Many interactions are due to inhibition or induction of metabolising enzymes or drug transporters. Enzyme, transporter, and drug half-lives dictate duration.

Enzyme inhibition or induction interactions

Enzymes metabolise many drugs to active or inactive metabolites before excretion. Some of the most important are members of the cytochrome P450 family: CYP3A4, CYP2D6, CYP2C9, CYP1A2, CYP2C8, and CYP2C19.

Some enzymes can be inhibited (prevented from acting). This usually reduces conversion of the substrate to metabolites, so its levels rise. Inhibition is usually reversible but is sometimes irreversible.

Some enzymes can be induced (more of the enzyme is available, so there is more activity). Enzyme induction usually increases conversion of the substrate to metabolites, so its levels fall.


  • Inhibitors are drugs which can inhibit enzymes.
  • Inducers are drugs which can induce enzymes.
  • Substrates are drugs which are metabolised by the enzyme.

Reversible enzyme inhibition

Reversible inhibition is the most common form of enzyme inhibition. The inhibitor forms a temporary bond with the enzyme. While the inhibitor is bonded to the enzyme, the enzyme cannot interact with the substrate.
The interaction usually starts with the first dose of the inhibitor.

The interaction stops when the inhibitor is eliminated (five half-lives after the last dose).

For example, ketoconazole and itraconazole are reversible inhibitors of CYP3A4.

Irreversible enzyme inhibition

In irreversible inhibition (sometimes called “mechanism-based inhibition”), the inhibitor forms a long-lasting or permanent complex with the enzyme. The enzyme is then unusable for the rest of its lifespan.

The interaction can start with the first dose of the inhibitor or slightly later if the inhibiting molecule is a metabolite. Stronger inhibitors and short half-life drugs tend to produce inhibition faster than weaker ones.

The interaction stops up to five drug half-lives plus up to five enzyme half-lives after the last dose of the inhibitor. A rule of thumb for irreversible inhibition of CYP3A4 is to assume it will last for approximately ten days after the last dose of the inhibitor, if the inhibitor has a relatively short half-life, for example, less than 18 hours.

For example, erythromycin and clarithromycin are irreversible inhibitors of CYP3A4.

Useful enzyme inhibition

Enzyme inhibition can be beneficial. Some formulations use a low dose of a potent enzyme inhibitor to reduce metabolism of the active drug. This allows a lower dose of the active drug to be used.

For example, in Paxlovid, nirmatrelvir is co-formulated with low-dose ritonavir to inhibit CYP3A4.

Enzyme induction

Not all CYP enzymes are inducible. CYP2C9 and 3A4 are known to be inducible.

Enzyme induction by short half-life drugs occurs quickly, as the drug reaches steady state quickly. When the inducer has a long half-life, induction may take longer to appear. Rifampicin (half-life 2 to 3 hours) produces enzyme induction within 24 hours; phenobarbital (half-life 3 to 5 days) takes approximately a week.

The interaction stops when the inducer has been eliminated, and the extra enzymes are degraded. This depends on the drug and enzyme half-lives. A rule of thumb for CYP3A4 inducers is to assume that the reaction will reach its maximum at least 14 days after starting the inducer and will persist for at least 14 days after stopping the inducer, provided the inducer has a relatively short half-life.

For example, rifampicin is an inducer of CYP2C8, 2C9, 3A4/5/7, 2C19, and 2B6.

CYP enzymes in the gut

CYP enzymes, mostly CYP3A4, are also present in the gut wall. Drug molecules caught and metabolised by gut enzymes do not reach the systemic circulation to exert a therapeutic effect. Inhibiting gut enzymes therefore allows more of the drug to be absorbed, increasing bioavailability. Inducing gut enzymes reduces bioavailability.

Inhibition or induction of gut enzymes can occur regardless of the route of systemic administration of the enzyme inhibitor or inducer, but the substrate drug must be administered orally to be affected.

The half-life of the turnover of gut cells is probably 2.4 to 3.5 days. Consequently, clinically relevant intestinal enzyme inhibition/induction is likely to last for 7 to 10 days after the last dose of inducer/inhibitor. This is independent of any effect on enzymes in the liver.

For example, grapefruit juice irreversibly inhibits gastrointestinal CYP3A4; the interaction lasts for 3 to 7 days after consumption of grapefruit juice stops.

Enzyme half-lives

Enzyme half-lives vary between individuals, but approximate median turnover half-lives of human hepatic CYP enzymes are:

  • CYP1A2: 39 hours
  • CYP2C8: 23 hours
  • CYP2C9: 104 hours
  • CYP2C19: 26 hours
  • CYP2D6: 51 hours
  • CYP3A4: 72 hours

Transporter interactions – P-glycoprotein (P-gp)

Drugs and other substances are sometimes actively carried across membranes by transporters. The best-studied transporter is P-glycoprotein (P-gp). P-gp is present in various tissues, including the kidney, the gut and the liver. It acts by pushing drugs out of cells. P-gp in the gut wall cells pushes drug molecules that have already been absorbed back into the gut lumen. This reduces the amount of drug absorbed.

Inhibition of P-gp in the gut

P-gp inhibition in the gut increases drug absorption.

P-gp inhibition starts with the first dose of the inhibitor. Inhibition of gut P-gp may be very short-acting, stopping once the inhibitor has been absorbed. Consequently, avoiding P-gp inhibition by staggering administration of the inhibitor and substrate drug is sometimes possible.

Induction of P-gp in the gut

P-gp induction in the gut reduces drug absorption.

The start of P-gp induction depends on the dose and half-life of the inducer. The end of induction is dependent on P-gp turnover rate (5 to 17 hours), so is usually within seven days after the last dose of the inducer. The effect of staggering administration of inducer and substrate drug varies between P-gp inducers. If you do not have drug-specific information, administer the two drugs at a consistent interval relative to each other each day.

For example, rifampicin is both an inhibitor and inducer of P-gp, but induction is more important in the gut.

P-gp in other areas of the body

Inhibition/induction of P-gp elsewhere has other effects, such as altering drug distribution or excretion, but we know less about the significance of this.

Interactions with pro-drugs

Some drugs are administered as inactive pro-drugs requiring activation – usually by enzymes – to produce the active drug entity. If the activating enzyme is inhibited, transformation to the active drug will not occur, and drug activity will decrease. The reverse is true with enzyme induction.

For example, codeine is an inactive pro-drug requiring conversion to morphine by CYP2D6. If CYP2D6 is inhibited, conversion to morphine does not occur, and there is less or no analgesic effect.

Clinical significance of interactions

An interaction will only be clinically significant if the extent and duration of the change in drug levels is sufficient to have an effect on the patient. This depends on:

  • strength of enzyme inhibition/induction
  • amount of inhibitor/inducer present
  • involvement of major/multiple metabolic pathways
  • therapeutic index of the substrate drug
  • duration of interaction

If the interaction affects only a minor metabolic pathway, or affects a major one but metabolism can shift to unaffected pathways, drug levels may not change significantly.
For substrate drugs with a narrow therapeutic index, small changes in levels may be significant.

What to do about an interaction will depend on the potential severity of any effects, the likelihood that they will occur, and how easy they are to manage (for example, by monitoring).

Understanding drug interactions provides further information on managing drug interactions, and interactions that are not due to enzyme or transporter induction or inhibition.

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