778 6. ARSENICALS 



by the trypanosomes, resulting in a shifting of the equilibrium. Evidently 

 these different derivatives depend for their activity on factors other than 

 pH and penetration, and it would be valuable to have data on the pH 

 dependency of the arsenical inhibition of trypanosomal respiration or 

 pyruvate oxidation to determine how much this contributes to the devia- 

 tions from the expected behavior. It should be pointed out that it is not 

 known to what extent the internal pH changes w^ith the external pH. In 

 any event, these results emphasize the major importance of penetration 

 in this group of arsenicals, 



TISSUE DISTRIBUTION 



The distribution of arsenicals between the tissues of animals in certainly 

 of significance in determining the toxicity pattern. A selection of results is 

 given in Table 6-18 wherein the distributions of arsenicals can be compared 

 in several ways.* The four major factors which influence distribution are: 

 (1) the arsenical used, (2) the species, (3) the route of administratioji, and 

 (4) the time after administration. The figures in the table thus represent 

 cross sections, as it were, of individual instances and are not indicative of 

 the generalized picture of distribution. We shall discuss these four points 

 briefly before proceeding to the mechanisms involved and the relations 

 between distribution and action. 



Dependence of Distribution on the Arsenical 



Even a cursory glance at the table will make it clear that marked differ- 

 ences between the arsenicals exist. A particularly good comparison may 

 be made between phenylarsenoxide, phenylarsonate, and oxophenarsine 

 in rabbits since all were used and determined in the same way. Even oxo- 

 phenarsine and phenylarsenoxide differ significantly, particularly in such 

 tissues as the lungs and heart, and there are further differences between 

 the oxidized and reduced forms, although this latter is obscured somewhat 

 by the oxidation and reduction which may occur in the tissues (i. e., the 

 distribution pattern of phenylarsonate may be altered by a fairly large 

 fraction of it being reduced soon after administration). The studies of 

 Murgatroyd et al. (1934) comparing the trypanocidal levels in serum after 

 injections of tryparsamide and tryparsamide oxide suggest that reduction 

 must occur before activity appears, and that this occurs quite rapidly, 



* Radioactive arsenic has been known since 1938 and has been incorporated as 

 As'* (half-Hfe = 19 days) or As'^ (half-Hfe = 26.4 hr) into various compounds in 

 order to trace the fates of these substances in the body. Such isotopes have been very 

 valuable for this work, but it is clear that the activity as determined is not necessarily 

 in the form of the administered arsenical. 



