Drug-efflux pump

Mdr-1 Drug-efflux pump Reduction in resistance to chemotherapeutic drugs... 

Except for its narrow specificity, the ATRI gene product shares a number of properties with the higher eukaryotic MDR proteins responsible for multidrug resistance in tumour cells. The MDR gene products are also transmembrane proteins which seem to function as ATP-dependent drug-efflux pumps pumping out a variety of structurally unrelated compounds (see [25,26]). 

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. 

Chen, Y., Simon, S. M., In situ biochemical demonstration that P-glyco-protein is a drug efflux pump with broad specificity, J. Cell Biol. 2000,... 

Bronger, H., Konig, J., Kopplow, K., Steiner, H.H., Ahmadi, R., Herold-Mende, C., Keppler, D. and Nies, A.T. (2005) ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood-tumor barrier. Cancer Research, 65, 11419-11428. 

Zaman, G.J., Flens, M.J., van Leusden, M.R., de Haas, M., Mulder, H.S., Lankelma, J., Pinedo, H.M., Scheper, R. J., Baas, F. and Broxterman, H.J., (1994) The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proceedings of the National Academy of Sciences of the United States of America, 91, 8822-8826. 

Fardel, O. et al. (2001) Regulation of biliary drug efflux pump expression by hormones and xenobiotics. Toxicology, 167 (1). 37-46. 

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... 

Higgins, M. K., Bokma, E., Koronakis, E., Hughes, C., and Koronakis, V. (2004). Structure of the periplasmic component of a bacterial drug efflux pump. Proc. Natl. Acad. Sci. 101, 9994-9999. 

Zaman, G.J., et al. 1994. The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proc Natl Acad Sci 91 8822. 

Cancers can become resistant to drugs through several different mechanisms. One common mechanism occurs when the cancer cell synthesizes a glycoprotein that acts as a drug efflux pump.15,74 The glycoprotein pump is inserted into the cancer cell s membrane and effectively expels different types of anticancer drugs from the cancer cell. Thus, cancer chemotherapeutic agents are ineffective because they are removed from the cell before they have a chance to exert cytotoxic effects. 

Bronger H, Konig J, Kopplow K, et al. ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood-tumor barrier. Cancer Res 2005 65 11419-11428. 

Kage K, Tsukahara S, Sugiyama T, et al. Dominant-negative inhibition of breast cancer resistance protein as drug efflux pump through the inhibition of S-S dependent homodimerization. Int J Cancer 2002 97 626-630. 

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. 

Werle M. (2008b) Natural and synthetic polymers as inhibitors of drug efflux pumps. Pharm Res, 25, (3), 500-11. 

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... 

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... 

A similar domino sequence in an intramolecular Diels-Alder version of the previous example provided access to pyrano benzo-[60] and naphtho-[61] quinones as shown in Scheme 25. Depending on substitution patterns of the aldehyde 111, para-(112 and 116) or ortho- H3 and 117) adducts or both were obtained. Typically high diastereoselectivity was observed. Libraries 114 and 115 were tested for their ability to reverse the multidrug resistance phenotype resulting from overexpression of drug efflux pumps. The compounds were evaluated in mammalian... 

MDRl is a member of a family of ATP-dependent drug efflux pumps (32). Several of these pumps, including MDRl, have been shown to mediate lipid translocation and phospholipid bilayers (33). This translocation activity has been implicated in part as the mechanism for dmg efflux by which the hydrophobic cytotoxic drug is translocated from the cytosolic to the external leaflet of the plasma membrane bilayer. MDRl first was shown to translocate glucosyl ceramide analogs from the cytosolic to the external leaflet of the plasma membrane (33). However, the major glucosyl ceramide translocation activity of MDRl later... 

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