DBL Vincristine Sulfate Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: The precise mechanism of action of vincristine sulfate remains under investigation. It appears to bind to or crystallise critical microtubular proteins of the mitotic spindle, thus preventing their proper polymerisation and causing metaphase arrest. The antineoplastic effects of the vinca alkaloids are related to their ability to bind specifically with the intracellular protein tubulin, a key component of cellular microtubules.
Clinical trials: No data available.
Pharmacokinetics: Distribution: Distribution of vincristine and its metabolites into human body tissue and fluids has not been fully characterised, but the drug is rapidly and apparently widely distributed following intravenous administration.
Vincristine sulfate is extensively protein bound (75%) and is reported to be concentrated in blood platelets. Within 15 to 30 minutes after intravenous administration, over 90% of the drug is distributed from the blood into tissue, where it remains tightly, but not irreversibly, bound.
Vincristine sulfate and its metabolites are rapidly and extensively distributed into bile, with peak biliary concentrations occurring within 2 to 4 hours after rapid intravenous administration.
Central nervous system leukaemia has been reported in patients undergoing otherwise successful therapy with vincristine sulfate. This suggests that vincristine sulfate does not penetrate well into cerebro-spinal fluid.
Excretion: Pharmacokinetic studies in patients with cancer have shown a triphasic serum decay pattern following rapid intravenous administration. The initial, middle, and terminal half-lives are 5 minutes, 2.3 hours and 85 hours respectively; however the range of the terminal half-life in humans is from 19 to 155 hours.
The liver is the major excretory organ in humans and animals; about 80% of an intravenous dose of vincristine sulfate appears in the faeces and 10% to 20% can be found in the urine.
Toxicology: Preclinical safety data: Genotoxicity: Neither in vivo nor in vitro laboratory tests have conclusively demonstrated the mutagenicity of vincristine sulfate. As a classic tubulin binder, the primary mode of action of vincristine is aneugenicity, but at higher doses and over prolonged dosing intervals, the expression of clastogenicity becomes a possibility.
Carcinogenicity: Patients who receive vincristine sulfate chemotherapy in combination with anticancer drugs known to be carcinogenic have developed secondary malignancies. The contributing role of vincristine sulfate in this development has not been determined. No evidence of carcinogenicity was found following intraperitoneal administration of vincristine in rats and mice, although this study was limited.