Cytochrome P450 Inhibition

CYP inhibition is a reduction in the activity level of a CYP enzyme due to the presence of an inhibitor — a compound (e.g., medication, supplement, or other substance) that impairs normal enzyme activity. CYP inhibition can result in reduced drug metabolism, leading to drug interactions that may impact treatment outcomes and side effect risk.

Summary

Cytochrome P450 (CYP) inhibition occurs when a compound (e.g., medication, supplement, or other substance) impairs the activity of a CYP enzyme. This compound would be considered an inhibitor. CYP inhibition is the most common mechanism leading to pharmacokinetic drug interactions, ultimately causing reduced drug metabolism which may alter the efficacy and safety of a medication or supplement.[1]

Example: CYP Inhibition

Medication A decreases (inhibits) the activity of a CYP enzyme that medication B relies on for metabolism. Medication B is broken down slower than normal, leading to higher levels of medication B in the body, which could increase the risk of side effects or toxicity.

Alternatively, if medication B is a prodrug, meaning it relies on the CYP enzyme for activation, its effectiveness could be reduced.

Types of CYP Inhibition

There are two main types of CYP inhibition: reversible and irreversible inhibition.

Reversible Inhibition

Reversible inhibition is when a CYP enzyme is temporarily inhibited. It includes competitive, uncompetitive, and noncompetitive inhibition.

Competitive inhibition is the most common type of CYP inhibition. It occurs when an inhibitor binds to the enzyme at the same site that a substrate (a compound metabolized by the enzyme) would normally bind, forcing the substrate to compete for the enzyme. Often, the inhibitor is another substrate that has a greater strength of attraction (affinity) for the enzyme or is present at a higher concentration.[1]

Noncompetitive inhibition occurs when the inhibitor binds to the enzyme at a different site than the substrate, causing a change in the structure of the enzyme that prevents the substrate from being able to bind.[1]

Uncompetitive inhibition is very rare but occurs when the inhibitor exclusively binds to the enzyme when the substrate is already bound and effectively prevents the normal reaction from occurring.[2]

Irreversible Inhibition

Irreversible inhibition, also called mechanism-based inhibition, occurs when an inhibitor forms a strong and stable covalent bond with a CYP enzyme, rendering the enzyme inactive. This results in permanent inactivation of the enzyme. In general, inhibition will continue until the enzyme is eventually broken down and replaced with a new enzyme.[1]

References

1.^Deodhar M, Al Rihani SB, Arwood MJ, Darakjian L, Dow P, Turgeon J, Michaud VMechanisms of CYP450 Inhibition: Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice.Pharmaceutics.(2020-Sep-04)
2.^Zhao M, Ma J, Li M, Zhang Y, Jiang B, Zhao X, Huai C, Shen L, Zhang N, He L, Qin SCytochrome P450 Enzymes and Drug Metabolism in Humans.Int J Mol Sci.(2021-Nov-26)