DRUG INTERACTIONS—PART III
ENZYME induction is defined as an increase in the specific activity of enzymes which metabolize foreign substances (e.g., drugs, chemicals, and insecticides) and certain endogenous compounds (e.g., steroids and fatty acids). In practice, activity, rather than actual enzyme protein mass relative to structural cellular components, is usually determined. Most of the drug-metabolizing (microsomal) enzymes are in the liver; however, lesser activity is found in the skin, placenta, kidney, lung, etc., and induction in these organs has been demonstrated. In 1956 Conney et al.1 observed that chronic administration of 3-methylcholanthrene (3-MC) caused an increase in its own rate of metabolism, thereby decreasing its carcinogenic potential. Remmer and Merker2 found that the tolerance of animals to chronic barbiturate administration was partly due to an increased rate of metabolic inactivation, and that hypertrophy of the smooth endoplasmic reticulum of hepatocytes resulted from such treatment. Subsequent investigations have shown that more than 200 drugs and chemicals cause enzyme induction in animals3 and several of these are known to be active in man. Inducers are of three types: small organic molecules, e.g., phenobarbital; chlorinated hydrocarbons, e.g., DDT; and polycydic hydrocarbons, e.g., the environmental polycyclic carcinogens 3-MC and 3,4 benzpyrene. Many clinical reports indicate that important modifications of a drug's effectiveness and safety may arise through induction during continued administration, or through concurrent administration of other drugs. These modifications are: (1) a decrease in effectiveness from acceleration of the rate of inactivation and excretion, (2) an increase in effectiveness from an increase in the rate of biotransformation to an active metabolite, or (3) either of these arising from the action of a previously or concurrently administered inducing drug.