400 



8. INHIBITOR DISTRIBUTION IN LIVING ORGANISMS 



or inhibitor in the plasma to follow the dosage linearly, due to the binding 

 of the substance by the plasma proteins or the erythrocytes. Inhibitors 

 may be bound to different cell components with varying affinities; at low 

 doses, relatively more will be taken up, but as the high-affinity binding 

 sites disappear, the uptake will fall off as the dose rises. It is conceivable 

 that in the case of acetazolamide above, a tissue with a relatively large 

 amount of carbonic anhydrase, such as brain, would bind a large frac- 

 tion from a small dose, but when the enzyme molecules have become satu- 

 rated with inhibitor, any further increase in concentration would be due 

 to nonspecific binding or merely the inhibitor in solution. 



Vascularity or Blood Supply of the Tissues 



The initial distribution of an injected inhibitor will often depend pri- 

 marily on the blood flow through the various organs. The concentration 

 of the inhibitor in the tissue is related, not to the total blood supply, but 

 to the flow volume per unit weight per unit time. In Table 8-3 the blood 

 flow in human tissues is given in milliliters/ 100 gm of tissue/minute and 

 these values are more pertinent than the total flow in milliliters per minute. 

 However, the total amount of inhibitor in tlie various organs is related to 

 the total flow. To what degree this initial distribution will determine even- 

 tual distribution will depend for one thing on the affinity of the inhibitor 

 for the tissues. An inhibitor with little affinity will rapidly become equili- 

 brated throughout the body and the final distribution may bear little re- 

 lationship to the relative blood flows, whereas an inhibitor reacting rapidly 

 and strongly with the tissue components, as would arsenicals or DFP, will 

 tend to remain fixed in the initial pattern. 



The fractionation of the cardiac output between several organs has been 

 determined in the rat by intravenous injections of K^- and analysis of the 

 tissues for radioactivity during the first few minutes (Sapirstein, 1956). 

 Immediately following injection the clearance of K^- from the blood is 

 essentially complete and during the first minute the tissue concentrations 

 remain constant, following which the K^^ may leave a tissue and redistri- 

 bution occur. The average results for the first minute in terms of the per 

 cent of total cardiac output are given in the tabulation. 



