Paclitaxel Paclitaxel was originally isolated from the bark of the Pacific yew tree, Taxus brevifolia. Its

chemical structure was determined in 1971, and its mechanism of action was elucidated in 1979 (33). Paclitaxel is an anti-microtubule agent that irreversibly binds specifically to the subunit of the protein tubulin and promotes the assembly of microtubules. The stabilization of microtubules though prevents normal mitotic spindle formation and Inhibitors,research,lifescience,medical function. This disruption of normal spindle function, which is the primary mechanism of action of paclitaxel (34),(35) ultimately results in chromosome breakage and inhibition of cell replication and migration. Therefore, paclitaxel inhibits cell replication by blocking cells in the late G2 and/or M phases of the cell cycle(35). Another important mechanism of action of paclitaxel includes induction of apoptosis via binding to and subsequently blocking the function of the apoptosis inhibitor-protein, bcl-2. Inhibitors,research,lifescience,medical Pharmacokinetics studies with paclitaxel have demonstrated that its distribution is a biphasic process, with values for α and β half-lives

of approximately 20 minutes and 6 hours, respectively (33). True nonlinear pharmacokinetics may have important clinical implications, particularly in regards to dose modification, because a small increase in drug exposure and hence toxicity (33). More than 90% of the time, paclitaxel Inhibitors,research,lifescience,medical binds to plasma proteins. Approximately 71% of an administered dose of paclitaxel is excreted in the stool via Inhibitors,research,lifescience,medical the enterohepatic circulation (33). Renal clearance is minimal, accounting for 14% of the administered dose(33). In humans, paclitaxel is metabolized by cytochrome P-450 (CP-450) mixed-function oxidases. Specifically, either isoenzymes CYP2C8 and CYP3A4 of CP-450 will metabolize paclitaxel to hydroxylated 3′ phydroxypaclitaxel Inhibitors,research,lifescience,medical (minor) and 6α-hydroxyplacitaxel (major), as well as to other forms of dihydroxylated metabolites. Paclitaxel

is typically administered intravenously at a dose of 135-175 mg/m2 every 21 days (33),(36). Docetaxel While paclitaxel is a natural product, docetaxel is a semi-synthetic product. Docetaxel inhibits microtubule disassembly and promotes microtubule stabilization, leading to disruption of microtubule-mediated cellular function during cell division, cell cycle arrest at G2/M transition, and cell death (37). Like paclitaxel, docetaxel induces the activation of several molecular pathways GSK-3 leading to cellular apoptosis by disorganizing the microtubule structure (38). However, another proposed mechanism of action of docetaxel is related to its effect on phospholipase-D (PLD) (38). PLD has been implicated in several physiological processes, such as membrane trafficking, cytoskeletal reorganization, cell proliferation, differentiation, survival, and apoptosis (38). Pharmacokinetics studies with docetaxel have demonstrated a linear pharmacokinetic behavior with a 3-compartment model.