Enhanced Anticoagulant Effect of Warfarin When Co-administered With Quercetin

Case Report

A 79-year-old man on stable warfarin therapy for atrial fibrillation presented with an international normalized ratio (INR) of 7.5. The patient started quercetin supplementation several days prior to a routine INR monitoring appointment, taking 1 capsule daily. The supplement was made by Natural Factors and came in a dosage strength of 250 mg quercetin and 500 mg of Vitamin C. The patient previously had a stable INR between 2 and 3 for months, with an INR of 2.5 five days beforehand. The patient had no recent changes to contributing factors. The patient was taking stable amiodarone therapy for 4 months prior to this episode with no other critical INR values. No adverse bleeding events were reported by the patient. The patient had been taking 1 warfarin 7.5 mg tablet once daily with a weekly dose of 52.5 mg. After the INR of 7.5, the patient stopped taking the quercetin supplement indefinitely and restarted warfarin therapy after missing one day. Five days after the initial INR, the INR was found to be 2.5. The patient’s most recent labs were red blood cell (RBC) count of 4.48 10³/mm³, hemoglobin (HGB) of 13.7 g/dL, aspartate aminotransferase (AST) of 26 IU/L, alanine aminotransferase (ALT) of 18 IU/L, and a calculated creatinine clearance (CrCl) of 91 mL/min.

Discussion

Quercetin is a flavonoid that occurs in foods such as onions, apples, berries, teas, and red wine. ¹ This dietary supplement is often used by patients for the treatment of cardiovascular conditions and cancer prevention due to its potential antioxidant and anti-inflammatory effects. ¹ Dietary quercetin glycosides are hydrolyzed in the intestine to aglycone which is further conjugated to glucuronides or sulfates that are then absorbed. ¹ Once absorbed, quercetin is highly protein bound. Its half-life, along with its metabolites, range from 6 to 28 hours. ¹ Quercetin is known to inhibit CYP2C9 activity. ¹ It is excreted in the urine as glucuronide derivatives and methylated metabolites. ¹ Flavonoids are known to be highly protein bound in plasma. ²

Warfarin is a vitamin K antagonist used as an anticoagulant. ² It is primarily metabolized by CYP2C9 which is inhibited by quercetin. ² More than 98% of warfarin is protein-bound and only unbound warfarin is biologically active. ³ The mechanism of the interaction is theorized to be warfarin being displaced from albumin by quercetin in the blood plasma and inhibition of CYP2C9. ⁴ There is evidence to show the metabolites of quercetin bind to albumin with high affinity, leading to strong displacement of warfarin. ⁴ This suggests that high doses of quercetin can lead to an increased INR and risk of bleeding.

Based on the multiple factors involved in INR levels and brief timeframe of the interaction, the calculated drug interaction probability scale score was 3, suggesting possible drug interaction between warfarin and quercetin, and the Naranjo adverse drug reaction probability scale score was 5, indicating a probable adverse drug event.^5,6 The patient’s otherwise stable condition and critical INR after initiation of quercetin follows a temporal pattern suggesting that stopping the quercetin resolved the issue. Health care professionals should be aware of this possible interaction when managing a patient’s warfarin therapy.