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Etoposide


ACCESSION NB: DB00773 (APRD00239)


TYPE: small molecule


GROUP: approved


DESCRIPTION:
A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle. [PubChem]

VOLUME OF DISTRIBUTION: Not Available

CATEGORIES:
Nucleic Acid Synthesis Inhibitors Antineoplastic Agents, Phytogenic

ABSORPTION: Absorbed well, time to peak plasma concentration is 1-1.5 hrs. Mean bioavailability is 50%.

INDICATION:
For use in combination with other chemotherapeutic agents in the treatment of refractory testicular tumors and as first line treatment in patients with small cell lung cancer. Also used to treat other malignancies such as lymphoma, non-lymphocytic leukemia, and glioblastoma multiforme.

PHARMACODYNAMICS:
Etoposide is an antineoplastic agent and an epipodophyllotoxin (a semisynthetic derivative of the podophyllotoxins). It inhibits DNA topoisomerase II, thereby ultimately inhibiting DNA synthesis. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases. Two different dose-dependent responses are seen. At high concentrations (10 µg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 µg/mL), cells are inhibited from entering prophase. It does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA-topoisomerase II or the formation of free radicals.

MECHANISM OF ACTION:
Etoposide inhibits DNA topoisomerase II, thereby inhibiting DNA re-ligation. This causes critical errors in DNA synthesis at the premitotic stage of cell division and can lead to apoptosis of the cancer cell. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases of cell division.

PROTEIN BINDING:
97%

METABOLISM:
Primarily hepatic (through O-demethylation via the CYP450 3A4 isoenzyme pathway) with 40% excreted unchanged in the urine. Enzyme Metabolite Reaction Km Vmax Cytochrome P450 3A4 3'-demethyletoposide 3'-demethylation 53.9 0.25

TOXICITY:
Side effects include alopecia, constipation, diarrhea, nausea and vomiting and secondary malignancies (leukemia).

AFECTED ORGANISMS:
Humans and other mammals