TISSUE DISTRIBUTION 779 



the activity being high within 30 min after intravenous injection (Fig. 6-9). 

 The distribution in the tissues would then reflect a combination of both 

 forms. Excretion of the arsenicals is mainly in the pentavalent forms. 

 Injection of phenylarsen oxide or phenylarsonate into rabbits leads to 

 urinary excretion of the latter (Crawford and Levvy, 1947), and administra- 

 tion of arsenite to man results in 70 80% excretion as arsenate (Mealey 

 et al., 1959). These excretion values, however, do not accurately reflect 

 the situation immediately after injection of the valence state of an arsenical 

 in the blood or tissues. 



Some very interesting work comparing the tissue binding and the excre- 

 tion of various arsenicals was reported by Hogan and Eagle (1944), and 

 it was shown that these factors to some extent determine the toxicity. 

 The compounds most readily bound and the least readily excreted are those 

 with high toxicity (see tabulation on page 724). Equimolar amounts of the 

 arsenicals were injected and the amounts bound or excreted were deter- 

 mined after 48 hr. It is probable that the differences observed here are 

 partly due to the differential permeabilities of the tissues to these compounds 

 The distribution of carbarsone oxide is somewhat different from that of 

 oxophenarsine (Anderson et al., 1947), particularly with respect to tissues 

 such as liver and muscle, and similar variations with the substituent 

 groups may be observed in other studies, indicating perhaps that uptake 

 rather than binding is the critical process. 



Differences between Species 



One of the most striking differences was reported by Hunter and Kip 

 (1941), who injected radioarsenite into animals for several days and de- 

 termined the tissue activity. In rats a large amount is always found in the 

 blood, whereas in guinea pigs, rabbits, and man very little occurs in the 

 blood. Another marked difference is that in the rat there is more in the 

 spleen than in the liver or kidneys, whereas in other species the reverse 

 is true (part of this may be due to contamination of the rat spleen by blood). 

 Differences have also been observed with carbarsone oxide: the liver and 

 kidney of rats do not contain particularly high levels, whereas in rabbits 

 the kidney has the greatest amount, and the liver is not far behind (Anderson 

 et al., 1947). The tissue distribution may be secondarily affected by the 

 degree of binding in the blood by proteins or cells; i. e., the more bound 

 in the blood, the less will be available for the other tissues. Some of these 

 species differences in distribution may account in part for the different 

 toxicity patterns observed. 



No studies comparing the various routes of administration have been 

 done under controlled conditions, but there is no doubt that the rate and 

 site at which a substance enters the blood stream are usually important 

 factors in determining the distribution in the body and the rate of excretion. 



