PHARMACOLOGY 



effect of a drug on isolated systems has been studied in an attempt to 

 explain the physiological action of the compound. In some of these 

 investigations attention has not been directed toward certain factors 

 which, in the opinion of the authors, are of importance. It is suggested 

 that, among others, the following criteria should be considered before 

 the physiological action of a drug is attributed to an effect on an isolated 

 enzyme system. 



(1) The concentrations of the drug or poison which produce the 

 effect in vitro and which obtain at the anatomical site of action should be closely 

 similar. 



(2) If a drug or poison exerts its effect primarily on a specific tissue 

 in vivo, either the effect on this tissue in vitro should be more pronounced than 

 the effects on other tissues, or the system inhibited must be shown to have more 

 functional significance in this than in other tissues. 



(3) Among structurally related compounds there should be close 

 parallelism between the pharmacological activities in vitro and in vivo: all drugs 

 of the same chemical series which are active in vivo must also be active in vitro, 

 and those inactive in vivo must also be inactive in vitro, unless the discrepancy 

 can be accounted for by poor absorption, by inadequate distribution to or 

 penetration of the cells involved, by too rapid excretion, or by metabolic 

 alteration. 



These criteria may be of value in avoiding premature explanations of 

 the physiological action of drugs on the basis of effects exerted on 

 isolated systems. 



Until very recently, the search for new chemotherapeutic agents 

 has progressed along almost exclusively empirical lines. Such an 

 approach, though tedious, has, nevertheless, yielded many drugs of 

 importance, and will undoubtedly continue to do so in the future. 

 Recently, however, largely on the basis of the theory of the mode of 

 action of sulfonamides, concepts have been developed that promise 

 to be of value in the development of compounds of utility in chemo- 

 therapy and in the study of intermediary metabolism. 



According to these concepts, which are reviewed in detail else- 

 where (19,37,38), interference with biological processes may result 

 from the use of compounds structurally related to, but not utilizable 

 in place of, substances essential for life or reproduction (essential 

 metabolites). Interference of this type can be explained most simply 

 on the basis of a direct competition between the essential metabolite 



407 



\\ 



