From the Guidelines
CYP3A4 inhibitors include azole antifungals, such as ketoconazole and itraconazole, as well as macrolide antibiotics like erythromycin and clarithromycin, which can significantly interact with medications metabolized by CYP3A4, potentially leading to increased blood levels and enhanced side effects 1. Some key points to consider when evaluating CYP3A4 inhibitors include:
- Azole antifungals, such as ketoconazole, itraconazole, voriconazole, and fluconazole, are known to be potent CYP3A4 inhibitors 1
- Macrolide antibiotics, including erythromycin and clarithromycin, can also inhibit CYP3A4 activity 1
- HIV protease inhibitors, such as ritonavir and indinavir, are another class of medications that can inhibit CYP3A4 1
- Calcium channel blockers, including diltiazem and verapamil, may also have CYP3A4 inhibitory effects 1
- Other notable CYP3A4 inhibitors include grapefruit juice, cimetidine, amiodarone, and nefazodone When prescribing medications that are metabolized by CYP3A4, healthcare providers must carefully consider potential interactions with these inhibitors, as they can lead to increased blood levels and enhanced side effects, and often require dose adjustments or alternative treatments to avoid adverse effects 1. In particular, the concomitant administration of rivaroxaban with strong CYP3A4 inhibitors, such as ketoconazole and ritonavir, can result in significantly increased plasma concentrations of rivaroxaban, leading to enhanced anticoagulant effects and increased risk of bleeding 1. Therefore, it is essential to carefully evaluate the potential interactions between CYP3A4 inhibitors and medications metabolized by this enzyme to ensure safe and effective treatment.
From the FDA Drug Label
Moderate inhibitors of CYP3A4 such as fluconazole may increase plasma ibrutinib concentrations and increase risk of adverse reactions associated with ibrutinib Moderate inhibitors of CYP3A4 such as fluconazole may increase lurasidone plasma concentrations. Moderate inhibitors of CYP3A4 such as fluconazole increase olaparib plasma concentrations;
- Examples of CYP3A4 inhibitors are not explicitly listed, but fluconazole is stated to be a moderate inhibitor of CYP3A4.
- Other substances that are affected by CYP3A4 inhibition include ibrutinib, lurasidone, and olaparib.
- The label does not provide a comprehensive list of CYP3A4 inhibitors 2
From the Research
Cytochrome P450 3A4 (CYP3A4) Inhibitors
- The following are examples of CYP3A4 inhibitors:
- Macrolide antibiotics (e.g., clarithromycin, erythromycin) 3, 4, 5, 6, 7
- Anti-HIV agents (e.g., ritonavir, delavirdine) 3, 5, 6, 7
- Antidepressants (e.g., fluoxetine, fluvoxamine) 3, 5, 6, 7
- Calcium channel blockers (e.g., verapamil, diltiazem) 3, 5, 6, 7
- Steroids and their modulators (e.g., gestodene, mifepristone) 3, 6
- Azole antifungal agents (e.g., fluconazole, itraconazole, ketoconazole) 5, 7
- Grapefruit juice 5, 7
- HIV protease inhibitors (e.g., amprenavir, indinavir, nelfinavir, ritonavir, saquinavir) 7
- Other drugs such as amiodarone, cimetidine, isoniazid, metronidazole, quinine, quinupristin/dalfopristin, and zileuton 7
Mechanism of CYP3A4 Inhibition
- CYP3A4 inhibition can occur through various mechanisms, including:
Clinical Implications of CYP3A4 Inhibition
- CYP3A4 inhibition can lead to significant drug-drug interactions, including:
- Increased plasma concentrations of CYP3A4 substrates, which can lead to enhanced adverse effects or toxicity 3, 4, 5, 6, 7
- Decreased efficacy of CYP3A4 substrates, which can lead to reduced therapeutic effects 3, 4, 5, 6
- Increased risk of torsades de pointes, a life-threatening ventricular arrhythmia, when CYP3A4 inhibitors are coadministered with certain drugs such as cisapride, terfenadine, or astemizole 5, 7