Doxorubicin Ebewe Mechanism of Action

ATC classification: L01D B01.
Pharmacology: Pharmacodynamics: Doxorubicin has been shown to have antineoplastic activity in several animal models and is effective in humans but there is as yet no consensus as to how doxorubicin and other anthracyclines exert their antitumour activity. Three principal biochemical mechanisms have been proposed: DNA intercalation, membrane binding and metabolic activation via reduction.
An important cause of treatment failure with doxorubicin and other anthracyclines is the development of resistance. In an attempt to overcome cellular resistance to doxorubicin the use of calcium antagonists such as verapamil has been considered since the primary target is the cell membrane; verapamil inhibits the slow channel of calcium transport and can enhance cellular uptake of doxorubicin. Chang et al, 1989 have shown that the cytotoxicity of doxorubicin is potentiated by verapamil in vitro using three pancreatic cancer cell lines.
They also investigated a possible role of its major reduction metabolite, doxorubicinol, which occurs in human plasma, but concluded that it was not involved in the intracellular accumulation/retention of doxorubicin. It should be noted that a combination of doxorubicin and verapamil has been shown to be associated with severe toxic effects in animal experiments. (Sridhar et al, 1992).
Pharmacokinetics: The intravenous administration of doxorubicin is followed by a rapid plasma clearance (t_1/2 = 10 min.) and significant tissue binding. The terminal half-life is approximately 30 hours.
Doxorubicin is partly metabolised, mainly to doxorubicinol and to a lesser extent, to the aglycon, and is conjugated to the glucuronide and sulfate. Biliary and fecal excretion represents the major excretion route. About 10% of the dose is eliminated by renal excretion. Plasma protein binding of doxorubicin ranges from 50-85%. The volume of distribution is 800-3500L/m².
Doxorubicin is not absorbed after oral administration; it does not cross the blood-brain barrier.
Impairment of liver function may decrease the clearance of doxorubicin and its metabolites.
Toxicology: Preclinical safety data: The LD₅₀ after a single intravenous bolus injection of doxorubicin to rats, mice and rabbits were 12.6, 9.4 and 6mg/kg, respectively.
Reduction in body weights and survival times were seen in old and young rats administered a single intravenous dose of 2.5 and 5mg/kg, respectively.
The animal data show an increased toxicity in elder rats.
As expected from its interaction with DNA and cytotoxic properties doxorubicin is mutagenic, showing chromosome damage in vitro in human lymphocytes and is also carcinogenic in animals. The compound is also teratogenic and embryocidal. Although i.v. and i.p. dosage to mice and rats at doses up to 1mg/kg from days 7 to 13 of gestation produced no evidence of teratogenicity a higher dose of 2mg/kg i.p. for longer to rats caused atresia of the oesophagus and intestine and cardiovascular abnormalities. In rabbits dosed i.v. at up to 0.6mg/kg on days 16-18 abortions occurred but there were no foetal abnormalities. Post-natal renal damage was produced in rats dosed with 1 or 1.5mg/kg of doxorubicin during days 6-9 or 10-12.
Microscopic examination of the heart of patients shows evidence of a severe cardiomyopathy and a variety of alterations have been described the majority of which have been reproduced in animal models in the mouse, rat, rabbit, dog and monkey; the development and character of the lesions in the rat and rabbit closely resemble those in humans although rats develop cardiomyopathy at lower total doses than rabbits. The pathogenesis is difficult to assess since a large number of complex biochemical effects have been shown to occur in the heart.