Pathways

Paclitaxel is an antineoplastic drug used for the treatment of breast, lung and ovarian cancers and Kaposi’ sarcoma. It targets the microtubules in cancer cells. Microtubules are polymers of alpha and beta tubulin (the building block of microtubules) which form part of the skeleton and provide support and shape to cells. It is involved in many important cellular processes such as cellular transport and cell division. Paclitaxel is administered intravenously, and enters the cancer cell via solute carrier organic anion transporter family member 1B3. In the cytosol, it binds to beta-tubulin and is incorporated into the microtubule during microtubule polymerization. The paclitaxel-microtubule complex promotes stabilization of the microtubule structure preventing its disassembly. This prevents the dynamic function of microtubules by preventing their shortening and lengthening, therefore, the cell is unable to use its cytoskeleton in a flexible manner. This effect on the microtubules inhibit the cell cycle, specifically, phases G2 and M, and as a result, cell replication is prevented. This prevents growth and progression of cancer in patients. Side effects from taking paclitaxel may include bone marrow suppression, hypersensitivity reactions, alopecia, nausea and vomiting, peripheral neuropathy, myalgia, weakness, arthralgia, mucositis and diarrhea.

Paclitaxel is an anticancer agent isolated from the bark of the yew tree. It is classified as a microtubule-stabilizing agent and exerts cell killing effects by disrupting mitosis in dividing cells. Microtubules are made up of α- and β- tubulin heterodimers arranged head to tail and assembled to form a cylinder. Microtubules possess complex polymerization dynamics that are essential for movement of chromosomes and proper segregation of daughter cells during mitosis. Paclitaxel binds directly to the inner surface of β-subunits along the length of microtubules. Binding is thought to induce a conformational change in tubulin that increases its affinity for neighbouring molecules. At sufficiently high concentrations, paclitaxel can bind to β-tubulin in a one to one ratio and stimulate microtubule polymerization. At lower clinically relevant drug concentrations, paclitaxel stabilizes microtubules and prohibits further polymerization and depolymerization. Suppression of microtubule dynamics may prevent chromosomes from moving from the spindle poles to the metaphase plate slowing or preventing progression from metaphase to anaphase. Cells enter a state of mitotic arrest from which they may progress to one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur causing cell death. Paclitaxel is susceptible to cellular drug resistance caused by drug efflux via a number of multidrug resistance-associated proteins.

Metabolites of Paclitaxel are predicted with biotransformer.

Padeliporfin is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Padeliporfin passes through the liver and is then excreted from the body mainly through the kidney.

Pafolacianine is a folate analogue used for the treatment of ovarian cancer. It targets the folate receptor in cancer cells where they are overexpressed. Pafolacianine binds to the receptor and is absorbed via receptor-mediated endocytosis. It is an optical imaging drug that binds to the overexpressed folate receptors in cancer cells that allows the visualization of the tumors. The metabolism of pafolacianine is not known, with the knowledge cytochrome P450 enzymes do not metabolize the drug. It is administered intravenously and is eliminated through the urine and feces.