Enzyme Induction and Inhibition

Enzyme induction and inhibition are the two main ways one substance can change how fast another drug is metabolised. Induction increases the amount or activity of a metabolizing enzyme, speeding clearance and often lowering drug levels, while inhibition blocks enzyme activity, slowing clearance and raising drug levels. Together they account for a large share of clinically important metabolic drug-drug interactions.

Definition

Enzyme induction is an increase in the expression or activity of a drug-metabolizing enzyme caused by a drug or other agent, whereas enzyme inhibition is a decrease in that enzyme's activity; both alter the metabolic clearance of co-administered drugs and underlie many metabolic drug-drug interactions.

Scope

This topic covers the mechanisms of enzyme induction (largely through nuclear-receptor-mediated gene transcription) and enzyme inhibition (competitive, mechanism-based, and other), their time courses, and how they produce drug-drug interactions. It is a reference description of mechanisms and does not provide prescribing or dose-adjustment instructions.

Core questions

• What molecular mechanisms cause a metabolizing enzyme to be induced or inhibited?
• How do the time courses of induction and inhibition differ?
• How do these processes give rise to clinically important drug-drug interactions?

Key concepts

• Enzyme induction (increased enzyme synthesis or activity)
• Enzyme inhibition (competitive and mechanism-based)
• Nuclear receptor regulation (pregnane X receptor, constitutive androstane receptor)
• Perpetrator and victim drugs
• Differing time courses of induction versus inhibition
• Metabolic drug-drug interactions

Mechanisms

Induction usually works through ligand-activated nuclear receptors: an inducing drug binds a receptor such as the pregnane X receptor, which then increases transcription of target genes including the CYP3A enzymes, raising enzyme levels over days as new protein accumulates (Goodwin et al., 2002). Inhibition acts more directly and often more rapidly: a drug may compete reversibly with another for the enzyme's active site, or it may form an inactivating complex in mechanism-based (irreversible) inhibition, reducing metabolic activity until the affected drug is removed or new enzyme is made (Wienkers & Heath, 2005). Because metabolic clearance sets steady-state drug concentrations, an inducer that speeds metabolism tends to lower the level of a co-administered "victim" drug, while an inhibitor tends to raise it (Wilkinson, 2005).

Clinical relevance

Induction and inhibition explain a large proportion of clinically significant drug-drug interactions and are a routine consideration when medicines are combined. This entry describes the mechanisms as reference material; decisions about specific drug combinations and dose changes are made by clinicians using current interaction resources and are outside its scope.

History

Enzyme induction by agents such as phenobarbital was observed in the mid-twentieth century, but its molecular basis became clear only with the discovery in the late 1990s of xenobiotic-sensing nuclear receptors - the pregnane X receptor and constitutive androstane receptor - that regulate CYP gene transcription (Goodwin et al., 2002). The systematic prediction and management of metabolic interactions from in vitro enzyme data developed alongside modern drug discovery (Wienkers & Heath, 2005).

Key figures

• Steven Kliewer
• Bryan Goodwin
• Larry Wienkers
• Grant Wilkinson

Seminal works

• goodwin-2002
• wienkers-heath-2005

Frequently asked questions

Why does enzyme induction take longer to develop than inhibition?

Induction usually requires the cell to make more enzyme protein through increased gene transcription, which builds up over days, whereas inhibition can occur as soon as the inhibiting drug reaches the enzyme.

What are perpetrator and victim drugs?

In a metabolic interaction, the perpetrator is the drug that induces or inhibits the enzyme, and the victim is the co-administered drug whose metabolism - and therefore blood level - is changed as a result.