Saturable Transport

The hallmark of non-saturable passage is that the percent of material orossing into the CNS is not affected by the amount of material available for transport. The tw o main mechanisms of non-satiu able passage are transmembrane diffusion and the extracellular pathw ays. The former is much better studied and its principles are wddely applied by industry for the development of CNS drugs the latter has received much less attention. 

There seems to be no absolute molecular w eight cut-off for transmembrane diffusion. A previous study, w hich had thought to define such an absolute limit had discovered, in retrospect, early evidence for an efflux system (Levin, 1980). The largest substance to date noted to have a measurable uptake by brain 

The amount of a substance that can enter the brain by the exdacellular pathw ays is small. However, this route may be therapeutically relevant for compounds that have favorable peripheral pharmacokinetics, such as a long serum half-life and a small volume of distribution (Banks, 2004). Therapeutic antibodies and erythropoietin can access the brain by v ay of the extracellular pathways (Banks et al., 2004a Banks et al., 2002 Banks et al., 2005a Kozlowski et al., 1992) and this may underlie their therapeutic benefits (Alafaci et al., 2000 Ehrenreich et al., 2002 Erbyraktar et al., 2003 Morgan et al., 2000 Janus et al., 2000 DeMattos et al., 2002 Farr et al., 2003 Hock et al., 2003). 

Saturable processes represent a diverse group of mechanisms. Included in this group for puiposes of discussion are two processes, which share some characteristics with the saturable systems cUapedesis and adsoipfive endocytosis/transcytosis. 

Most known saturable transporters at the BBB are facilitated diffusion systems (Davson and Segal, 1996c). For example, GLUT-1, the transporter for glucose, is a facilitated diffusion transporter. If the level of glucose is artificially raised above that of serum (or if radioactive glucose is introduced into the CNS, but not the serum), efflux of glucose can be shown. 

The concept of the neurovascular unit (NVU) emphasizes the interactive role that cells and events within the CNS and in the circulation play on BBB permeability, as well as the role that 

Satnrableandnon-satnrable modes predominate influx. Within each of these categories are a diverse nnmber of mechanisms. These different mechanisms tend to favor certain groups or types of substances. 

Capillary Wall (luminal abluminal cell membranes and cytoplasm) 100-150 nm thick 

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Pardridge, W.M., and Connor, J.D. Saturable transport of amphetamines across the blood-brain barrier. Experientia 29 302-304, 1973. 

BH Stewart, AR Kugler, PR Thompson, NN Bock-brader. A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharmaceut Res 10 276-281, 1993. 

Lee, K. and D. R. Thakker. Saturable transport of H2-antagonists ranitidine and famotidine across Caco-2 cell monolayers, J. Pharm. Sci. 1999, 88, 680-687... 

Vmaxiinjlux or efflux) = Maximal velocity of the saturable transporter Km(injiux or efflux) = Michaelis constant for the saturable transporter Q = Concentration of drug inside the lumen of the intestine CSnt(i) = Concentration of drug inside the enterocyte in compartment i... 

Presence of active (saturable) transport mechanisms places a limit on the amount of a chemical that may be absorbed. 

Table 3.1 Saturable transport in the rat colon of selected compounds which...

On the other hand, when the membrane is saturated, transport still occurs. This transport must be due to a hydraulic-pressure gradient because oversaturated activities are nonphysical. In addition, Buechi and Scherer found that only a hydraulic model can explain the experimentally observed sharp drying front in the membrane. Overall, both types of macroscopic models describe part of the transport that is occurring, but the correct model is some kind of superposition between them. - The two types of models are seen as operating fully at the limits of water concentration and must somehow be averaged between those limits. As mentioned, the hydraulic-diffusive models try to do this, but from a nonphysical and inconsistent standpoint that ignores Schroeder s paradox and its effects on the transport properties. 

Non-ruminants possess several intestinal Na+-dependent saturable transport systems. These include the well-known sodium-glucose co-transporter (SGLT1), responsible for the active uptake of glucose, and it appears to be specific for cinnamic and ferulic acid and possibly for other hydroxy-cinammic acids [112]. 

When a saturable transporter is involved in the permeation process, the permeability is no longer a constant value but is dependent on the concentration of the substrate. In that case it is necessary to characterize the parameters of the carrier-mediated process, Km, the Michaelis-Menten constant related with the affinity by the substrate and Vmax, the maximal velocity of transport. If a passive diffusion process occurs simultaneously to the active transport pathway then it is necessary to evaluate the contribution of each transport mechanism. An example of how to characterize the parameters in two experimental systems and how to correlate them are described in the next section. 

To date, TL-2 is the only cytokine known to be transported from the brain to the blood by a saturable transporter (Banks... 

The endothelial cell is an anatomical location of barrier function and of the various saturable transporters (Figure 4.1). Capillary beds from peripheral tissues have numerous intracellular and intercellular pores and fenestrations and high rates of pinocytosis that account for their leakiness. The brain endothelial cell engages in comparatively little pinocytosis, has few intracellular pores or fenestrations, and intercellular pores or gaps are eliminated because of tight junctions. 

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