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

HISTORICAL BACKGROUNDThe modiﬁcation of the enzymatic activity of the cytochrome P450 (CYP)enzymes by inhibition, induction, or activation is of great interest toenzymologists, pharmacologists, and chemists who are interested in mechanismsrelating to these three effectors of enzyme activity. When the activity of a CYP ismodiﬁed in vivo in humans, these effects are a major concern for clinicians andpatients due to the potential for these alterations to greatly change the metabolismof the drug substrate(s) for that enzyme and thereby alter the biological activity ofthe drug leading to the potential for harmful drug–drug interactions. Theinhibition and induction of the CYP enzymes are probably the most commoncauses for most drug interactions that have been documented in the literature (1).The inhibition of the metabolism of one drug, as a result of competitionbetween two different drugs for metabolism by the same CYP, may result inunexpected elevations in the plasma concentrations of one or both drugs that canultimately result in a variety of minor as well as serious adverse effects. Thesetypes of interactions have led to very serious adverse events including fatalitiesand ultimately have resulted in several prominent drugs being withdrawn from themarket (2,3). The onset of inhibition is usually rapid following a singleadministration of the inhibitory compound. However, as will be discussed later,some types of inhibition are not manifested rapidly. On the other hand, enzymeinduction, which results in an increase in the total amount of an enzyme with aconcomitant increase in its drug metabolizing ability, may attenuate thepharmacological effect of a drug as a result of increasing the metabolism andsubsequent elimination leading to marked decreases in plasma concentrations.