Formation of Reactive Drug Metabolites as a Basis of Drug Action and Toxicity

Abstract

AbstractMost drugs are converted by diverse reactions to various metabolites before they are eliminated from the body. Many of these metabolites cause pharmacologic or toxicologic effects, some of which may differ from those of the parent drug. Some metabolites are chemically inert and, therefore, exert their effects by combining reversibly with specific receptor sites in target organs. But some drug metabolites are chemically reactive and exert their effects by combining covalently with various macromolecules in tissues. The formation of chemically reactive metabolites is important because they frequently cause a number of different toxicities, including tumorogenesis, mutagenesis, tissue necrosis, and hypersensitivity reactions. For example, my colleagues have discovered that the liver necrosis caused by halogenated benzene derivatives, paracetamol, furosemide, and isoniazid is mediated by chemically reactive metabolites of these substances. In assessing the effects of various treatments that alter drug metabolism on the magnitude of covalent binding, we have found it useful to think of the incidence of toxicity as the product of several ratios, i.e., Incidence = Dose AB …. MP. When the foreign compound is converted directly to a chemically reactive metabolite, (A) is the proportion of the dose that is converted to the reactive metabolite, (B) is the proportion of the reactive metabolite that becomes covalently bound, (M) is the proportion of the covalently bound metabolite that combines with “target macromolecules”, and (P) is the probability that a given amount of covalently bound metabolite attached to target macromolecule will result in toxicity. With this concept it becomes evident that the magnitude of covalent binding depends on the rate of formation of the reactive metabolite, on the rate at which the parent drug is eliminated from the body by other processes, on the rate at which the reactive metabolite is covalently bound, and on the rate at which it is inactivated by other processes.