Efflux barrier

Eletriptan is metabolized mainly by the CYP3A4 isoenzymes and is subject to activity of the P-gp efflux barrier in the brain. 

The Efflux Barrier Transport Proteins at the Blood-Brain Barrier... 

The study of active transport mechanisms has grown substantially in recent years, with transport proteins such as P-gp, BCRP, and MRP-2 among the most studied [59]. Several types of in vitro assays to assess substrates of transporters have been established these include assays directed toward intestinal and biliary efflux [60]. Assays that measure passive and active transport are also used to assess penetration of the blood-brain barrier. In addition to the assays described above, transfected cell lines that overexpress transporters present in the blood-brain barrier are also employed [61]. 

In microbes without a permeability barrier, or when the barrier fails, a mechanism must be in place to export metals from the cytoplasm. These active transport systems involve energy-dependent, membrane-bound efflux pumps that can be encoded by either chromosomal- or plasmid-borne genes. Active transport is the most well-studied metal resistance mechanism. Some of these include the ars operon for exporting arsenic from E. coli, the cad system for exporting cadmium from Staphylococcus aureus, and the cop operon for removing excess copper from Enterococcus hiraeP i9A0... 

Burton PS, JT Goodwin, RA Conradi, NFH Ho, AR Hilgers. (1997). In vitro permeability of peptidomimetic drugs—The role of polarized efflux pathways as additional barriers to absorption. Adv Drug Delivery Rev 23 143-156. 

Culture protocols have been published which describes an accelerated differentiation process where monolayers are ready to be used after 3-7 days of culture [90-92]. One of these systems, the so-called BD BioCoat Intestinal Epithelium Differentiation Environment, is commercially available through BD Bioscience. This system is described to produce monolayers of a quality that are comparable with the typical Caco-2 cells with respect to permeability for drugs transported transcellularly. The paracellular barrier function is however low, as indicated by high mannitol permeability and low TER. The functional capacity for active uptake and efflux is not as thoroughly characterized as for the standard Caco-2 mono-layers. 

Smith, B. J., Doran, A. C., Mclean, S., Tingley III, F. D., O Neil, C. A., Kajiji, S. M., P-glycoprotein efflux at the blood-brain barrier mediates differences in brain disposition and pharmacodynamics between two structurally related neurokinin-1 receptor antagonists, J. Pharmacol. Exp. Ther. 2001, 298, 1252-1259. 

From the above, it is clear that the gut wall represents more than just a physical barrier to oral drug absorption. In addition to the requirement to permeate the membrane of the enterocyte, the drug must avoid metabolism by the enzymes present in the gut wall cell as well as counter-absorptive efflux by transport proteins in the gut wall cell membrane. Metabolic enzymes expressed by the enterocyte include the cytochrome P450, glucuronyltransferases, sulfotransferases and esterases. The levels of expression of these enzymes in the small intestine can approach that of the liver. The most well-studied efflux transporter expressed by the enterocyte is P-gp. 

D. J., Roffey, S. J., Jezequel, S. G., Abbott, N. J., The effect of drug lipophilicity on P-glycoprotein-mediated colchicine efflux at the blood-brain barrier, Int. J. Clin. Pharmacol. Ther. 1998, 36, 84-86. 

Cholesterol transport and regulation in the central nervous system is distinct from that of peripheral tissues. Blood-borne cholesterol is excluded from the CNS by the blood-brain barrier. Neurons express a form of cytochrome P-450, 46A, that oxidizes cholesterol to 24(S)-hydroxycholesterol [11] and may oxidize it further to 24,25 and 24,27-dihydroxy products [12]. In other tissues hydroxylation of the alkyl side chain of cholesterol at C22 or C27 is known to produce products that diffuse out of cells into the plasma circulation. Although the rate of cholesterol turnover in mature brain is relatively low, 24-hydroxylation may be a principal efflux path to the liver because it is not further oxidized in the CNS [10]. 

The distribution of Li+ in vivo is primarily due to the relative rates of entry and efflux of the cation in the different tissues. The uptake of Li+ from the blood is relatively rapid into the kidney and is slower into the liver, bone, and muscle. The movement of Li+ both into and out of the brain is very slow compared to other organs and this is thought to be due to the low permeability of the blood-brain barrier for this cation [50]. 

In order for allelochemicals to enter the body of a herbivore, absorption must occur across the gut lining. Curtailing the initial absorption of dietary allelochemicals may be a herbivore s first line of defense against plant toxins. Studies have citied the lack of absorption or metabolism of lipophilic plant secondary metabolites (i.e., terpenes), conducive to phase I or II detoxification, in the gut of terrestrial herbivores rather these compounds are excreted unchanged in the feces (Marsh et al. 2006b). While physical barriers or surfactants have been used to explain this limited adsorption in both marine and terrestrial herbivores (Lehane 1997 Barbehenn and Martin 1998 Barbehenn 2001 for review of marine herbivores, see Targett and Arnold 2001), active efflux of plant allelochemicals out of enterocytes into the gut lumen has received limited attention until now. 

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. 

Keywords Inner blood-retinal barrier Transporter Influx transport Efflux transport Microdialysis Cell line Drug delivery... 

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