Mechanism of action The mechanism of action of<unk>  is similar to that of doxorubicin and other anthracycline drugs. The observed clinical differences between<unk>  and doxorubicin can be explained by the pharmacokinetic differences based on the different affinity to DNA and lipophilicity, as there is no indication that different mechanisms are involved in their activity.<unk>  first forms a complex with DNA by intercalation of its planar rings between nucleotide base pairs. (Pharmacia & Upjohn Company LLC, 1999) This inhibits replication and transcription and triggers DNA cleavage by topoisomerase II.<unk>  then stabilizes the topoisomerase II-DNA complex, resulting in irreversible DNA strand breakage, leading to cell death.<unk>  is also capable of generating cytotoxic free radicals, which are very reactive against DNA, cell membranes and mitochondria.<unk>  exhibits activity in all phases of the cell cycle, but maximal cell kill occurs during the S and G2 phases of the cell cycle. Pharmacokinetics The pharmacokinetic properties of<unk>  can be described by a 3-compartment model, with half-lives for the initial (alpha), intermediate (beta) and terminal (gamma) elimination phases of approximately 3 minutes, 1 hour and 30 hours, respectively. Only the latter differs substantially compared to doxorubicin, as the terminal elimination half-life of doxorubicin is estimated to be approximately 40-70% longer than that of<unk> . The pharmacokinetics of<unk>  appear to be linear for doses in the range of 40 – 150 mg/m2. The volume of distribution of<unk>  is found to be high and variable (1 000- 1 500), but similar to those reported for doxorubicin. This indicates extensive distribution into the tissue. The total plasma clearance of<unk>  is approximately 45 to 50 L/h/m2, which is almost 2-fold higher than that of doxorubicin. Area under the plasma concentration versus time curve values (adjusted for dose) are 1.3 to 1.7 times higher for doxorubicin than<unk>  following single-dose intravenous administration.<unk>  shows a 77% binding to plasma proteins, predominantly albumin, which is not affected by drug concentration. Metabolism<unk>  is rapidly metabolized by the liver to relatively or totally inactive metabolites:<unk> ol, 2 glucuronides and 4 aglycones. As plasma levels of<unk> ol are lower than those of the unchanged drug and the metabolite has an in vitro cytotoxic activity 10% of that of<unk> , it is unlikely to reach in vivo concentration sufficient for cytotoxicity. No significant toxicity has been reported for the other metabolites.<unk> ol is the 13(S)-dihydro derivative formed via the reduction of the C-13 keto-group. Both the unchanged drug and<unk> ol can be conjugated with glucuronic acid, creating the 2 glucuronides. This glucuronidation pathway is unique to<unk>  metabolism in humans as<unk>  is the only anthracycline that serves as a substrate for beta-glucuronidation. This unique pathway might explain the better tolerability of this drug compared with doxorubicin. The 4 aglycones are formed by losing the amino sugar moiety through a hydrolytic process or redox process, creating the doxorubicin and doxorubicinol aglycones and 7-deoxy-doxorubicin and 7-deoxy-doxorubicinol aglycones, respectively. Excretion<unk>  and its metabolites are primarily eliminated through biliary excretion. About 11 to 15% of the administered dose is eliminated as an unchanged drug, which makes up 6 to 7% of the excreted compounds, and metabolites.
Epirubicin
Valrubicin
Ifosfamide
Vincristine
Doxorubicin
Daunorubicin
Mitoxantrone
Etoposide