FATE OF INHIBITORS IN THE ANIMAL 413 



FATE OF INHIBITORS IN THE ANIMAL 



Following administration of an inhibitor, and either during or after its 

 distribution throughout the body, there is disappearance of the inhibitor. 

 This may take ])lace ])y a metabolic degradation or inactivation of the inhibi- 

 tor, or by excretion from the body, or by both. The curve representing the 

 variation in inhibitor concentration with time in a tissue will rise to a 

 maximal value, at a rate depending on the factors previously discussed, and 

 will then fall according to principles to be considered in this section. Some 

 inhibitors that are tightly bound to the tissues will remain in the body 

 for many days or weeks and it may be that the rate of removal from the 

 body is dependent on the rate of dissociation, rather than on processes of 

 destruction or excretion. 



Variation of Intracellular Inhibitor Concentration with Time: Sinnplified 



System 



The usual representation of tlie fate of a substance in the body is: 



I„-^I,^X (8-1) 



where I, is the inhibitor outside the region considered, I,, is the inhibitor 

 inside this region, and X is either a metabolic product or represents the 

 excretion of the inhibitor from this region. This system implies a one-way 

 passage of inhibitor into the region and its application would be limited 

 to certain cases where loss from the region by this route is negligible. 

 There are two situations to be considered: either (I^) remains constant or 

 it decreases as the inhibitor is taken up. The outside concentration of the 

 inhibitor may be considered practically constant over an interval when 

 the amount of uptake is negligible compared to the supply. Tissue slices 

 or cell suspensions in large volumes of medium or with relatively high con- 

 centrations of inhibitor might be examjiles. Also, constant intravenous in- 

 fusion can maintain the concentration in the plasma constant, the plasma in 

 this case being the outside phase relative to the tissue. Where (Ig) remains 

 constant, the differential equation: 



'^^^'^ = A-i(I„) - l;{l,) (8-2) 



(It 



may be directly integrated to give the internal inhibitor concentration at 

 any time: 



(I,) = do) , ^\ [1 - e-<'^i+^2"l (8-3) 



ki + A-2 



Equilibrium will be reached theoretically when (IJ = k-^ (Io)/(^i + ^^2) since 



