P-glycoprotein Drug Discovery


The development of Multidrug Resistance (MDR) is a major obstacle to the long-term success of cancer treatment. Pglycoprotein (Pgp) is a well-known membrane transporter with the ability to deliver drug molecules from cancer cells, reducing the effectiveness of chemotherapy. Cancer cells regulate Pgp expression as an adaptive response to avoid chemotherapymediated cell death. Excretion transporters such as pglycoprotein play an important role in drug transport in many organs. In the intestine, p-glycoprotein sends the drug back into the lumen, reducing absorption. The use of chemotherapy to treat cancer is limited by the development of resistant cancer cell variants. Tolerance can usually occur against individual cytotoxic drugs, usually through changes in the targets of those drugs, but more generally to many different drugs with different chemical structures and various mechanisms of action. This latter form of resistance is called Multidrug Resistance. MDR seems to be the main reason for the failure of cancer chemotherapy, as several different classes of chemotherapeutic agents are used to treat most types of cancer. Many different MDR mechanisms have been elucidated, including changes in cell cycle, failed apoptosis mechanisms, repair of damaged cell targets, and reduced drug accumulation. There are basically two mechanisms of drug uptake. For water-soluble hydrophilic drugs such as cisplatin, nucleoside analogs, and folic acid antagonists, the drug cannot cross the plasma membrane unless it returns back on an existing transporter/carrier or penetrates through the hydrophilic channels of the membrane. Resistance to such drugs due to reduced accumulation occurs because of individual mutations in the carrier that confer resistance to a single drug. For hydrophobic drugs such as the natural products vinblastine, vincristine, doxorubicin, daunorubicin, actinomycin D, etoposide, teniposide, and paclitaxel, invasion occurs by diffusion across the progenitor membrane without a specific drug carrier. The only way to keep such drugs out of cells is by activation of energy dependent transport systems. P-glycoprotein is also important for the blood-brain barrier as a defense against toxins and drugs that enter the central nervous system. P-glycoprotein plays a modest role in drug clearance. It is expressed in the luminal membrane of the proximal tubular cells of the kidney. P-glycoprotein delivers the drug into the urine. Pglycoprotein is an important mediator of drug interactions. The pharmacokinetics of a drug can change when co-administered with a compound that inhibits or induces p-glycoprotein Substrate of p-glycoprotein can be further divided into drugs that are not metabolized in humans such as digoxin and drugs that are substrates of both P-glycoprotein and drug-metabolizing enzymes. Some common pharmacological inhibitors of pglycoprotein include amyodaron, clarithromycin, cyclosporin, corhitin, diltiazem, erythromycin, felodipine, ketoconazole, lansoprazole, omeprazole and other proton pump inhibitors, nifedipine, paroxetine, reselpin, sakinavir, sertralin, quinidine. The Journal of Bioequivalence & Bioavailability (JBB) is an academic journal that encompasses a wide range of current research on FDA Bioequivalence, Bioequivalence antipsychotics, Bioequivalence anticancers, Bioequivalence antidiuretics, Bioequivalence antipsychotics, BA/BE Studies, Biosimilars, Advances in Bioavailability and offers a promising platform for the authors to make their valuable contributions towards the journal. Visit: https://www.walshmedicalmedia.com/bioequivalence-bioavailability.html Submit Manuscript at: https://www.walshmedicalmedia.com/submissions/bioequivalence-bioavailability.html Instructions for Authors: https://www.walshmedicalmedia.com/bioequivalence-bioavailability/instructionsforauthors.html Journal Archive: https://www.walshmedicalmedia.com/bioequivalence-bioavailability/archive.html