Drug Actions and Interactions: Theoretical Considerations

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During the past several years, it has become increasingly evident that the pharmacologic and toxicologic actions of drugs may be frequently altered by treatments that change the rates at which drugs are metabolized and eliminated. Such changes in the rates of drug metabolism can be important in the clinic because they can markedly alter the steady-state plasma levels of drugs in patients and thereby alter the intensity of the therapeutic or toxicologic responses of drugs. In addition, however, pharmacologists have utilized changes in drug metabolism to determine whether the pharmacologic responses evoked by a drug are mediated by the drug itself or by its metabolites. In these experiments, it has been frequently assumed that when the intensity of the duration or the response is increased by inhibitors of cytochrome P-450 enzymes in liver or shortened by inducers of these enzymes, the response must be mediated solely by the parent compound. Conversely, when the intensity or the duration of the response is decreased by inhibitors or increased by inducers of these enzymes, the response is assumed to be mediated by an active metabolite. Studies during the past several years have revealed, however, that changes in the activity of the enzymes involved in drug metabolism do not always result in alterations of the biologic half-lives or of the pharmacologic actions of drugs to the extent predicted by in vitro experiments.