DIFFERENCES IN THE METABOLISM OF DRUGS DEPENDING UPON THEIR ROUTES OF ADMINISTRATION *

Drugs are administered by many different routes. The most common of these is the gastrointestinal tract, but parenteral administration, such as subcutaneous, intramuscular, or intravenous injection, is also frequently employed. Drugs are also administered locally by application to the skin or inhalation into the bronchial tree to achieve a high local concentration in a diseased tissue. It is well established that drugs given parenterally may have a different effect from the same substance given by mouth. This is especially true of drugs that have an immediate pharmacological action on the brain or heart and are given by bolus intravenous injection. Such an injection causes a very high initial concentration in organs with a high blood flow. For example, a small intravenous bolus of sodium thiopentone will cause anesthesia for a brief period. The drug enters the brain in a high concentration during the first circulation and is later redistributed into tissues with a larger capacity but a lower blood flow, and the patient wakes up. Some drugs are so poorly and unpredictably absorbed when given by mouth that it is necessary to inject them to achieve a reliable therapeutic effect. For example, the quaternary ammonium ganglion-blocking drugs, such as pentolinium, or the adrenergic neurone blocking drug bretylium, are highly ionized at physiological pH and are poorly lipid-soluble. The proportion absorbed when the drug is given by mouth ranges between 5 and 15%. If the same agent is given by injection, the whole dose exerts a pharmacological effect. Less attention has been paid to the possibility that substantial differences in drug action might arise because the drug is differently metabolized when given by different routes. We have had the opportunity to study the pharmacological effect and metabolism in man of two drugs, propranolol and isoproterenol, with which there are important differences in metabolism when administered by different routes.