What is the severity of the interaction between quercetin and prednisone (corticosteroid) on the Cytochrome P450 (CYP) enzymes?

Quercetin-Prednisone CYP Interaction Severity

The interaction between quercetin and prednisone on CYP enzymes is likely clinically insignificant and represents a low-risk interaction, as prednisone is primarily metabolized by non-CYP pathways (11β-hydroxysteroid dehydrogenase) rather than the CYP enzymes that quercetin inhibits.

Mechanism of Quercetin's CYP Inhibition

Quercetin acts as a potent competitive inhibitor of multiple CYP enzymes, but its inhibitory profile does not align with prednisone's metabolic pathway 1, 2:

• CYP1A2: Quercetin shows potent competitive inhibition with Ki = 0.93 μM 2
• CYP2C9: Potent competitive inhibition with Ki = 1.67 μM 2
• CYP2C19: Potent competitive inhibition with Ki = 1.74 μM 2
• CYP3A4: Potent competitive inhibition with Ki = 4.12 μM 2
• CYP2E1: Demonstrated inhibition in human studies, increasing substrate exposure by 69.3% 3
• CYP2D6: Moderate competitive inhibition with Ki = 18.72 μM 2

Why This Interaction is Minimal for Prednisone

Prednisone undergoes rapid conversion to prednisolone (its active form) via 11β-hydroxysteroid dehydrogenase, not CYP enzymes. Prednisolone is then metabolized primarily through reduction and conjugation pathways, with minimal CYP involvement. Since quercetin's inhibitory effects target CYP enzymes that are not the primary metabolic route for corticosteroids, the clinical impact is expected to be negligible.

Clinical Evidence from Human Studies

Human intervention studies with quercetin supplementation have demonstrated:

• Dose-dependent effects: Studies using 500 mg twice daily for 10 days showed significant CYP inhibition for substrates like diclofenac (CYP2C9) and chlorzoxazone (CYP2E1) 1, 3
• Safety profile: Adverse effects from quercetin supplementation (up to 1000 mg daily) have been rarely reported and were mild in nature 4
• Timing of inhibition: CYP inhibition occurs rapidly after introduction of quercetin, unlike enzyme induction which takes 2-4 weeks 5

Quercetin Metabolites and Drug Interactions

Not only quercetin aglycone but also its conjugated metabolites can interact with drug-metabolizing enzymes 6:

• Quercetin-3'-sulfate, quercetin-3-glucuronide, isorhamnetin, and isorhamnetin-3-glucuronide showed weak inhibitory effects on CYP2C19 and CYP3A4 6
• These metabolites are the predominant circulating forms due to extensive first-pass metabolism 6

Practical Recommendations

For patients taking prednisone with quercetin supplementation, no dose adjustment of prednisone is necessary based on the following considerations:

• Monitor for typical corticosteroid side effects (hyperglycemia, hypertension, mood changes) as you would normally, but do not expect quercetin to alter these 4
• If the patient is taking other medications that ARE CYP2C9, CYP2C19, CYP3A4, or CYP2E1 substrates concurrently, those drugs may require closer monitoring or dose adjustment 1, 2, 3
• Quercetin doses ≥1000 mg daily lack long-term safety data (>12 weeks), so caution is warranted at higher doses regardless of drug interactions 4

Important Caveats

Avoid extrapolating this low-risk assessment to other corticosteroids or immunosuppressants that may have different metabolic pathways:

• Drugs like cyclosporine (a P-glycoprotein substrate) could theoretically interact with quercetin through transporter inhibition 6
• The interaction risk profile differs substantially for drugs that are true CYP3A4 substrates compared to prednisone 7
• Patients with pre-existing kidney damage should use quercetin cautiously due to potential nephrotoxicity enhancement observed in animal studies 4