Etoposide Teva Mechanism of Action

Pharmacology: Pharmacodynamics: Action: Etoposide is a semisynthetic podophyllotoxin-derivative antineoplastic agent.
Etoposide has cytostatic action which prevents the cells from entering mitosis or destroys them in the premitotic phase. The exact mechanism of action of etoposide is not known, but the drug appears to produce its cytotoxic effects by damaging DNA and thereby inhibiting or altering DNA synthesis. Etoposide appears to be cell-cycle dependent and cycle-phase specific, inducing G2-phase arrest and preferentially killing cells in the G2 and late S phases.
Pharmacokinetics: Absorption and Distribution: On intravenous administration, the disposition of etoposide is best described as a biphasic process with a distribution half-life of about 1.5 hours and terminal elimination half-life ranging from 4-11 hours. Total body clearance values range from 33-48 ml/min or 16-36 ml/min and, like the terminal elimination half-life, are independent of dose over a range 100-600 mg/m². Etoposide is distributed minimally into pleural fluid and has been detected in the saliva, liver, spleen, kidney, myometrium, healthy brain tissue, and brain tumor tissue. Limited data suggest that distribution of the drug into bile is minimal. It is not known if etoposide is distributed into milk. The drug apparently crosses the placenta in animals. Etoposide apparently does not readily penetrate the CNS (although CSF etoposide concentrations generally range from undetectable to less than 5% of concurrent plasma concentrations during the initial 24 hours after IV administration of the drug, even after administration of very high doses). In vitro, etoposide is highly protein bound (97%) to human plasma proteins.
Metabolism and Excretion: The metabolic fate of etoposide has not been completely determined. Etoposide appears to be metabolized principally to produce the resulting hydroxy acid; this metabolite appears to be pharmacologically inactive. Other metabolites include glucuronide and sulfate conjugates. In vitro, they have minimal cytotoxic activity. Etoposide is cleared by both renal and nonrenal processes, i.e. metabolism and biliary excretion. The effect of renal disease on plasma etoposide clearance is not known. Biliary excretion appears to be a minor route of etoposide elimination. Only 6% or less of an intravenous dose is recovered in the bile as etoposide. Metabolism accounts for most of the nonrenal clearance of etoposide. The major urinary metabolite of etoposide in adults and children is the hydroxy acid. Glucuronide and/or sulfate conjugates of etoposide are excreted in urine and represent 5-22% of the dose. In adults, the total body clearance of etoposide is correlated with creatinine clearance, serum albumin concentration and nonrenal clearance. In children, elevated serum SGPT levels are associated with reduced total body clearance of the drug. Prior use of cisplatin may also result in a decrease of etoposide total body clearance in children. In children, approximately 55% of the dose is excreted in the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7-10 ml/min/m² or about 35% of the total body clearance over a dose range of 80 to 600 mg/m².