DISTRIBUTION AND METABOLISM 581 



distributed and metabolized quite differently. These differences, and in 

 most cases even the possibility of metabolic alteration of the quinones, 

 have been mostly ignored. The reports on the metabolism of the quinones 

 may not be uniform but there is much to indicate that most quinones are 

 not as stable as many investigators believe, and that this must be taken 

 into account particularly in experiments of long duration. 



Binding to Serum 



Since most quinones react readily with proteins, it is not surprising that 

 the presence of protein reduces the inhibitory activity. It has been reported 

 several times that protein-containing media diminish the growth-inhibiting 

 activity. It is obvious from such studies that the effective concentrations 

 reported must be considered with respect to the conditions under which 

 the experiments were done. The marked binding to human serum proteins 

 is a major factor in limiting the clinical effectiveness of many quinones. 

 We have noted that the inhibition of schistosomal glycolysis by menadione 

 is reduced by serum, approximately 5 times the concentration being required 

 in human serum relative to a salt medium (Bueding, 1950), and such bind- 

 ing of menadione not only must play an important role in any in vivo 

 anthelmintic effects, but will in general suppress all the pharmacological 

 actions of menadione. Many of the antimalarial naphthoquinones, which 

 are quite effective in treating animal infections, are valueless clinically be- 

 cause of the tight complexing with the serum proteins in man. This factor 

 also makes it very difficult to compare the effects of quinones on isolated 

 enzymes with the effects observed on living tissues, since even under the 

 simplest conditions of a protein-free medium, there is much so-called non- 

 metabolic protein with which the quinones may react. The thiols in sera 

 and experimental media likew^ise contribute to the reduction in effective 

 quinone concentration, and limit the distribution into cells and tissues. 



Permeability of Cells to Quinones and the Effects of pH 



Very little is known about the rates of penetration of the quinones 

 into cells and we have only indirect evidence. For example, succinate oxi- 

 dase extracted from heart muscle is quite sensitive to various naphthoqui- 

 nones but within heart slices it is resistant and inhibited only after prolonged 

 exposure (Ball et al., 1947). This was interpreted as indicating a permeability 

 factor, but actually the difference may be attributed to a variety of fac- 

 tors, such as protection of the enzyme intracellularly by substrate or thiols, 

 or different physical states of the enzyme. Some failures to find evidence 

 for penetration may be due to binding or reaction with extracellular sub- 

 stances. The low levels of menadione in the tissues following intramuscular 

 administration to mice (Solvonuk et al, 1952) may be related primarily 



