P-glycoprotein drug efflux pump

P Saha, J Yang, VHL Lee. (1998). Existence of a p-glycoprotein drug efflux pump in cultured rabbit conjunctival epithelial cells. Invest Opthalmol Vis Sci 39 1221-1226. 

Sirolimus is metabolized by CYP2A4 and is a substrate of the P-glycoprotein drug efflux pump drugs like voriconazole, itraconazole, fluconazole and erythromycin increase its blood concentration. Conversely, the inducers of CYP3A4 will decrease blood levels of sirolimus. Cyclosporine increases the bioavailability of sirolimus, possibly due to P-GP inhibition and competition for CYP3A4. The bioavailability is more than 30-40% when the two drugs are administered 4 h apart and is more than... 

Larotaxel (XRP-9881, RPR 109881A) 59 (Sanofi-Aventis) is undergoing Phase III trials in patients with advanced pancreatic cancer who had been previously treated with gemcitabine, as well as in combination with cisplatin to treat locally advanced/metastatic urothelial tract or bladder cancer.124 A Phase III trial for the treatment of advanced breast cancer has been completed. Larotaxel 59129>130 js a semi-synthetic derivative of 10-deacetyl baccatin III with a docetaxel-like side chain that has a low affinity for the P-glycoprotein drug efflux pump, an efflux mechanism that diminishes the effectiveness of the marketed drugs paclitaxel 60 and docetaxel. Importantly, this low affinity should enable larotaxel 59 to be effective in tumours resistant to paclitaxel 60... 

Fox E, Bates SE (2007) Tariquidar (XR9576) a P-glycoprotein drug efflux pump inhibitor. Expert Rev Anticancer Ther 7(4) 447 59... 

Tsuji A, Terasaki T, Takabatake Y, et al. P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells. Life Sci 1992 51 (18) 1427-1437. 

Consider two examples. First, in the brain capillary endothelium, luminal expression of the ATP-driven drug efflux pump, p-glycoprotein, provides a formidable barrier to drug penetration from blood to brain (Figure 15.2). This is best seen in... 

Y. Chen and S.M. Simon. 2000. In situ biochemical demonstration that P-glycoprotein is a drug efflux pump with broad specificity Cell Biol. 148 863-870. (PubMed)... 

Renal tubular dysfunction is described in animals but human expression in unclear [12]. Most use of mTOR inhibitors is in conjunction with lowered doses of calcineurin inhibitors since it is known that these two drug classes have a potent drug-drug interaction leading to enhanced renal dysfunction compared to the calcineurin inhibitor alone [782]. This may be explained by inhibition of drug efflux pump P-glycoprotein since both siroiimus and the calcineurin inhibitors are competitive substrates [783, 784]. 

P-glycoprotein (P-gp) is an ATP-dependent drug efflux pump. In humans, P-gp is encoded by the multi-drug resistance gene (MDR-1) that is located on the long arm of chromosome 7. Overexpression of P-gp in neoplastic cells is associated with the phenomenon of multidrug resistance to chemotherapeutic agents... 

Among all ABC transporters, P-gp, also known as MDRl protein, ABCBl or CD243, is probably the most studied and characterized member. It was first found as a 170-kDa ATP-dependent membrane glycoprotein that acts as a drug efflux pump [15], P-gp is a broad-spectrum transporter, capable of transporting several structurally and functionally unrelated substrate molecules. Its substrates are typically hydrophobic, amphipathic products, including many chemotherapeutic compounds used for cancer treatment, e.g., vinca alkaloids (vincristine, vinblastine), taxanes (paclitaxel, docetaxel), epipodophyllotoxins (etoposide, teniposide), anthracyclines (doxorubicin, daunorubicin, epirubicin), topotecan, dactinomycin, and mitomycin-C [37]. 

P-glycoprotein (P-gp), also known as ABCBl, or multi-drug resistance protein 1 (MDRl), is a multi-drug efflux pump (a protein that removes drugs and related compounds from cells) that can move a wide variety of compounds across cellular membranes. P-gp is concentrated in the excretory tissues (liver and kidney) and in barrier tissues (intestines, blood-brain barrier, placental barrier, blood-testes barrier,... 

Both influx and efflux transporters are located in intestinal epithelial cells and can either increase or decrease oral absorption. Influx transporters such as human peptide transporter 1 (hPEPTl), apical sodium bile acid transporter (ASBT), and nucleoside transporters actively transport drugs that mimic their native substrates across the epithelial cell, whereas efflux transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP) actively pump absorbed drugs back into the intestinal lumen. 

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