Hentaxel Mechanism of Action

Pharmacology: Docetaxel is an antineoplastic agent belonging to paclitaxel family. It acts by disrupting the microtubular network in cells. Such action is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin thereby resulting in the formation of stable microtubules and subsequently into microtubule bundles without normal function. This leads to the inhibition of mitosis in cells. Docetaxel's binding to microtubules does not alter the number of protofilaments in the bound microtubules, a characteristic not found in most spindle poisons currently in clinical use.
Pharmacokinetics: The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20-115 mg/m² in phase I studies. The area under the curve (AUC) was dose proportional following doses of 70-115 mg/m² with infusion times of 1-2 hrs. Docetaxel's pharmacokinetic profile is consistent with a 3-compartment pharmacokinetic model, with half-lives for the α, β and γ phases of 4 min, 36 min and 666 min, respectively. The initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part to a relatively slow efflux of docetaxel from the peripheral compartment. IV infusion of docetaxel at a dose of 100 mg/m² within 1 hr, mean peak concentration is 3.7 mcg/mL and AUC is 4.6 mcg/mL·hr. Mean values for total body clearance and steady-state volume of distribution were 21 L/hr/m² and 113 L, respectively. Docetaxel and its metabolites are eliminated in the urine and feces, 75 and 6%, respectively. Only little amount is excreted in original drug. In vitro studies showed that docetaxel is about 94-97% protein bound. Dexamethasone does not affect the protein binding of docetaxel. In vitro studies revealed that docetaxel is metabolized by the CYP3A4 isoenzyme and its metabolism is inhibited by CYP3A4 inhibitors.
Toxicology: Docetaxel for injection has been shown to be clastogenic in the in vitro chromosome aberration test in CHO-K₁ cells and in the in vivo micronucleus test in the mouse, but it did not induce mutagenicity in the Ames test or the CHO/HGPRT gene mutation assays.
Teratogenicity: Docetaxel for injection produces no impairment of fertility in rats when administered at the dose of 0.3 mg/kg (about 1/50 the recommended human dose on a mg/m² basis), but decreased testicular weights were reported. This correlates with the finding of 10-cycle toxicity study (dosing once every 21 days for 6 months) in rats and dogs in which testicular atrophy or degeneration was observed at doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3 and 1/15 the recommended dose on a mg/m² basis). An increased frequency of dosing in rats produced similar effects at lower dose levels.
Docetaxel for injection can cause fetal harm when administered to pregnant women. Studies in both rats and rabbits at doses ≥0.3 and 0.03 mg/kg/day, respectively (about 1/50 and 1/300 the daily maximum recommended human dose on an mg/m² basis), administered during the period of organogenesis, have shown that docetaxel for injection is embryotoxic and fetotoxic (characterized by intrauterine mortality, increased resorption, reduced fetal weight and fetal ossification delay). Previously mentioned dosages may cause maternal toxicity.