Adriamycin

Absorption

Following a 10 mg/m2 administration of liposomal doxorubicin in patients with AIDS-related Kaposi's Sarcoma, the Cmax and AUC values were calculated to be 4.12 ± 0.215 μg/mL and 277 ± 32.9 μg/mL?h respectively.

Toxicity

Doxorubicin hydrochloride treatment can increase the risk of secondary malignancies based on postmarketing reports. Doxorubicin hydrochloride was mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay.
Doxorubicin hydrochloride decreased fertility in female rats at doses of 0.05 and 0.2 mg/kg/day (approximately 0.005 and 0.02 times the recommended human dose, based on body surface area). In females of reproductive potential, Doxorubicin hydrochloride may cause infertility and result in amenorrhea. Premature menopause can occur. Recovery of menses and ovulation is related to age at treatment.
A single intravenous dose of 0.1 mg/kg doxorubicin hydrochloride (approximately 0.01 times the recommended human dose based on body surface area) was toxic to male reproductive organs in animal studies, producing testicular atrophy, diffuse degeneration of the seminiferous tubules, and oligospermia/hypospermia in rats. Doxorubicin hydrochloride induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice.
Based on findings in animals and its mechanism of action, Doxorubicin Hydrochloride Injection/for Injection can cause fetal harm when administered to a pregnant woman; avoid the use of Doxorubicin Hydrochloride Injection/for Injection during the 1st trimester. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. Doxorubicin hydrochloride was teratogenic and embryotoxic in rats and embryotoxic in rabbits when administered during organogenesis at doses approximately 0.07 times (based on body surface area) the recommended human dose of 60 mg/m2. Advise pregnant women of the potential risk to a fetus.
Based on postmarketing reports, pediatric patients treated with doxorubicin hydrochloride are at risk for developing late cardiovascular dysfunction. Risk factors include young age at treatment (especially < 5 years), high cumulative doses and receipt of combined modality therapy. Long-term periodic cardiovascular monitoring is recommended for all pediatric patients who have received doxorubicin hydrochloride. Doxorubicin hydrochloride, as a component of intensive chemotherapy regimens administered to pediatric patients, may contribute to prepubertal growth failure and may also contribute to gonadal impairment, which is usually temporary.

Chemical properties

Adriamycin is an orange to red cake-like or needle-like crystalline solid.

Originator

Adriblastina,Farmitalia,Italy,1971

The Uses of Adriamycin

Doxorubicin (adriamycin) is the most extensively studied of a family of highly fluorescent anthracycline antibiotics produced by several Streptomyces species, first reported in 1967 and later approved for human therapeutic use as an antitumour agent for the treatment of a wide range of cancers. Doxorubicin also exhibits anti-HIV and antibacterial activity. The mode of action of doxorubicin is thought to be due to intercalation of DNA and inhibition of nucleic acid synthesis.

The Uses of Adriamycin

Doxorubicin USP (Adriamycin) is used to traet soft-tissue and osteogenic sarcomas; Hodgkin’s disease; non-Hodgkin’s lymphomas; acute leukemia; cancer of thyroid, breast, lung, genitourinary (GU) tract; Wilm’s tumor; neuroblastoma.

The Uses of Adriamycin

Doxorubicin is one of the most effective neoplastic drugs, and is mainly used in combination with other drugs for treating solid tumors. This drug is used for leukemia, various sarcomas, practically every type of cancer, neuroblastomas, leukoses, and lymphomas.

What are the applications of Application

Doxorubicin is an immunosuppresive antineoplastic antibiotic

Background

Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius along side with daunorubicin, another cytotoxic agent, in 1970. Although they both have aglyconic and sugar moieties, doxorubicin's side chain terminates with a primary alcohol group compared to the methyl group of daunorubicin. Although its detailed molecular mechanisms have yet to be understood, doxorubicin is generally thought to exert its effect through DNA intercalation, which eventually leads to DNA damage and the generation of reactive oxygen species. Thanks to its efficacy and broad effect, doxorubicin was approved by the FDA in 1974 to treat a variety of cancer, including but not limited to breast, lung, gastric, ovarian, thyroid, non-Hodgkin’s and Hodgkin’s lymphoma, multiple myeloma, sarcoma, and pediatric cancers. However, one of the major side effects of doxorubicin is cardiotoxicity, which excludes patients with poor heart function and requires treatment termination once the maximally tolerated cumulative dose is reached.

Indications

Doxorubicin is indicated for the treatment of neoplastic conditions like acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin and non-Hodgkin lymphoma, metastatic breast cancer, metastatic Wilms’ tumor, metastatic neuroblastoma, metastatic soft tissue and bone sarcomas, metastatic ovarian carcinoma, metastatic transitional cell bladder carcinoma, metastatic thyroid carcinoma, metastatic gastric carcinoma, and metastatic bronchogenic carcinoma. 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. For the liposomal formulation, doxorubicin is indicated for the treatment of ovarian cancer that has progressed or recurred after platinum-based chemotherapy, AIDS-Related Kaposi's Sarcoma after the failure of prior systemic chemotherapy or intolerance to such therapy, and multiple myeloma in combination with bortezomib in patients who have not previously received bortezomib and have received at least one prior therapy.

Indications

Doxorubicin binds tightly to DNA by its ability to intercalate between base pairs and therefore is preferentially concentrated in nuclear structures. Intercalation results in steric hindrance, hence production of single-strand breaks in DNA and inhibition of DNA synthesis and DNA-dependent RNA synthesis. The enzyme topoisomerase II is thought to be involved in the generation of DNA strand breaks by the anthracyclines. Cells in S-phase are most sensitive to doxorubicin, although cytotoxicity also occurs in other phases of the cell cycle.

Definition

ChEBI: Doxorubicin is a deoxy hexoside, an anthracycline, an anthracycline antibiotic, an aminoglycoside, a member of tetracenequinones, a member of p-quinones, a primary alpha-hydroxy ketone and a tertiary alpha-hydroxy ketone. It has a role as an Escherichia coli metabolite. It is a conjugate base of a doxorubicin(1+). It derives from a hydride of a tetracene.

Manufacturing Process

Two 300 ml Erlenmeyer flasks, each containing 60 ml of the following culture medium for the vegetative phase, were prepared: peptone 0.6%; dry yeast 0.3%; hydrated calcium carbonate 0.2%; magnesium sulfate 0.01%; the pH after sterilization was 7.2. Sterilization has been effected by heating in autoclave to 120°C for 20 minutes. Each flask was inoculated with a quantity of mycelium of the mutant F.I.106 (the new strain thus obtained has been given the code F.I.106 of the Farmitalia microbiological collection and has been called Streptomycespeucetius var. caesius) corresponding to 1/9 of a suspension in sterile water of the mycelium of a 10 day old culture grown in a big test tube on the following medium: saccharose 2%; dry yeast 0.1%; bipotassium phosphate 0.2%; sodium nitrate 0.2%; magnesium sulfate 0.2%; agar 2%; tap water up to 100%. The flasks were then incubated at 28°C for 48 hours on a rotary shaker with a stroke of 30 mm at 220 rpm.，
2 ml of a vegetative medium thus grown were used to inoculate 300 ml Erlenmeyer flasks with 60 ml of the following medium for the productive phase: glucose 6%; dry yeast 2.5%; sodium chloride 0.2%; bipotassium phosphate 0.1%; calcium carbonate 0.2%; magnesium sulfate 0.01%; ferrous sulfate 0.001%; zinc sulfate 0.001%; copper sulfate 0.001%; tap water to 100%. The glucose was previously sterilized separately at 110°C for 20 minutes. The resulting pH was 7. This was sterilized at 120°C for 20 minutes and incubated at 28°C under the same conditions by stirring, as for the vegetative media.
The maximum concentration of the antibiotic was reached on the 6th day of fermentation. The quantity of adriamycin produced at this time corresponds to a concentration of 15 μg/ml.

brand name

Adriblastina (Farmitalia, Societa Farmaceutici Italia, Italy).

Therapeutic Function

Cancer chemotherapy

Biological Activity

doxorubicin is a semi-synthesized anticancer agent derived from bacterial culture. [1] it is an anthracycline antibiotic. it is been widely used in blood cancers, solid tumors and sarcomas.doxorubicin intercalates into dna double strand and inhibits the progression of dna topoisomerase ii, stopping replication process. [2] doxorubicin also induces histone eviction from open chromatin, causing dna damage and epigenetic deregulation. [3]doxorubicin is administrated intravenously. approximately 75% of doxorubicin and its metabolites bind to plasma protein. doxorubicin does not cross blood brain barrier. 50% of the drug is eliminated unchanged from the body mainly though bile excretion. the remaining undergoes one-electron reduction, two-electron reduction, and deglycosidation. the major metabolite is a potent membrane ion pump inhibitor, which is associated with cardiomyopathy. [4]

Mechanism of action

Doxorubicin is not absorbed orally, and because of its ability to cause tissue necrosis must not be injected intramuscularly or subcutaneously. Distribution studies indicate rapid uptake in all tissues except the CNS. Extensive tissue binding, primarily intranuclear, accounts for the prolonged elimination half-life.The drug is extensively metabolized in the liver to hydroxylated and conjugated metabolites and to aglycones that are primarily excreted in the bile.

Pharmacokinetics

Doxorubicin is a cytotoxic, cell-cycle non-specific anthracycline antibiotic. It is generally thought to exert its antitumor effect by destabilizing DNA structures through intercalation, thus introducing DNA strand breakages and damages. Not only does it alter the transcriptomes of the cells, failure in repairing DNA structures can also initiate the apoptotic pathways. Additionally, doxorubicin intercalation can also interfere with vital enzyme activity, such as topoisomerase II, DNA polymerase, and RNA polymerase, leading to cell cycle arrests. Finally, doxorubicin can also generate cytotoxic reactive oxygen species to exert cellular damages.

Clinical Use

Doxorubicin is one of the most effective agents used in the treatment of carcinomas of the breast, ovary, endometrium, bladder, and thyroid and in oat cell cancer of the lung. It is included in several combination regimens for diffuse lymphomas and Hodgkin’s disease. Doxorubicin can be used as an alternative to daunorubicin in acute leukemias and is useful in Ewing’s sarcoma, osteogenic sarcoma, soft-tissue sarcomas, and neuroblastoma. Some activity has been reported in non–oat cell lung cancer, multiple myeloma, and adenocarcinomas of the stomach, prostate, and testis.

Side Effects

The most important toxicities caused by doxorubicin involve the heart and bone marrow.Acutely, doxorubicin may cause transient cardiac arrhythmias and depression of myocardial function. Doxorubicin may cause radiation recall reactions, with flare-ups of dermatitis, stomatitis, or esophagitis that had been produced previously by radiation therapy. Less severe toxicities include phlebitis and sclerosis of veins used for injection, hyperpigmentation of nail beds and skin creases, and conjunctivitis. Because of its intense red color, doxorubicin will impart a reddish color to the urine for 1 or 2 days after administration.

Safety Profile

Confirmed carcinogen with experimental carcinogenic, neoplastigenic, and tumorigenic data. Poison by intraperitoneal, subcutaneous, parenteral, and intravenous routes. Human systemic effects by intravenous route: cardiac myopathy including infarction, nausea or vomiting, and effects on the hair. An experimental teratogen. Other experimental reproductive effects. Human mutation data reported. When heated to decomposition it emits very toxic fumes of NO, and HCl

Potential Exposure

An antibiotic product from streptomyces, used as anticancer drug

Carcinogenicity

Adriamycin is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.

Metabolism

Doxorubicin is capable of undergoing 3 metabolic routes: one-electron reduction, two-electron reduction, and deglycosidation. However, approximately half of the dose is eliminated from the body unchanged.
The two-electron reduction is the major metabolic pathway of doxorubicin. In this pathway, doxorubicin is reduced to doxorubicinol, a secondary alcohol, by various enzymes, including Alcohol dehydrogenase [NADP(+)], Carbonyl reductase NADPH 1, Carbonyl reductase NADPH 3, and Aldo-keto reductase family 1 member C3.
The one-electron reduction is facilitated by several oxidoreductase, both cytosolic and mitochondrial, to form a doxirubicin-semiquinone radical. These enzymes include mitochondrial and cystolic NADPH dehydrogenates, xanthine oxidase, and nitric oxide synthases. This semiquinone metabolite can be re-oxidized to doxorubicin, although with the concurrent formation of reactive oxygen species (ROS) and hydrogen peroxide. It is the ROS generating through this pathway that contributes most to the doxorubicin-related adverse effects, particularly cardiotoxicity, rather than through doxorubicin semiquinone formation.
Deglycosidation is a minor metabolic pathway, since it only accounts for 1 to 2% of doxorubicin metabolism. Under the catalysis of cytoplasmic NADPH quinone dehydrogenase, xanthine oxidase, NADPH-cytochrome P450 reductase, doxorubicin can either be reduced to doxorubicin deoxyaglycone or hydrolyzed to doxorubicin hydroxyaglycone.

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.

References

[1]brayfield, a, ed. (2013). doxorubicin. martindale: the complete drug reference. pharmaceutical press. retrieved 15 april 2014.
[2]pommier y., et al. (2010). dna topoisomerases and their poisoning by anticancer and antibacterial drugs. chemistry & biology 17 (5): 421–433.
[3]pang, b., et al. (2013). drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin. nature communications 4 (5): 1908
[4]boucek rj., et al. (1987). the major metabolite of doxorubicin is a potent inhibitor of membrane-associated ion pumps. a correlative study of cardiac muscle with isolated membrane fractions. j of biol chem 262: 15851-15856.