Enzyme inducers and inhibitors: addition, subtraction and synergism

Abstract

Enzymes are biological catalysts that play a crucial role in metabolism. In some instances, their activity is induced or inhibited by other agents. Enzyme induction and inhibition are particularly important in hepatic cytochrome P450, which mediates most drug metabolism in humans. Drug breakdown is mainly dependent on seven different isoforms of cytochrome P450; the most important is CYP 3A4, which mediates most oxidation and reduction and is often involved in drug interactions. Several drugs selectively induce the activity of cytochrome P450 (including the barbiturates, phenytoin, carbamazepine and rifampicin). Enzyme induction usually increases glucuronyl transferase activity, and thus enhances drug conjugation; it may also decrease intracellular haem and enhance porphyrin synthesis. Drugs that inhibit cytochrome P450 may increase plasma concentrations of other concurrently used drugs, resulting in drug interactions. Many other enzyme systems are inhibited by drugs, and enzyme inhibition may be the main mechanism of drug action. When two or more drugs are used concurrently, one drug may affect the action of the other. Summation refers to the additive effects usually observed when two drugs with similar actions are used simultaneously. Thus, when different inhalational anaesthetics are administered together, their activities (expressed as MAC values) are additive. This phenomenon has been used to determine the MAC of nitrous oxide (104% v/v). Synergy occurs when combinations of similar drugs produce supra-additive effects; potentiation is a similar phenomenon observed when drugs have dissimilar actions. Subtraction (drug antagonism) occurs when the effects of one drug are reduced by another.