402 8. INHIBITOR DISTRIBUTION IN LIVING ORGANISMS 



surface area of the capillaries. However, most inhibitors would not neces- 

 sarily follow this simple scheme because of the restriction in diffusion 

 brought about by the binding to plasma proteins and the possibly slow 

 penetration into the tissues. In this case, the capillary surface within a tissue 

 may be important, the rate of absorption being directly proportional to the 

 diffusion surface. If it is assumed that the capillaries are all of approxi- 

 mately the same diameter, the volume of blood flowing through a tissue in 

 unit time will be proportional to the number of capillaries and thus the 

 surface for diffusion. Hence, the rate of absori^tion of an inhibitor and 

 the tissue concentration will be proportional to the tissue blood flow. 

 The surface for diffusion, however, may also depend on the length of the 

 capillaries in a tissue; a tissue with cax)illaries twice as long as another 

 tissue might pick up twice as much of an inhibitor in unit time with a 

 comparable blood flow through each tissue. Finally, it must be remembered 

 that the inhibitor can alter the blood flow by a dilating or constricting ef- 

 fect on the blood vessels. 



The fractionation of the blood flow through the various tissues is by no 

 means constant but may be altered markedly by a number of factors. The 

 activity of a tissue is perhaps the most important variable. The blood flow 

 through skeletal muscles may increase as much as fifteen-fold during intense 

 activity and the coronary flow increase eight-fold upon stimulation of the 

 heart. The blood flow through the central nervous system also depends on 

 the state of functional activity. Anesthesia will alter blood flow by sev- 

 eral mechanisms, i)rincipally by elimination of the normal control of the 

 vascular tone. The skin vessels are particularly sensitive to nervous con- 

 trol and environmental temperature. A frightened animal will have a differ- 

 ent pattern of blood flow than a normal animal due to nervous factors and 

 the release of epinephrine. 



The role of vascularity in the distribution of isoniazid in the central 

 nervous system would appear to be of some importance, since there is a pro- 

 gressive decrease in vascularity from the cerebral cortex (2.22) to the glo- 

 bus pallidus (1.18) (See Table 8-2) (Barlow et al, 1957). However, the 

 hippocampus was unusual in that it showed a relatively high concentration 

 of the inhibitor and yet has a low vascularity: also it retained the isoniazid 

 for a longer time than the other tissues. 



Penetration of Inhibitors into Tissues 



An inhibitor may enter tissue cells either by simple diffusion or by an 

 active transport process. The latter is uncommon and mainly confined to the 

 analogs of actively transported substrates or metabolites. The permeability 

 properties of the plasma membrane are important in determining the de- 

 gree of inhibition in some cases but usually only affect the rate at which 

 inhibition develops. Malonate, occurring mainly in the doubly-charged ionic 



