Pharmacology: Pharmacodynamics: Mechanism of Action: Though not completely elucidated, the mechanism of action of doxorubicin is related to its ability to bind to DNA and inhibit nucleic acid synthesis. Cell culture studies have demonstrated rapid cell penetration and perinucleolar chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, mutagenesis and chromosomal aberrations.
Doxorubicin has immunosuppressive effects. It inhibits the titre of haemolytic and haemagglutinating antibodies in mice immunised with sheep red blood cells. Similar evidence in man indicates that doxorubicin is a powerful, but temporary immunosuppressant agent.
Doxorubicin is a cell cycle, phase non-specific cytotoxic drug.
The toxic effects of doxorubicin on the bone marrow appear to be related to its action on proliferating myeloid cells. The cardiotoxicity of doxorubicin is probably mediated by different mechanisms. Although, in animal systems, doxorubicin does inhibit DNA synthesis in cardiac muscle, it is probable that cardiotoxicity is not directly related to inhibition of cardiac muscle replication. There are some data which suggest that it is due to the generation of free radicals which damage cardiac muscle in some uncertain way. These data also suggest that concurrent administration of Vitamin E and other free radical acceptors may prevent cardiotoxicity in experimental animal systems without impairing its antitumour efficacy. These studies need confirmation but they do suggest that it may be possible to divorce the antitumour effects of the drug from its cumulative cardiotoxic effects.
The specificity of doxorubicin toxicity appears to be related primarily to proliferative activity of normal tissue. Thus, bone marrow, gastrointestinal tract and gonads are the main normal tissues damaged.
Clinical Trials: No data available.
Pharmacokinetics: Absorption/Distribution: ADRIAMYCIN is not suitable for oral administration as less than 5% of the drug is absorbed.
Pharmacokinetic studies show the intravenous administration of normal or radiolabelled ADRIAMYCIN (doxorubicin hydrochloride) for injection is followed by rapid plasma clearance and significant tissue binding. No information on plasma-protein binding of doxorubicin is available. Doxorubicin does not cross the blood brain barrier.
Metabolism: The metabolism and disposition of doxorubicin is still to be defined. The drug is metabolised predominantly by the liver to adriamycinol and several aglycone metabolites. It should be noted that several of the metabolites are cytotoxic. However, it is not certain whether any are more cytotoxic than the parent compound. High levels of metabolites appear rapidly in plasma and undergo a distribution phase with a measurable short initial half-life. Metabolism may be impaired in patients with abnormal liver function.
The disappearance of doxorubicin and its metabolites from the plasma follows a triphasic pharmacokinetic pattern with a mean half-life of the first phase of 12 minutes, of a second phase of 3.3 hours and a prolonged third phase of 29.6 hours.
Excretion: Urinary excretion, as determined by fluorimetric methods, accounts for approximately 4%-5% of the administered dose in five days. Biliary excretion represents the major excretion route, 40%-50% of the administered dose being recovered in the bile or the faeces in seven days. Impairment of liver function results in slower excretion, and consequently, increased retention and accumulation in plasma and tissues.
Toxicology: Preclinical safety data: Genotoxicity: Doxorubicin was genotoxic in a battery of in vitro or in vivo tests. An increase in the incidence of mammary tumours was reported in rats, and a trend for delay or arrest of follicular maturation was seen in female dogs. Doxorubicin and related compounds have been shown to have mutagenic properties when tested in experimental models.
Carcinogenicity: Doxorubicin and related compounds have been shown to have carcinogenic properties when tested in experimental models.