DISTRIBUTION OF INHIBITORS IN ANIMALS 403 



form at physiological pH's, often has very little or no effect on the metabo- 

 lism or function of intact tissues at concentrations capable of almost com- 

 plete inhibition of succinic dehydrogenase and blocking of the tricarboxylic 

 acid cycle. Of course, the various tissues may differ appreciably in their 

 permeabilities to inhibitors, and it is this that may be a factor in the 

 distribution of inhibitors in the body. Unfortunately very few adequate 

 studies have been made on the permeabilities of different cells to the impor- 

 tant enzyme inhibitors. There is general opinion that certain inhibitors 

 penetrate into cells rapidly (cyanide, carbon monoxide, dimercaprol, DFP, 

 bipyridine, dinitrophenol), some moderately well (fluoroacetate, idoacetate, 

 fluoride, arsenite), and some poorly [malonate, parapyruvate, ethylene- 

 diaminetetraacetate (EDTA)], but quantitative data are lacking and our 

 knowledge of differences between tissues or cells is meager. Permeability, 

 in isolated instances, has been shown to be a primary factor in inhibition. 

 The actions of organic arsenicals on protozoa depend on the degree of pen- 

 etration and the development of resistance to the arsenicals often involves 

 a limitation on the uptake of the inhibitor. The problems of permeability 

 will be discussed wherever possible when the individual inhibitors are 

 treated in later chapters. The effects of pH on penetrability into cells will 

 be discussed in Chapter 14. 



The kidney requires special consideration because the tubular cells are 

 not only in contact with arterial blood but also with the progressively 

 changing glomerular filtrate. Unless the inhibitor is resorbed as rapidly 

 as water, its concentration will rise in the tubular fluid; at the maximum 

 it is possible for the concentration to rise approximately a hundred-fold 

 over the plasma value. The urinary concentration of many drugs and inhi- 

 bitors is constantly higher than the level in plasma. Thus one side of the 

 tubular cell, especially in the distal segment, may be exposed to higher 

 concentrations of inhibitor than any other tissue. In addition to this, the 

 large amount of fluid continually passing through the tubular cells may carry 

 with it the inhibitor, so that even though the concentration in the tubular 

 fluid does not rise, the cells will be presented with much more inhibitor 

 than are other cells. An inhibitor that is picked up readily by the cells will be 

 accumulated there. Many inhibitors, such as the mercurials, exert their 

 actions primarily on the kidney and their concentration there is undoubt- 

 edly the important factor, rather than any special sensibility of the renal 

 cells. 



There has been much discussion of penetration into the central nervous 

 system and the slow rates of entry often observed have given rise to the 

 concept of the blood-brain barrier, which is supposed to exist at or near 

 the vascular wall. Since the brain has an excellent vascular supply, this 

 hypothetical barrier must be very impermeable to certain substances to 

 limit their entry into the brain cells; it must also be very specific, since many 



