404 8. INHIBITOR DISTEIBUTION IN LIVING ORGANISMS 



compounds enter and affect the brain very rapidly. It is probable that some 

 phenomena attributed to the blood-brain barrier are the result of other fac- 

 tors. For example, the brain is a tissue with a relatively small extracellular 

 free fluid space and the nerve cells possess membranes specialized for the 

 control of ionic movements and the conduction of impulses. These mem- 

 branes exhibit somewhat unique permeability properties. Furthermore, the 

 myelin sheaths can also impede the movement of small molecules, particu- 

 larly when they are charged. This combination of circumstances makes it 

 difficult for some substances to enter the brain cells in appreciable concentra- 

 tion and no special barrier need be assumed. There is. of course, a "barrier" 

 of living cells between the blood and the cerebrospinal fluid, so that charged 

 drugs and inhibitors usually enter this space slowly. 



Chemical Composition of the Tissues 



Tissues vary in their lipid contents (Table 8-3). When equilibrium of the 

 inhibitor in the body has been reached, a lipid-soluble inhibitor will be found 

 in relatively high concentrations in the lipid-rich organs. However, this 

 probably has little bearing on the inhibition of enzymes, since the enzymes 

 are not located in the lipid material. Much of the lipid analyzed in tissues 

 is extracellular and if pure cells could be worked with, it would be likely 

 that little difference in lipid content would be observed. Of course, there are 

 cells that contain many fat droplets but these are spatially separated from 

 the enzymically active regions. The distribution coefficient of an inhibitor 

 between lipid and water may be of importance in determining the total 

 amount of inhibitor in a tissue but is probably of little significance in enzyme 

 inhibition. As mentioned previously, the water content of a tissue (Table 

 8-3) may be a factor in the tissue concentration of an inhibitor if the inhibitor 

 is tightly bound to proteins or other cell components. Some tissues possess 

 50% more solids than other tissues and an increased concentration of the 

 inhibitor in the former may relate to this rather than to any more specific 

 mechanism of uptake. However, the water content is of no importance in 

 enzyme inhibition. 



Binding of the Inhibitor to Plasma Proteins 



Many inhibitors, just as drugs, are probably bound to plasma i)roteins 

 with varying degrees of affinity. This effectively reduces the concentration 

 of the free inhibitor in the blood and thus slows down penetration into the 

 tissues and delays excretion. Such binding will not alter the distribution 

 of the inhibitor among the tissues to a large extent because only the availa- 

 ble concentration is reduced. But it may alter the initial distribution in 

 favor of an equilibrium distribution, just as slow absorption into the blood 

 stream does. Protein binding may also be a factor in deviating the relation 

 between the tissue concentration and the dose from linearity. 



