Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: Accord Healthcare Limited, Sage House, 319, Pinner Road, North Harrow, Middlesex, HA1 4HF, United Kingdom
Pharmacotherapeutic group: Anthracyclines and related substances
ATC code: L01DB01
Doxorubicin is an anthracycline antibiotic. The mechanism of action is not completely elucidated. It is postulated that doxorubicin hydrochloride exerts its antineoplastic effect via cytotoxic mechanisms of action especially intercalation into DNA, inhibition of the enzyme topoisomerase II, and formation of reactive oxygen species (ROS). All of these have a deleterious effect on DNA synthesis: Intercalation of the doxorubicin molecule leads to all inhibition of RNA and DNA polymerases by way of disturbances in base recognition and sequence specificity. The inhibition of topoisomerase II produces single and double strand breaks of the DNA helix. Scission of DNA also originates from the chemical reaction with highly reactive oxygen species like the hydroxyl radical OH•. Mutagenesis and chromosomal aberrations are the consequences.
The specificity of doxorubicin toxicity appears to be related primarily to proliferative activity of normal tissue. Thus, bone marrow, gastro-intestinal tract and gonads are the main normal tissues damaged.
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. A combination of doxorubicin and verapamil is associated with severe cardiotoxic effects.
Following intravenous injection, doxorubicin is rapidly cleared from the blood and widely distributed into tissues including lungs, liver, heart, spleen, lymph nodes, bone marrow and kidneys. The volume of distribution is about 25 litres. The degree of protein binding is 60-70%.
Doxorubicin does not cross the blood-brain barrier, although higher levels in liquor may be reached in the presence of brain metastases or leukemic cerebral dissemination. Doxorubicin is rapidly distributed into the ascites, where it reaches higher concentrations than in plasma. Doxorubicin is secreted into breast milk.
The elimination of doxorubicin from the blood is triphasic with mean half-lives of 12 minutes (distribution), 3.3 hours and about 30 hours. Doxorubicin undergoes rapid metabolism in the liver. The main metabolite is the pharmacologically active doxorubicinol. Other metabolites are deoxyrubicin aglycone, glucuronide and sulphate conjugate. About 40 to 50% of a dose is excreted in bile within 7 days, of which about half is excreted as unchanged drug and the rest as metabolites. Only 5-15% of the administered dose is eliminated in urine.
As the elimination of doxorubicin is mainly hepatic, impairment of liver function results in slower excretion, and consequently, increased retention and accumulation in plasma and tissues. Dose reduction is generally advised.
Although renal excretion is a minor elimination pathway for doxorubicin, severe renal impairment might affect total elimination and require dose reduction.
In a study in obese patients (>130% of ideal bodyweight) the doxorubicin clearance was reduced and the half life increased compared with a normal-weight control group. Dose adjustments might be necessary in the obese.
In cancer patients, doxorubicin is reduced to adriamycinol, which is an active cytotoxic agent. This reduction appears to be catalysed by cytoplasmic nadph-dependent aldo-keto reductases that are found in all tissues and play an important role in determining the overall pharmacokinetics of doxorubicin.
Microsomal glycosidases present in most tissues split doxorubicin and adriamycinol into inactive aglycones. The aglycones may then undergo 0-demethylation, followed by conjugation to sulphate or glucuronide esters, and excretion in the bile.
Animal studies from literature show that Doxorubicin affects the fertility, is embryo- and foetotoxic and teratogenic. Other data shows that Doxorubicin is mutagenic.
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