394 8. INHIBITOR DISTRIBUTION IN LIVING ORGANISMS 



DISTRIBUTION OF INHIBITORS IN ANIMALS 



The relative concentrations of inhibitor in the various tissues depend 

 on several factors but before discussing these it is necessary to present 

 some examples of inhibitor distribution to establish clearly the fact of 

 differential patterns of concentration. The many recent studies of drug 

 distribution in the body have demonstrated (1) that drugs are essentially 

 never homogeneously partitioned between the body tissues and (2) that 

 marked differences in distribution are observed for drugs of different types. 

 These two basic findings undoubtedly aj^ply equally to inhibitors. One 

 must always anticipate, in the absence of experimental data, that an 

 inhibitor will be selectively picked up by certain tissues and rejected by 

 others. It will also be clear that prediction of the distribution of an in- 

 hibitor must be highy speculative since the behavior of the substance in 

 the body depends strongly on the physical and chemical characteristics 

 of the molecule. We know virtually nothing of the distributions of the 

 most commonly used inhibitors and for examples in this chapter it will 

 be necessary to refer to results on drugs whose mechanism of action is 

 likely to be enzyme inhibition. Table 8-1 shows the distribution of certain 

 arbitrarily chosen substances in various animals in both absolute amounts 

 and relative to the concentrations in plasma. Unfortunately, all the inhi- 

 bitors for which adequate data are available are those reacting with or 

 bound tightly to tissue, and thus the results on these should not be 

 taken to represent inhibitors in general. The purpose in presenting this 

 table is to illustrate the marked differences in concentrations in the various 

 tissues for any one inhibitor and between the inhibitors for any one tissue; 

 species variation is demonstrated in the results with Paludrine. 



The methods of expressing tissue inhibitor concentration call for some 

 comment at this point. In Table 8-1 all data are given in terms of wet 

 weight of tissue and one may very well question the significance of the ratios 

 to the concentration in plasma (which is about 8.7% solids compared to 

 18-25% solids in most tissues). Especially in the case of inhibitors which 

 react with or are bound to i^roteins, the expression of concentrations in 

 terms of dry weight may well be preferable, since insignificant amounts of 

 the inhibitors would be present in the fluid component. In this case the 

 ratios would be roughly one-tenth those shown in the table. The units of 

 concentration chosen should depend on the type of inhibitor and the use to 

 which the values are put. Ideally, one would often wish to know the actual 

 concentration of inhibitor acting on the cellular enzymes during the devel- 

 opment of inhibition. The closest approximation to this might be analyses 

 made soon after application of the inhibitor and the expression of the results 

 in terms of intracellular water. The data in Table 8-1 show differential 

 uptake but actually are not particularly pertinent to the subject of enzyme 

 inhibition for at least two reasons. In the first place, over-all tissue con- 



