytotoxic activity one-tenth that of epirubicin. As plasma levels of epirubicinol are lower than those of the unchanged drug, they are unlikely to reach in vivo concentrations sufficient for cytotoxicity. No significant activity or toxicity has been reported for the other metabolites.

Secondary alcohol metabolites have been proposed to mediate chronic cardiotoxicity induced by doxorubicin (DOX) and other anticancer anthracyclines. In this study, NADPH-supplemented human cardiac cytosol was found to reduce the carbonyl group in the side chain of the tetracyclic ring of doxorubicin, producing the secondary alcohol metabolite doxorubicinol (DOXol). A decrease in the level of alcohol metabolite formation was observed by replacing doxorubicin with epirubicin (EPI), a less cardiotoxic analogue characterized by an axial-to-equatorial epimerization of the hydroxyl group at C-4 in the amino sugar bound to the tetracyclic ring (daunosamine). A similar decrease was observed by replacing doxorubicin with MEN, a novel anthracycline with preclinical evidence of reduced cardiotoxicity. MEN is characterized by the lack of a methoxy group at C-4 in the tetracyclic ring and by intercalation of 2, 6-dideoxy-L-fucose between daunosamine and the aglycone. Multiple comparisons with methoxy- or 4-demethoxyaglycones, and a number of mono- or disaccharide 4-demethoxyanthracyclines, showed that both the lack of the methoxy group and the presence of a disaccharide moiety limited alcohol metabolite formation by MEN. Studies with enzymatically generated or purified anthracycline secondary alcohols also showed that the presence of a disaccharide moiety, but not the lack of a methoxy group, made the metabolite of MEN less reactive with the [4Fe-4S] cluster of cytoplasmic aconitase, as evidenced by its limited reoxidation to the parent carbonyl anthracycline and by a reduced level of delocalization of Fe(II) from the cluster. Collectively, these studies (i) characterize the different influence of methoxy and sugar substituents on the formation and [4Fe-4S] reactivity of anthracycline secondary alcohols, (ii) lend support to the role of alcohol metabolites in anthracycline-induced cardiotoxicity, as they demonstrate that the less cardiotoxic EPI and MEN 10755 share a reduction in the level of formation of such metabolites, and (iii) suggest that the cardiotoxicity of MEN might be further decreased by the reduced [4Fe-4S] reactivity of its alcohol metabolite.

Many antineoplastic drugs were found to have carcinogenic, mutagenic and teratogenic potential. The aim of this study was to carry out cytogenetic and internal dose monitoring of hospital pharmacy personnel regularly involved in the preparation of cytostatic agents, in order to test possible cytostatics-induced genotoxic effects due to occupational exposure under routine working conditions, and in cases of accidental contamination. ... Platinum in whole blood and anthracyclines in plasma were measured to assess internal exposure to cytostatics. The level of cytogenetic damage was determined in peripheral blood lymphocytes with the micronucleus test and the sister chromatid exchange assay. Five series of monitoring were performed over a period of 2 years. ... No significant differences in the mean frequencies of sister chromatid exchanges (SCE) and micronuclei (MN) were found between occupationally exposed probands and controls (9.9 +/- 1.4 vs 10.1 +/- 1.2 SCEs/cell and 21.2 +/- 7.2 vs 23.3 +/- 7.5 MN/2000 binucleated (BN) cells, n = 16). Significant elevations of SCE or MN were detected in seven out of 12 cases of accidental contamination at the workplace, whereas no increase in platinum in blood and anthracyclines in plasma was observed in these probands. Two cases of non-reported contamination were identified by measurement of epirubicin in plasma. Smoking was found to increase the SCE significantly. No correlation between individual SCE scores and MN scores was observed. ... /The authors/ findings support a transient increase in SCE or MN after relevant exposure to cytostatic drugs in cases of accidental contamination. The lack of significant differences in SCE and MN between hospital pharmacy personnel and unexposed controls, points to high standards of safety at the corresponding workplaces.

There is compelling in-vitro evidence that the evaluation of doxorubicin or epirubicin pharmacokinetics based solely on plasma concentration may not fully elucidate the differences between the two drugs. Both compounds bind to erythrocytes and their different binding to hemoglobin may influence their disposition in the body. The purpose of the present study was to compare the pharmacokinetics and metabolism of doxorubicin and epirubicin based on the plasma concentration, amount associated with blood cells and simultaneous monitoring of biliary and urinary elimination of unchanged drug and metabolites after single- and multiple-dose injections. The level of sarcoplasmic reticulum Ca2+ATPase in the heart was also measured as a biomarker of cardiotoxicity. Male Sprague-Dawley rats were treated in a parallel design with doxorubicin or epirubicin on a multiple-dosing basis (4 mg kg(-1) per week) or as a single dose injection (20 mg kg(-1)). Blood, urine and bile samples were collected periodically after each dose in the multiple-dosing regimen and the single dose injection, and at the end of each experiment the hearts were removed. The concentrations of each drug in plasma, blood cells, bile and urine samples were determined, and by simultaneous curve-fitting of plasma and bile data according to compartmental analysis, the pharmacokinetic parameters and constants were estimated. The concentration of drug associated with blood cells was analyzed according to non-compartmental analysis. The bile and urine samples provided the in-vivo metabolic data. The level of Ca2+ATPase in the heart, determined by Western blotting, was used as the toxicodynamic parameterto correlate with the kinetic data. Multiple-dosing regimens reduced the total plasma clearance and increased the area under the plasma concentration-time curve of both drugs. Also, the area under the curve of doxorubicin associated with blood cells increased with the weekly doses, and the related mean residence time (MRT) and apparent volume of distribution (Vdss) were steadily reduced. In contrast to doxorubicin, the mean residence time and Vdss of epirubicin increased significantly. Metabolic data indicated significant differences in the level of alcohol and aglycones metabolites. Doxorubicinol and doxorubicin aglycones were significantly greater than epirubicinol and epirubicin aglycone, whereas epirubicinol aglycone was greater than doxorubicinol aglycone. The area under the blood cells concentration-time curve correlated linearly with the changes in Ca2+ATPase net intensity. The results of this study demonstrate the importance of the kinetics of epirubicin and doxorubicin associated with blood cells. Linear correlation between the reduction of net intensity of the biomarker with the area under the curve of doxorubicin associated with blood cells confirms that the differences between the two compounds are related to their interaction with blood cells. This observation together with the observed differences in metabolism may underline a significant role for blood cells in distribution and metabolism of doxorubicin and epirubicin.

For more Metabolism/Metabolites (Complete) data for EPIRUBICIN (6 total), please visit the HSDB record page.

3Z8479ZZ5X

EPIRUBICIN

Established Pharmacologic Class [EPC] - Anthracycline Topoisomerase Inhibitor

Chemical Structure [CS] - Anthracyclines

Mechanisms of Action [MoA] - Topoisomerase Inhibitors

Epirubicin is an Anthracycline Topoisomerase Inhibitor. The mechanism of action of epirubicin is as a Topoisomerase Inhibitor.

Chemical substances, produced by microorganisms, inhibiting or preventing the proliferation of neoplasms.

Compounds that inhibit the activity of DNA TOPOISOMERASE II. Included in this category are a variety of ANTINEOPLASTIC AGENTS which target the eukaryotic form of topoisomerase II and ANTIBACTERIAL AGENTS which target the prokaryotic form of topoisomerase II.

100%

Epirubicin and its major metabolites are eliminated through biliary excretion and, to a lesser extent, by urinary excretion.

21 ± 2 L/kg [60 mg/m2 Dose]

65 +/- 8 L/hour [Patients1 with Solid Tumors Receiving Intravenous Epirubicin 60 mg/m2]

... The plasma and tissue distribution of /anthracyline antibiotics/ doxorubicin (1), 4' epidoxorubicin (epirubicin; II) and daunorubicin (daunomycin; III) were studied in patients. Plasma levels of I and II and their 13 hydroxy metabolites were determined by LC, as were plasma levels of III. It was concluded that plasma kinetics for the 3 drugs were similar, and that tissue uptake for I and II were virtually the same. Tumor tissue concentrated the drugs to the greatest extent, while adipose tissue had the lowest concentrations.

... The preparation and in vitro and in vivo evaluation of egg albumin microspheres containing epirubicin hydrochloride (I) are /detailed/, I pharmacokinetics were studied in rats following single intravenous doses and efficacy studies were carried out in mice with Ehrlich ascites carcinoma and in rats with Walker carcinoma. The kinetics of in vitro release of the drug complied partially with first order as well as with a diffusion model from a matrix. The pharmacokinetics in serum, heart and lungs of rats could be described by the equation of the 2 compartment open model. The pharmacokinetic parameters calculated suggest the possibility of improving the selective entrapment of I by the lungs. In the animal efficacy studies I increased the survival times in all treated groups. It was concluded that the data suggest the possibility of organ targeting of I microspheres.

MEDICATION (VET)

MEDICATION

Antibiotics, Antineoplastic; Topoisomerase II Inhibitors

Use (kg; approx.) in Germany (2009): >10

For use as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer.

Sicor developed a route from doxorubicin, in which the hydroxyl groups at C-9 and C-14 are protected as dioxanones (by reaction of doxorubicin with triethyl orthoformate), the 3'-amino group is protected as its N-trifluoroacetyl derivative, the hydroxyl groups of ring B as their trimethylsilyl derivatives, and the 4'-hydroxy group of the daunosamine residue is converted to a triflate group, which by nucleophilic substitution of the triflate by formate and then deprotection leads to /epirubicin/.

The most direct route starts with the N-trifluoroacetyl derivative of daunorubicin, which is oxidized at very low temperature (-70 °C) with dimethylsulfoxide activated by trifluroacetanhydride to afford the 4'-keto derivative. Stereoselective reduction with sodium borohydride at -30 °C gives the 4'-epi-N-trifluoroacetyl daunorubicin, which after alkaline hydrolysis of the trifluoroacetyl group can be converted into /epirubicin/ ...

Preparation: E. Arcamone et al., German patent 2510866; eidem, United States of America patent 4058519 (1975, 1977 both to Soc. Farmaceut. Italia)