METABOLISM OF THE ARSENICALS 787 



Crawford (1947) pointed out that, although it has been assumed that 

 pentavalent arsenicals must be reduced to the trivalent forms before being 

 active, the evidence is all indirect and no one had demonstrated the pre- 

 sence of the oxidized or reduced products of the organic arsenicals in tissues, 

 and no data had been obtained on whether inorganic arsenic can arise from 

 organic arsenicals in the body. Methods for the improved analysis of the 

 various forms were thus developed (page 607). Eabbits were then injected 

 with both valence forms and the excretion pattern determined (see accom- 

 panying tabulation) (Crawford and Levvy, 1947). Thus in whichever form 



Arsenical Dose (mg As/kg) % Excreted % as 99-AsO % as 99-AsO(OH)2 



it is injected, the major form excreted is the pentavalent. Furthermore, 

 despite the small amount of phenylarsenoxide formed when phenylarsonate 

 is given, it is enough to account for the parasiticidal action. In the case 

 of phenylarsenoxide the rate of oxidation to phenylarsonate determines 

 the rate of excretion and the toxicity of the compound, so that here we 

 have another important factor in addition to the permeability differences. 

 It may be noted that no arsenite or arsenate was found to be formed from 

 either of these compounds. 



Chemical Alteration of the Arsenicals 



Although arsenic is retained in the blood for some time following the 

 intravenous injection of oxophenarsine to rats, the duration of the trypa- 

 nocidal activity is much shorter (Peters and Wright, 1951). There is a pro- 

 gressive divergence between the arsenic content and the trypanocidal 

 activity after 4 hr, the latter decreasing so that it is very low after 12 hr, 

 whereas the arsenic levels actually rise secondarily after the first day. 

 This loss of trypanocidal activity is more rapid than can be accounted for 

 by transfer of the arsenical from the plasma to the erythrocytes. The tryp- 

 anocidal activity also disapjiears when oxophenarsine is incubated with 

 blood in vitro, but at a slower rate than in vivo. These data suggest a fairly 

 rapid inactivation of oxophenarsine in the rat and that the principal site 

 is extra vascular. Little is known about the metabolic fate of oxophenarsine 

 or the other organic arsenicals in the tissues. 



One of the most interesting aspects of the metabolism of the arsenicals 

 is their methylation by certain molds to form volatile and toxic compounds. 



