Diffusion barriers, pumping cells

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. 

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

The endothelial cells actively, as well as passively, serve to protect the brain. Because they contain a variety of drug-metabolizing enzyme systems similar to the drug-metabolizing enzymes found in the liver, the endothelial cells can metabolize neurotransmitters and toxic chemicals and, therefore, form an enzymatic barrier to entry of these potentially harmful substances into the brain. They actively pump hydrophobic molecules that diffuse into endothelial cells back into the blood (especially xenobiotics) with P-glycoproteins, which act as transmembranous, ATP-dependent efflux pumps. Although lipophilic substances, water, oxygen, and carbon dioxide can readily cross the blood-brain barrier by passive diffusion, other molecules depend on specific transport systems. Differential transporters on the luminal and abluminal endothelial membranes can transport compounds into, as well as out of, the brain. 

If two such electrodes are separated by a thin layer of only zirconia, the application of a potential will lead to the pumping of oxygen from the cathode to the anode. This device can be used as an amperometric sensor for oxygen if a diffusion barrier restricts the flux of oxygen to the cathode. Note that similar devices are also often used as potentiometric sensors according to the Nernst equation (i.e., the lambda-probe in cars with catalytic converters). In this case one side of the cell has to act as a reference, e.g., by using ambient air. 

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. 

The lipid bilayer of natural membranes presents a complete barrier to the free diffusion of inorganic ions which, being strongly hydrated, lack lipophilicity. However, ionophores are usually on hand to facilitate this transport. There are two kinds of ionophore, the mobile and the stationary. The latter ( ion pumps ) consist of a water-filled channel spanning the bilayer. Much of what we know of ionophores has been learnt from the mobile type, derived from microbes (e.g. valinomycin, gramicidin). Such foreign ionophores, if effective, are toxic to mammalian cells except in low doses. 

---