CHAPTER 8 



DISTRIBUTION AND FATE OF INHIBITORS 

 IN LIVING ORGANISMS 



The subject of multienzyme systems leads logically to the problems 

 of inhibition within cells and whole animals. However, the action of an 

 inhibitor in a complex living system depends on the concentrations of 

 the inhibitor in the various regions in which the susceptible enzyme is 

 located. The present chapter, therefore, will discuss briefly the distribu- 

 tions of inhibitors within living organisms and the ultimate fate of these 

 inhibitors as they are chemically altered or excreted. When an inhibitor 

 is introduced into -a system of cells (whether a multicellular plant or ani- 

 mal, isolated organ, tissue slice, or cell suspension), the inhibitor concen- 

 tration in each type of cell and in each region within the cells rises and falls 

 with characteristic time variations that are best expressed by a family of 

 concentration-time curves. The individual curves may differ in several 

 respects: the rate of rise to the maximal concentration and the rate of loss 

 of the inhibitor, the maximal level reached, and the over-all configuration 

 of the curve. The primary aim will be to present some of the factors that 

 determine the nature of such curves. 



The most difficult correlations in the study of inhibition are those one 

 wishes to make between the primary action of an inhibitor on an enzyme 

 and the effects that are exerted on whole animals when the inhibitor is 

 introduced into the systemic circulation. One of the most important factors 

 is the distribution of the inhibitor and without knowledge of this an accu- 

 rate correlation between fundamental and final actions is impossible. It 

 must be admitted that this is one aspect of inhibition which has not been 

 intensively studied and unfortunately in most instances we lack quanti- 

 tative information on the behavior of inhibitors in organisms. Nevertheless, 

 an appreciation of the factors that are involved can be useful and may 

 eventually stimulate accurate experimental investigation. The importance 

 of this subject becomes greater each year as the possibility of using specific 

 inhibitors in disease becomes more evident. The specificity of action on 

 invasive or abnormal cells depends on the characteristic distribution of 

 the inhibitor as well as the specificity of the primary enzyme attack. 



393 



