Chemical formula: C₂₇H₂₉NO₁₁ Molecular mass: 543.519 g/mol PubChem compound: 31703
Doxorubicin is a cytotoxic anthracycline antibiotic obtained from Streptomyces peucetius var. caesius. The exact mechanism of the antitumour activity of doxorubicin is not known. It is generally believed that inhibition of DNA, RNA and protein synthesis is responsible for the majority of the cytotoxic effects. This is probably the result of intercalation of the anthracycline between adjacent base pairs of the DNA double helix thus preventing their unwinding for replication.
It is postulated that doxorubicin 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.
The pharmacokinetics of doxorubicin was evaluated in 120 patients from 10 different clinical trials using the population pharmacokinetic approach. The pharmacokinetics of doxorubicin over the dose range of 10 mg/m² to 60 mg/m² was best described by a two compartment non-linear model with zero order input and Michaelis-Menten elimination. The mean intrinsic clearance of doxorubicin was 0.030 l/h/m² (range 0.008 to 0.152 l/h/m²) and the mean central volume of distribution was 1.93 l/m² (range 0.96-3.85 l/m²) approximating the plasma volume. The apparent half-life ranged from 24-231 hours, with a mean of 73.9 hours.
The pharmacokinetics of doxorubicin determined in 18 patients with breast carcinoma were similar to the pharmacokinetics determined in the larger population of 120 patients with various cancers. The mean intrinsic clearance was 0.016 l/h/m² (range 0.008-0.027 l/h/m²), the mean central volume of distribution was 1.46 l/m² (range 1.10-1.64 l/m²). The mean apparent half-life was 71.5 hours (range 45.2-98.5 hours).
The pharmacokinetics of doxorubicin determined in 11 patients with ovarian carcinoma were similar to the pharmacokinetics determined in the larger population of 120 patients with various cancers. The mean intrinsic clearance was 0.021 l/h/m² (range 0.009-0.041 l/h/m²), the mean central volume of distribution was 1.95 l/m² (range 1.67-2.40 l/m²). The mean apparent half-life was 75.0 hours (range 36.1-125 hours).
The plasma pharmacokinetics of doxorubicin were evaluated in 23 patients with KS who received single doses of 20 mg/m² administered by a 30-minute infusion. The pharmacokinetic parameters of doxorubicin (primarily representing pegylated liposomal doxorubicin hydrochloride and low levels of unencapsulated doxorubicin hydrochloride) observed after the 20 mg/m² doses are presented in Table 10.
Table 10. Pharmacokinetic parameters in doxorubicin-treated AIDS-KS patients:
| Mean + standard error | |
|---|---|
| Parameter | 20 mg/m² (n=23) |
| Maximum plasma concentration* (μg/ml) | 8.34 ± 0.49 |
| Plasma clearance (l/h/m²) | 0.041 ± 0.004 |
| Volume of distribution (l/m²) | 2.72 ± 0.120 |
| AUC (μg/ml·h) | 590.00 ± 58.7 |
| λ1 half-life (hours) | 5.2 ± 1.4 |
| λ2 half-life (hours) | 55.0 ± 4.8 |
* Measured at the end of a 30-minute infusion
Animal studies from literature show that doxorubicin affects the fertility, is embryo- and foetotoxic and teratogenic. Other data shows that doxorubicin is mutagenic.
Studies in rabbits have shown that the cardiotoxicity of doxorubicin is reduced compared with conventional doxorubicin hydrochloride preparations.
In studies performed after the repeated administration of doxorubicin to rats and dogs, serious dermal inflammations and ulcer formations were observed at clinically relevant dosages. In the study in dogs, the occurrence and severity of these lesions was reduced by lowering the dose or prolonging the intervals between doses. Similar dermal lesions, which are described as palmar-plantar erythrodysesthesia were also observed in patients after long-term intravenous infusion.
During repeat dose toxicology studies in dogs, an acute response characterised by hypotension, pale mucous membranes, salivation, emesis and periods of hyperactivity followed by hypoactivity and lethargy was observed following administration of pegylated liposomes (placebo).
The hypotensive response was reduced in magnitude by pretreatment with antihistamines. However, the response was not life-threatening and the dogs recovered quickly upon discontinuation of treatment.
Subcutaneous tolerance studies indicate that doxorubicin, as against standard doxorubicin hydrochloride, causes slighter local irritation or damage to the tissue after a possible extravasation.
Although no studies have been conducted with doxorubicin, doxorubicin hydrochloride, the pharmacologically active ingredient of doxorubicin, is mutagenic and carcinogenic. Pegylated placebo liposomes are neither mutagenic nor genotoxic.
Doxorubicin resulted in mild to moderate ovarian and testicular atrophy in mice after a single dose of 36 mg/kg. Decreased testicular weights and hypospermia were present in rats after repeat doses >0.25 mg/kg/day and diffuse degeneration of the seminiferous tubules and a marked decrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day.
A study has shown that doxorubicin at a single intravenous dose of over twice the clinical dose produces renal toxicity in monkeys. Renal toxicity has been observed with even lower single doses of doxorubicin HCl in rats and rabbits. Since an evaluation of the post-marketing safety database for doxorubicin in patients has not suggested a significant nephrotoxicity liability of doxorubicin, these findings in monkeys may not have relevance to patient risk assessment.
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