DISTRIBUTION AND EFFECT OF INHIBITORS 425 



differ appreciably from that of the system assumed in this treatment. Ac- 

 tually, the time course of the concentration maxima is described quite 

 accurately by Eqs. 8-19 and 8-20, providing the costant k is evaluated proper- 

 ly. The determination of A: in any case is best done from a plot of the log 

 concentration (or log total amount in body or tissue) against time, since 

 in most cases an approximately straight line will be obtained. In the simple 

 case (Eq. 8-4), the slope will be — k, and in the more complex situation 

 of intracellular inhibitor (Eq. 8-9), the slope will be simply /? over most 

 of the range of falling concentration. It might also be pointed out in this 

 connection that the approximate values of ki and /bg may be found if the 

 behavior is similar to that in Fig. 8-4. The value of/? is determined as just 

 described and from the peak concentration reached (where ae"^ = ^e^^), 

 the value of a is obtained. Since the intercept on the In (I^) axis is k^ (Io)o/ 

 (/? — «), the value of k^ and hence A'g may be found. 



DISTRIBUTION AND EFFECT OF INHIBITORS 



Occasionally there may be a good correlation between the distribution 

 of an inhibitor in the tissues or cells of the body and the degree of inhi- 

 bition that is produced. However, when one is not determining the effective 

 concentration of inhibitor, a lack of correlation can be expected. It is 

 especially important to realize that the relative effects in the different 

 tissues need not correspond to differences in distribution. The rate of 

 accumulation of citrate following the aconitase block induced by the admin- 

 istration of fluoracetate is not necessarily proportional to the concentra- 

 tion of the inhibitor present in the tissue, but is perhaps more closely 

 related to the rate of cycle operation, that is the rate of citrate forma- 

 tion. Similarly, the degree to which an inhibitor affects the functioning 

 of the various tissues is even less likely to be related to the distribution 

 of the inhibitor for, as will be discussed in the following chapter, the 

 dependency of functional activity on metabolism varies markedly from 

 tissue to tissue. The distribution of an inhibitor throughout the body can 

 only be determined by direct analyses of the tissues and little reliance can 

 be placed on the differential effects on metabolism or function. Inasmuch as 

 the specific actions of certain inhibitors endow them with the possibility of 

 being useful either as experimental tools or in ,the treatment of disease, 

 it would seem that some quantitative studies of the correlation (or lack of 

 it) between distribution and inhibition would be quite valuable, not only 

 with single administrations but with repeated doses of the important inhi- 

 bitors. Such relationships will be discussed wherever possible in the chap- 

 ters on specific inhibitors but a deficiency will always be evident due to 

 the lack of comprehensive experimental data. 



