Paxol Mechanism of Action

Pharmacotherapeutic group: Antineoplastic agent/taxanes. ATC code: L01C D01.
Pharmacology: Pharmacodynamics: Mechanism of action: Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by preventing depolymerisation.
This stability inhibits the normal dynamic reorganisation of the microtubule network, which is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or bundles of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
Pharmacokinetics: Absorption: Following intravenous administration, paclitaxel exhibits a biphasic decline in plasma concentrations.
The pharmacokinetics of paclitaxel were determined following 3- and 24-hour infusions at doses of 135 and 175 mg/m². The mean half-life was between 3.0 and 52.7 hours, and the mean non-compartmentally derived value for total body clearance was between 11.6 and 24.0 l/hr/m². The total body clearance appeared to decrease with higher plasma concentrations. The mean steady-state volume of distribution was between 198 and 688 l/m², indicating extensive extravascular distribution and/or tissue binding. Dose increases associated with the 3-hour infusion resulted in non-linear pharmacokinetics. When the dose increased by 30% from 135 mg/m² to 175 mg/m², the maximum plasma concentration (C_max) increased max by 75% and the area under the plasma concentration time curve (AUC_0-∞) by 81%. The variation of systemic paclitaxel exposure in the same patient was found to be minimal. No signs of cumulative effects were found for paclitaxel in association with multiple treatment courses.
Distribution: In vitro studies of serum protein binding indicate that 89-98% of paclitaxel is bound to proteins. Cimetidine, ranitidine, dexamethasone or diphenhydramine were not found to affect the protein binding of paclitaxel.
Biotransformation and elimination: The distribution and metabolism of paclitaxel in humans has not been fully investigated. The cumulative excretion of unchanged paclitaxel in the urine has been between 1.3% and 12.6% of the dose on average, which is an indication of extensive non-renal clearance. Hepatic metabolism and biliary clearance are possibly the principal mechanisms for elimination of paclitaxel. Paclitaxel is primarily metabolised by the action of CYP450 enzyme. An average of 26% of the radioactively marked dose of paclitaxel was eliminated in the faeces as a 6α-hydroxypaclitaxel, 2% as 3'p-dihydroxypaclitaxel and 6% as 6α-3'p-dihydroxypaclitaxel. 6α-hydroxypaclitaxel is formed by the effect of CYP2C8, 3'p-hydroxypaclitaxel by CYP3A4 and 6α-3'p-dihydroxypaclitaxel by CYP2C8 and CYP3A4. The effect of renal or hepatic impairment on the elimination of paclitaxel after 3-hour infusions has not been studied. The pharmacokinetic parameters of a patient on haemodialysis were of values similar to those of non-dialysis patients when the administration rate was 135 mg/m² of paclitaxel as a 3-hour infusion.
For use of paclitaxel in combination with other therapies, consult the Summary of Product Characteristics of cisplatin, doxorubicin or trastuzumab for information on the use of these medicinal products.
Toxicology: Preclinical Safety Data: Not applicable.