Characteristics and common properties of inhibitors, inducers, and activators of CYP enzymes.

The modification of the enzymatic activity of the cytochrome P450 (CYP) enzymes by inhibition, induction, or activation is of great interest to enzymologists, pharmacologists, and chemists who are interested in mechanisms relating to these three effectors of enzyme activity. When the activity of a CYP is modified in vivo in humans, these effects are a major concern for clinicians and patients due to the potential for these alterations to greatly change the metabolism of the drug substrate(s) for that enzyme and thereby alter the biological activity of the drug leading to the potential for harmful drug–drug interactions. The inhibition and induction of the CYP enzymes are probably the most common causes for most drug interactions that have been documented in the literature (1). The inhibition of the metabolism of one drug, as a result of competition between two different drugs for metabolism by the same CYP, may result in unexpected elevations in the plasma concentrations of one or both drugs that can ultimately result in a variety of minor as well as serious adverse effects. These types of interactions have led to very serious adverse events including fatalities and ultimately have resulted in several prominent drugs being withdrawn from the market (2,3). The onset of inhibition is usually rapid following a single administration of the inhibitory compound. However, as will be discussed later, some types of inhibition are not manifested rapidly. On the other hand, enzyme induction, which results in an increase in the total amount of an enzyme with a concomitant increase in its drug metabolizing ability, may attenuate the pharmacological effect of a drug as a result of increasing the metabolism and subsequent elimination leading to marked decreases in plasma concentrations.