Pumping cells barriers

Fig. 3 Pumping cells with different diffusion barriers (a)...

Membranes are highly viscous, plastic structures. Plasma membranes form closed compartments around cellular protoplasm to separate one cell from another and thus permit cellular individuality. The plasma membrane has selective permeabilities and acts as a barrier, thereby maintaining differences in composition between the inside and outside of the cell. The selective permeabilities are provided mainly by channels and pumps for ions and substrates. The plasma membrane also exchanges material with the extracellular environment by exocytosis and endocytosis, and there are special areas of membrane strucmre—the gap junctions— through which adjacent cells exchange material. In addition, the plasma membrane plays key roles in cellcell interactions and in transmembrane signaling. 

Decreased cerebral blood flow, resulting from acute arterial occlusion, reduces oxygen and glucose delivery to brain tissue with subsequent lactic acid production, blood-brain barrier breakdown, inflammation, sodium and calcium pump dysfunction, glutamate release, intracellular calcium influx, free-radical generation, and finally membrane and nucleic acid breakdown and cell death. The degree of cerebral blood flow reduction following arterial occlusion is not uniform. Tissue at the... 

P-gp is expressed in tumor tissue and serves as a barrier to increased accumulation of cytotoxic anticancer drugs within the cancer cell by actively pumping the drug out of the cell. It is a multidrug resistance element by virtue of the fact that it is promiscuous in terms of substrate selectivity. It, like the cytochromes P450, will accept a wide diversity of structural types. For example, a small sampling of drugs that are substrates for P-gp... 

The Sartorius Absorption Model (26), which served as the forerunner to the BCS, simulates concomitant release from the dosage form in the GI tract and absorption of the drug through the lipid barrier. The most important features of Sartorius Absorption Model are the two reservoirs for holding different media at 37°C, a diffusion cell with an artificial lipid barrier of known surface area, and a connecting peristaltic pump which aids the transport of the solution or the media from the reservoir to the compartment of the diffusion cell. The set-up is shown in Figures 7a and b. 

Considering the spatial geometry of cerebral capillaries and capillary blood flow, a number of dynamic models of the blood-brain barrier have been developed, in which endothelial cells are cultured inside a permeable tube, the outer surface of which is coated with astrocytes. Supply of the cells with nutrients and artificial blood flow are maintained by using a peristaltic pump system [112, 113]. 

There are several efflux pumps which may affect absorption, blood-brain-barrier penetration, and reabsorption from kidney microtubules. The most commonly tested efflux pump in early drug discovery is the P-glycoprotein. Assays to identify P-glycoprotein substrates or inhibitors can be run using a variety of cell lines. 

Though drugs appear to cross the blood-brain barrier by passive diffusion, transporter systems in the blood-brain barrier pump drugs back out into the systemic circulation. As in the gut, the Pgp transporter system is the primary active transporter in the blood-brain barrier identified to date. This ATP-dependent transporter system picks up substrates that have crossed the capillary endothelial cells and transports them back to the systemic circulation, limiting their penetration into the CNS. Thus, not only are the physicochemical properties of the drug a determinant for penetration into the CNS but penetration also depends on whether the drug is a substrate for the Pgp transporter system. 

D) P glycoprotein serves to pump drugs back into the systemic circulation from endothelial cells lining the blood-brain barrier. 

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