Mechanisms of CYP450 Inhibition: Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice

Abstract

In an ageing society, polypharmacy has become a major public health and economic issue. Overuse of medications, especially in patients with chronic diseases, carries major health risks. One common consequence of polypharmacy is the increased emergence of adverse drug events, mainly from drug-drug interactions. The majority of currently available drugs are metabolized by CYP450 enzymes. Interactions due to shared CYP450-mediated metabolic pathways for two or more drugs are frequent, especially through reversible or irreversible CYP450 inhibition. The magnitude of these interactions depends on several factors, including varying affinity and concentration of substrates, time delay between the administration of the drugs, and mechanisms of CYP450 inhibition. Various types of CYP450 inhibition (competitive, non-competitive, mechanism-based) have been observed clinically, and interactions of these types require a distinct clinical management strategy. This review focuses on mechanism-based inhibition, which occurs when a substrate forms a reactive intermediate, creating a stable enzyme-intermediate complex that irreversibly reduces enzyme activity. This type of inhibition can cause interactions with drugs such as omeprazole, paroxetine, macrolide antibiotics, or mirabegron. A good understanding of mechanism-based inhibition and proper clinical management is needed by clinicians when such drugs are prescribed. It is important to recognize mechanism-based inhibition since it cannot be prevented by separating the time of administration of the interacting drugs. Here, we provide a comprehensive overview of the different types of mechanism-based inhibition, along with illustrative examples of how mechanism-based inhibition might affect prescribing and clinical behaviors.

Keywords: competitive inhibition; cytochromes P450; drug–drug interactions; inhibitor; mechanism-based inhibition; non-competitive inhibition; substrate.

Figure 1

Illustration of an enzyme with its active binding site for drug transformation and allosteric binding site (or regulatory site).

Figure 2

Illustration of reversible competitive inhibition where ligand A (orange) is a substrate with strong affinity and ligand B (yellow) is a substrate with a weaker affinity for a specific enzyme (purple). As long as the concentrations of the two substrates are comparable, the stronger affinity substrate with higher binding affinity will be preferred at the active site of the enzyme resulting in an accumulation of ligand B.

Figure 3

CYP450 metabolic pathways involved in the metabolism of duloxetine and theophylline and their respective affinities are depicted. Competitive inhibition between duloxetine and theophylline will be expected at CYP1A2. Duloxetine acts as the perpetrator drug over theophylline, the victim drug.

Figure 4

Illustration of reversible competitive inhibition where ligand A (orange) is a substrate with strong affinity and ligand B (yellow) is a substrate with weaker affinity for a specific enzyme (purple). When the concentrations of the weaker affinity substrate are sufficiently high, it can outcompete the stronger affinity substrate for the active site of the enzyme.

Figure 5

Illustration of reversible non-competitive inhibition. An inhibitor (red) binds to an allosteric site on the enzyme and causes conformational changes that prevent a substrate (orange) from binding to the active site. Over time, as the inhibitor is flushed out, the conformation of the enzyme can return to normal and substrate (orange) can bind to the active site again.

Figure 6

Illustration of mechanism-based inhibition. The mechanism-based inhibitor (orange) binds to the active site as a substrate. During the normal process of metabolism, it forms either stable intermediate–enzyme complexes or reactive electrophilic species that can lock up or destroy the enzyme, and new enzyme synthesis is required to restore the enzymatic activity.

Figure 7

CYP450 metabolic pathways involved in the metabolism of clopidogrel and omeprazole, and their respective affinities are depicted. Competitive inhibition will be expected at CYP3A4 and mechanism-based inhibition at the CYP2C19 enzymatic level. Clopidogrel is the victim drug and omeprazole acts as the perpetrator drug.

Figure 8

CYP450 metabolic pathways involved in the metabolism of nortriptyline and paroxetine and their respective affinities for the isoform are depicted. Mechanism-based inhibition at CYP2D6 enzymatic level will be expected. Nortriptyline is the victim drug and paroxetine acts as the perpetrator drug for the CYP2D6 elimination pathway.

Figure 9

CYP450 metabolic pathways involved in the metabolism of erythromycin and midazolam and their respective affinities for the isoform are depicted. Mechanism-based inhibition at the CYP3A4 enzymatic level will be expected. Midazolam is the victim drug and erythromycin acts as the perpetrator drug.

Figure 10

CYP450 metabolic pathways involved in the metabolism of desipramine, duloxetine, metoprolol, mirabegron, and their respective affinities for the isoform are depicted. Competitive inhibition will be expected at CYP2D6 between duloxetine (perpetrator; CYP2D6 substrate with higher affinity) and either desipramine or metoprolol (victim drugs; both CYP2D6 substrates with weaker affinity). Mechanism-based inhibition at CYP2D6 will be expected between mirabegron and desipramine, metoprolol, or duloxetine.

Figure 11

List of commonly prescribed medications producing mechanism-based inhibition.