PATHWAYS OF DRUG METABOLISM * , †

THE action of a drug would probably last a lifetime if the body did not have ways of limiting its duration. In this lecture I shall discuss the nature of a number of these mechanisms. At one time the kidney was considered the most important organ in enabling the body to dispose of drugs. But it is becoming more and more evident that the kidney usually excretes only a small proportion of a drug in an unchanged form and the bulk as inactive derivatives. Of course there are notable exceptions: tolazoline, an adrenergic blocking agent, is excreted almost entirely unchanged ; a number of sulphonamides are only in part metabolised ; and a considerable fraction of penicillin is found unchanged in urine. But, by and large, the action of most drugs is terminated by their biotransformation. Although the biotransformation of a vast number of drugs in the whole organism has been studied, we have known very little, until recently, of the nature of enzymatic mechanisms concerned in these processes of “detoxication.” The fate of drugs in the body has interested our laboratory for a number of reasons. At one time we considered it possible that biotransformation mechanisms might explain how certain drugs exert their pharmacological action; that is, drugs in being metabolised might become enmeshed in mechanisms involved in the normal economy of the body and thus interfere with normal function. As we shall see later, this viewpoint is difficult to entertain since most drugs are not measurably metabolised in the organ where they act. Another reason for our interest in drug metabolism was the possibility that this might be a backdoor approach to general biochemistry, with the drug being used as a bait to induce unknown enzymes to disclose themselves. Finally, it is thought that a detailed knowledge of enzymes involved in drug “detoxication” might help the medicinal chemist to develop compounds of either high or low stability in the body, whichever would be more desirable in gaining a desired therapeutic result.