Cytochrome P450 Enzyme Interactions

The cytochrome P450 (CYP) enzymes are a family of haem-containing oxidising enzymes, concentrated in the liver and intestine, that metabolise the majority of clinically used drugs. A cytochrome P450 enzyme interaction occurs when one drug or substance inhibits or induces a CYP enzyme that another drug depends on for clearance, changing that drug's concentration and therefore its effect.

Definition

A cytochrome P450 enzyme interaction is a pharmacokinetic interaction in which a substance inhibits or induces a CYP isoform responsible for metabolising a co-administered drug, thereby raising (inhibition) or lowering (induction) that drug's concentration at its site of action.

Scope

The topic covers how CYP enzymes metabolise drugs, the concepts of substrate, inhibitor, and inducer, the major individual isoforms involved in drug metabolism (such as CYP3A4 and CYP2D6), and how inhibition and induction translate into changed drug exposure. It is the enzyme-level mechanism behind a large share of pharmacokinetic interactions, presented as reference material rather than as dosing or prescribing guidance.

Core questions

• Which CYP isoform metabolises the object drug?
• Is the precipitant an inhibitor or an inducer of that isoform?
• How quickly and how strongly does the resulting change in exposure develop?

Key concepts

• Substrate, inhibitor, and inducer
• CYP3A4 and intestinal first-pass metabolism
• CYP2D6 and genetic polymorphism
• Enzyme inhibition (competitive and mechanism-based)
• Enzyme induction (increased enzyme synthesis)
• Object drug concentration and clinical effect

Mechanisms

Most drug oxidation is carried out by a small number of CYP isoforms, with CYP3A4 handling a large fraction of marketed drugs and being abundant in both liver and intestinal wall. When a precipitant inhibits the isoform that clears an object drug, the object drug accumulates and its effect — including any toxicity — increases; competitive inhibition resolves as the inhibitor is cleared, whereas mechanism-based inhibition can persist until new enzyme is made. When a precipitant induces the isoform, the body synthesises more enzyme over days to weeks, lowering the object drug's concentration and potentially its efficacy (tanaka-1998). Substances need not be prescription drugs: St John's wort induces CYP3A4 (and P-glycoprotein), while grapefruit constituents inhibit intestinal CYP3A4 and raise the absorption of some oral drugs (durr-2000; bailey-2012).

Clinical relevance

Because CYP enzymes metabolise most drugs, CYP-mediated inhibition and induction account for many of the clinically important pharmacokinetic interactions encountered in practice, including those involving foods and herbal products that patients may overlook (tanaka-1998; bailey-2012; durr-2000). This entry describes the enzyme-level mechanism to support evidence appraisal and is not a source of dosing, monitoring, or prescribing decisions, which require current professional guidance and individual assessment.

Evidence & guidelines

Identifying which CYP isoforms metabolise a drug, and whether a candidate drug inhibits or induces those isoforms, is a standard component of drug development and regulatory interaction assessment, because it predicts where CYP-mediated interactions will occur (tanaka-1998). Specific clinical recommendations about particular substrate-inhibitor or substrate-inducer pairs belong to current guidelines and are outside this reference entry.

History

Cytochrome P450 was named for the characteristic 450-nanometre absorption peak of its carbon-monoxide-bound reduced form, observed in the late 1950s and early 1960s. Over subsequent decades the family was resolved into distinct isoforms with defined substrate specificities, and the recognition of CYP3A4 and CYP2D6 as dominant drug-metabolising enzymes turned CYP inhibition and induction into a central organising principle for understanding and predicting drug interactions (tanaka-1998).

Seminal works

• tanaka-1998
• bailey-2012
• durr-2000

Frequently asked questions

Why does grapefruit affect some medicines?

Grapefruit constituents inhibit cytochrome P450 3A4 in the intestinal wall, reducing the first-pass metabolism of certain oral drugs so that more of the drug reaches the bloodstream. This is a classic example of a food-mediated CYP enzyme interaction.

Does enzyme induction act as quickly as enzyme inhibition?

Generally no. Inhibition can change a drug's level relatively quickly, whereas induction works by increasing enzyme synthesis and typically develops, and reverses, over days to weeks.