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Pharmacology: Pharmacodynamics: Daunorubicin is an antineoplastic drug that exerts its cytotoxic/antiproliferative effects through interference with a number of biochemical and biological functions in target cells. Although the precise mechanism(s) of action has not been fully elucidated, the drug appears mainly to inhibit DNA and DNA-dependent RNA synthesis by forming a complex with DNA, via intercalation between base pairs and uncoiling of the helix. Daunorubicin may also interfere with polymerase and topoisomerase II activities, with regulation of gene expression and with oxidation/reduction reactions (generating highly reactive/highly toxic free radicals). A direct interaction between daunorubicin and the cellular membrane yielding alterations on the cell surface double layer has also been speculated. Daunorubicin is maximally cytotoxic during the S phase, but the drug is not cycle- or phase-specific. Antibacterial and immunosuppressive properties have also been ascribed to daunorubicin.
No controlled paediatric studies have been conducted.
Pharmacokinetics: Absorption: Daunorubicin is not absorbed by the gastrointestinal tract. Since the drug is extremely irritating to tissues, it has to be administered by the IV route: under these conditions the absorption is expected to be complete (i.e., if no extravasation occurs).
Distribution: Daunorubicin is widely distributed into body tissues, with highest levels in the spleen, kidneys, lungs and heart. The drug enters into cells and binds to cellular components, particularly nucleic acids. There is no evidence that daunorubicin can cross the blood-brain barrier, but the drug apparently crosses the placenta.
Metabolism: The drug undergoes a rapid and extensive metabolism in the liver and other tissues, mainly by cytoplasmic aldo-keto reductases. One hour after drug administration the predominant plasma species is the active metabolite daunorubicinol (13-OH daunorubicin). Further metabolism via reduction cleavage of the glycosidic bond produces aglycones, which have little or no antiproliferative activity and are demethylated and conjugated via sulfate and glucuronide by microsomal enzymes.
Excretion: Following rapid IV administration, total plasma concentrations of daunorubicin and its metabolites decline in a triphasic fashion, while plasma concentrations of unchanged daunorubicin decline in a biphasic fashion. The half-life averages 45 minutes in the initial phase and 18.5 hours in the terminal phase. The daunorubicinol half-life exceeds the 24 hours. Daunorubicin and its metabolites are excreted in urine and bile (approximately 40% of the administered dose). Urinary excretion of the drug and its metabolites is reported to be 14% to 23% of the given dose, with most urinary excretion occurring within 3 days. After the first 24 hours, the drug is excreted in the urine mainly as daunorubicinol.
Toxicology: Preclinical safety data: The LD50 of daunorubicin is 17.3-20 and 13-15 in mice and rats, respectively and about 5 mg/kg for dogs. The main target organs after a single dose are the hemolymphopoietic system and, especially in dogs, the gastrointestinal tract.
The toxic effects after repeated administrations have been investigated in rabbits, dogs and monkeys. The main target organs of daunorubicin in these animal species resulted the hemolymphopoietic system, gastrointestinal tract, kidney, liver and reproductive organs. Subacute and cardiotoxicity studies indicate that daunorubicin is cardiotoxic in all the laboratory animals tested.
Daunorubicin is genotoxic in most of the in vitro and in vivo tests performed, toxic to the reproductive organs, embryotoxic in rats and rabbits and teratogenic in rats. There is no information available on the administration of daunorubicin in animals during the peri- and post-natal periods and it is not known whether the compound is excreted in breast milk. Daunorubicin, like other anthracyclines and cytotoxic drugs, is carcinogenic in rats. Toxicity studies show that extravasation of the drug cause tissue necrosis.
