CYP3A4hemmere

CYP3A4hemmere, or CYP3A4 inhibitors, are substances that decrease the activity of the cytochrome P450 3A4 enzyme, a key mediator of drug metabolism in the liver and intestinal wall. Inhibition can be reversible or time-dependent (mechanism-based), and it can markedly alter the pharmacokinetics of drugs that are CYP3A4 substrates, often increasing their plasma concentrations and risk of adverse effects.

Inhibitors are categorized by potency: strong, moderate, or weak. Strong inhibitors can cause substantial increases in exposure to substrates, while moderate and weak inhibitors have smaller effects. Inhibition can occur in the gut, the liver, or both, with intestinal inhibition sometimes increasing the oral bioavailability of drugs.

Common examples of CYP3A4 inhibitors include ketoconazole and itraconazole; macrolide antibiotics such as clarithromycin and erythromycin; HIV protease inhibitor ritonavir; and substances like grapefruit juice. Other drugs such as diltiazem and certain calcium channel blockers can act as CYP3A4 inhibitors to varying degrees. Some inhibitors act time-dependently, producing longer-lasting suppression of enzyme activity even after removal.

Clinical relevance is substantial because many medications, including statins, calcium channel blockers, immunosuppressants (for example tacrolimus or sirolimus), and anticoagulants, are CYP3A4 substrates. Inhibition can lead to higher drug exposure and increased risk of toxicity. Management involves reviewing medications for potential interactions, avoiding problematic combinations when possible, adjusting doses, using alternative therapies, and monitoring drug levels or clinical effects, especially with drugs that have narrow therapeutic indices.