PERMEABILITY FACTOR IN DRUG ACTION 71 



In chemical terms these specifications can be met in 

 the following ways. A dithiol grouping in the molecule 

 will provide for point i . Increasing the polarity of the 

 compound will comply with point 2 by reducing the 

 rate of penetration into cells: to increase the polarity 

 it is necessary to increase the number of OH, COOH or 

 SO3H groups in the molecule. Point 3 can be met by 

 having a relatively high concentration of the dithiol in the 

 blood stream: intracellular arsenic is not completely 

 incapable of diffusing out of cells, and if there is a high 

 concentration of external dithiol, every arsenic molecule 

 which diffuses out of a cell will be trapped by the dithiol. 

 To meet requirement 4 it is necessary that the molecule 

 should not be very large: for example, thiostarch or thio- 

 glycogen are excluded by this condition. The last re- 

 quirement, ready excretion, is achieved by the same 

 means as requirement 2. 



Thus the specification of the molecule appeared as fol- 

 lows: 



C.SH 2 COOH i 



I + 3 OH > as alternatives 



C.SH or I SO3H ) 



With a Specification as precise as this it was not necessary 

 to investigate many compounds. In fact, only two di- 

 thiols were studied, dithioadipic acid and the glucoside 

 of B.A.L. The glucoside of b.a.l. was the better, having an 

 L.D.50 of the order of 7.5 g/kg. When administered to 

 rabbits which had received an L.D.95 of lewisite, the 



