Abstract
Repeated administration of many drugs, especially central acting drugs, cause a development of tolerance to same or related drugs. The development of drug tolerance is an important problem for the evalution of drug actions and for the determination of a schedule of drug administration. However, the mechanism of development of drug tolerance is still in obscure. On the other hand, it is recently well demonstrated by several investigators that single or repeated administration of various drugs induces an increase in the activities of drug-metabolizing enzymes of liver microsomes (1-4). Thus, the actions of the same drugs or other drugs given successively are markedly decreased through the increased rates of drug metabolisms (2, 4, 5). It has been well known that most of the central acting drugs are the inducers of drug-metabolizing enzymes of liver microsomes (2, 4, 5). The purpose of present communication, therefore, is to analyse and differentiate the mechanism of the development of drug tolerance. The results of the present investigation showed that there are two kind of drug tolerances and the first one would be called as apparent tolerance and the second one would be called as real tolerance. The development of the first one is mainely due to the induction of drug-metabolizing enzymes of liver microsomes and the second one is mainely due to the decreased tissue sensitivity to the drug. A simple and effective method to differentiate the two kinds of drug tolerance is the joint injection of inhibitors of enzyme protein synthesis, such as ethionine, with the designed drugs.
