Passive diffusion blood-brain barrier

Eischer, H., Gottschlidi, R., Seelig, A. Blood-brain barrier permeation Molecular parameters governing passive diffusion, y. Membr. Biol. 1998, 165, 201-211. 

Computational models for blood-brain-barrier penetration have been well reviewed in detail by Clark [36]. Penetration of the blood-brain-barrier (BBB) via passive diffusion is dependent upon the hydrophilicity and lipophilicity of a molecule. However, the BBB is a thicker, more lipophilic membrane than the intestinal membrane. Kelder et al. [37] showed that very few of 776 orally administered CNS drugs had PSA >90, while a substantial fraction of 1590 orally administered non-CNS had PSA >90. These results demonstrate the poor BBB penetration by hydrophilic molecules. 

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. 

The other major class of transporter protein is the carrier protein. A prototypic example of a carrier protein is the large neutral amino acid transporter. An important function of the LNAA transporter is to transport molecules across the blood-brain barrier. As discussed previously, most compounds cross the BBB by passive diffusion. However, the brain requires certain compounds that are incapable of freely diffusing across the BBB phenylalanine and glucose are two major examples of such compounds. The LNAA serves to carry phenylalanine across the BBB and into the central nervous system. Carrier proteins, such as the LNAA transporter, can be exploited in drug design. For example, highly polar molecules will not diffuse across the BBB. However, if the pharmacophore of this polar molecule is covalently bonded to another molecule which is a substrate for the LNAA, then it is possible that the pharmacophore will be delivered across the BBB by hitching a ride on the transported molecule. 

The term blood-brain barrier (BBB) refers to the special obstacle that drugs encounter when trying to enter the brain from the circulatory system. The difference between the brain and other tissues and organs is that the capillaries in the brain do not have pores for the free flow of small molecules in the interstitial fluid of the brain. To enter the interstitial fluid, all molecules must cross a membrane. This design is a protective measure to defend the brain from unwanted and potentially hazardous xenobiotics. Traditionally, drugs that target the brain or central nervous system (CNS) cross the BBB by passive diffusion. Transport by carrier proteins across the BBB is becoming better understood but remains an area of active research. 

The particular way in which the walls of the blood vessels in the central nervous system are constructed results in their being impermeable to many substances, thereby limiting the ability of molecules to pass from the blood into the brain. This phenomenon is called the blood-brain barrier. Molecules may cross the blood-brain barrier by mechanisms of active transport, or by being sufficiently lipid soluble that they can diffuse through the hydrophobic core of the lipid membranes that form the boundaries of the cells composing the blood-brain barrier. Most psychoactive drugs are sufficiently lipid soluble that they can pass from the blood into the brain by passive diffusion. 

The existence of the blood-brain barrier does not preclude the passage of chemicals into the brain. As is the case with all other cellular membranes in the body, lipid-soluble nonionized chemicals enter the brain by passive diffusion. Anesthetics, ethanol, and CNS depressants, for instance, rapidly diffuse into the brain in a matter of a few seconds or minutes. They also exit the brain rapidly when the concentration gradient between blood and brain is reversed. Elemental mercury, methylmercury, and tetraethyl lead are examples of lipid-soluble forms of metals that easily enter the brain, while the ionized, much less lipid-soluble inorganic salts of mercury and lead penetrate only poorly. 

Ehrlich (1) and Goldman (2) were the hrst to observe the existence of the blood-brain barrier (BBB) after the inj ection of the hydrophilic compound trypan blue in a rat did not distribute into and out of the brain. It is now known that the cerebral capillary regulates the influx and efflux of biologically important molecules both by preventing passive hydrophilic diffusion and by providing transport processes whose activity can be regulated in accordance with the metabolic and homeostatic requirements of the brain. 

Figure 2 Schematic illustration of the (transport) properties of the blood-brain barrier. Shown is the influence of astrocyte endfeet at the brain capillary endothelial cell. This cell has narrow tight junctions, low pinocytotic activity, many mitochondria, and luminal anionic sites that hinder the transport of negatively charged compounds. Passive hydrophilic transport occurs via paracellular diffusion (tight junctions), whereas passive lipophilic transport is a transcytotic process. Adsorptive-, receptor-, and carrier-mediated transport has been indicated. The metabolic properties of the BBB are illustrated by the various enzymes at the BBB [from (157), with permission].

Figure 3.2. Potential mechanisms for drug movement across the blood-brain barrier. Routes of passage include passive diffusion through the brain capillary endothelial cells (A) utilization of inwardly directed (i.e. towards brain) transport or carrier systems expressed on brain capillary endothelial cells (B) utilization of outwardly directed (i.e. towards blood) efflux transport systems (C) or inclusion in various endocytic vesicular transport processes occurring within the brain capillary endothelial cells (D).

The predominant circulating form of vitamin Bg is pyridoxal phosphate. Absorbed pyridoxine is oxidized and phosphorylated in intestinal mucosal cells, liver, and erythrocytes. Pyridoxine enters hepatocytes and erythrocytes by passive diffusion and is mostly retained by phosphorylation. Pyridoxal phosphate is transported in the blood bound to albumin. The blood-brain barrier has limited permeability to pyridoxal. 

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