Pharmacotherapeutic Group Anticancer agent from the taxane class of drugs.
Pharmacology: Pharmacodynamics Mechanism of action: Paclitaxel is an antimicrotubule antineoplastic agent. It promotes microtubule assembly by enhancing the polymerisation of tubulin, the protein subunit of spindle microtubules, even in the absence of the mediators normally required for microtubule assembly (e.g., guanosine triphosphate [GTP]), thereby inducing the formation of stable, non-functional microtubules. While the precise mechanism of action of the drug is not completely known, paclitaxel disrupts the dynamic equilibrium within the microtubule system and blocks cells in the late G2 phase and M phase of the cell cycle, inhibiting cell replication and impairing function of nervous tissue.
Clinical trials: No data available.
Pharmacokinetics: Distribution: After paclitaxel is administered intravenously, its plasma concentration declines biphasically.
The first phase shows rapid decline representing distribution of paclitaxel to the peripheral compartment and elimination. This initial phase is followed by a relatively slow elimination of paclitaxel from the peripheral compartment.
Mean steady state volume of distribution following single dose infusion of 135 and 175 mg/m2 has ranged from 198 to 688 L/m2, indicating extensive extravascular distribution and/or tissue binding.
The serum protein binding of paclitaxel is 89% following a 3-hour infusion of 175 mg/m2 paclitaxel.
Metabolism: The liver is thought to be the primary site of metabolism for paclitaxel.
Excretion: In patients treated with doses of 135 and 175 mg/m2 given as 3- and 24-hour infusions, mean terminal half-life has ranged from 3.0 to 52.7 hours and total body clearance has ranged from 11.6 to 24.0 L/hour/m2.
Following 3-hour infusions of 175 mg/m2, mean terminal half-life was estimated to be 9.9 hours; mean total body clearance was 12.4 L/hour/m2.
The mean cumulative urinary recovery of unchanged paclitaxel has been reported as 1.8 to 12.6% of the dose.
Toxicology: Preclinical safety data: Genotoxicity: In vitro studies (chromosome abnormalities in human lymphocytes) and in vivo (micronucleus test using mice) mammalian test systems have shown paclitaxel to be mutagenic. When testing using the Ames test or the CHO/HGPRT gene mutation assay, paclitaxel did not induce mutagenicity.
Carcinogenicity: No studies have examined the carcinogenic potential of paclitaxel, however, drugs similar to paclitaxel are carcinogens.