Supplements That Interfere with Hepatic Clearance via CYP3A4
Several dietary supplements can significantly inhibit CYP3A4 enzyme activity, potentially causing dangerous drug interactions and increased toxicity of medications metabolized through this pathway. 1
Major CYP3A4 Inhibitors Among Supplements
Strong Inhibitors
- St. John's wort: Acts as a CYP3A4 inducer, reducing plasma concentrations of drugs metabolized by this enzyme. Should be discontinued 2 weeks before surgery or when taking CYP3A4 substrate medications 1
- Green tea extract: Shows variable but potentially significant inhibition of CYP3A4 (up to 89.9% inhibition with some brands), making it one of the most potent CYP3A4-inhibiting supplements 2
- Milk thistle: Listed as contraindicated with simeprevir due to strong CYP3A4 inhibition 1
- Grapefruit extract: Should be held for 2 weeks before surgery; can significantly increase plasma concentrations of CYP3A4 substrates 1
Moderate to Mild Inhibitors
- Fennel: Contains 5-methoxypsoralen which has been identified as a major component that inhibits CYP3A4 1
- Curcumin/turmeric extracts: Shown to be mild to potent inhibitors of several CYP enzymes including CYP3A4 1
- Grape seed extract: Shows variable inhibition of CYP3A4 ranging from 6.4% to 26.8% depending on the brand 2
- Echinacea: Should be held for 2 weeks before procedures due to potential CYP3A4 interactions 1
- Goldenseal: Should be held for 2 weeks before procedures due to potential CYP3A4 interactions 1
- Red clover: Should be held for 2 weeks before procedures due to potential CYP3A4 interactions 1
- Schisandra: Should be held for 2 weeks before procedures due to potential CYP3A4 interactions 1
Supplements with Minimal CYP3A4 Effect
- Garlic: In vitro studies show only modest or unlikely inhibition of CYP3A4 despite affecting other CYP enzymes 1
- Ginkgo: Doses >360 mg/day have shown only weak inhibitory effects on CYP3A4 1
- Vitamin E: Research suggests it does not significantly affect CYP3A4-mediated drug metabolism despite theoretical concerns 3
Clinical Implications
Drug Classes Affected by CYP3A4 Inhibition
- Tyrosine kinase inhibitors: Most TKIs (imatinib, dasatinib, nilotinib, etc.) are metabolized by CYP3A4 and are susceptible to interactions 1
- Direct oral anticoagulants: Rivaroxaban and other DOACs are metabolized by CYP3A4 and can have increased bleeding risk with inhibitors 1
- Statins: CYP3A4 inhibition can increase statin concentrations (e.g., simvastatin AUC increased 3-fold with imatinib) 1
- Antiviral medications: Many hepatitis C medications like simeprevir are metabolized by CYP3A4 1
Mechanism of Inhibition
- Many supplements cause mechanism-based inhibition of CYP3A4, which involves:
- This type of inhibition is particularly concerning as it can cause long-lasting drug interactions even after supplement discontinuation 4
Variability in Supplement Effects
- Brand-dependent variation: The same supplement from different manufacturers can have dramatically different inhibitory effects on CYP3A4 2
- For example, green tea extract inhibition ranged from 5.6% to 89.9% depending on the brand 2
- This unpredictability makes supplement-drug interactions particularly dangerous 2
Recommendations for Clinical Practice
- Screen for supplement use: Always ask patients about all supplements they are taking, as many don't consider these "medications" 1
- Discontinue high-risk supplements: For patients on medications with narrow therapeutic indices metabolized by CYP3A4, consider discontinuing potentially interacting supplements 1, 4
- Timing of discontinuation: Most supplements that inhibit CYP3A4 should be discontinued at least 2 weeks before surgery or starting new medications metabolized by CYP3A4 1
- Monitor for toxicity: When CYP3A4 inhibitors cannot be avoided, monitor closely for signs of drug toxicity and consider dose reductions of the affected medications 1
- Consider therapeutic drug monitoring: For medications with narrow therapeutic indices that are metabolized by CYP3A4 4