700 6. ARSENICALS 



in this case. The authors pointed out a factor which has been generally 

 neglected: the effect of pH on the polymerization of arsenious acid. Although 

 there is good evidence that polymerization occurs (page 602), there is 

 no general agreement about the states of arsenious acid in the physiological 

 pH range. Another factor of undoubted importance is the effect of pH on 

 the structure and permeability of the surrounding membranes. 



Organic Arsenicals 



The rates of penetration of the substituted phenylarsenoxides into cells 

 are dependent on the nature of the groups on the ring; indeed, in the case of 

 the trypanosomes, this is the determining factor. Observations such as those 

 on the accumulation of reduced tryparsamide by erythrocytes (Lourie 

 et al., 1935) are complicated by the binding of the arsenical to the mem- 

 brane and stroma, but it is likely that penetration here is fairly rapid, 

 half-uptake occurring in about 15 min, and that at least the initial uptake 

 is not due to tight binding because the arsenical can be readily washed out. 

 The penetration of phenylarsenoxide and p-aminophenylarsenoxide into 

 yeast follows first-order kinetics for a time, but secondary processes disturb 

 this simple relationship, the uptake becoming more and more irreversible 

 (Janke and Garzuly-Janke, 1936). Conformation to first-order kinetics, 

 of course, does not distinguish between adsorption, penetration, or chemical 

 reaction. Similar results have been obtained with trypanosomes (Hawking, 

 1937, 1938) and the initial fixation of the arsenicals was claimed to occur 

 within a few minutes. The very high cell/medium partition ratios (5000- 

 10,000 for phenylarsenoxide and reduced tryparsamide) point to binding 

 reactions as being more important than membrane penetration in deter- 

 mining the uptake kinetics. The effects of pH on the uptake of acidic 

 phenylarsenoxides by trypanosomes have been studied in detail by Eagle 

 (1945), but these results will be discussed in connection with the trypano- 

 cidal action (page 775); other investigations on pH effects, possibly relating 

 to penetration, will be mentioned at that time). Essentially nothing is 

 known about the rates of entrance of arsenicals into mammalian tissues, 

 but the rapid penetration of nonionic lewisite through the skin has been 

 demonstrated (Ferguson and Silver, 1947). The rate of movement through 

 such tissues may be limited by reaction of the arsenical with the tissue 

 proteins. It is probably safe to assume that the lipophilic alkyl and unsub- 

 stituted phenylarsenoxides pass rapidly through cell membranes, and 

 that accumulation relates to the binding and reaction within the cells. 

 The pentavalent phenylarsonates, being anionic within the physiological 

 pH range, presumably penetrate less readily. 



