Interaction between Warfarin and Mango Fruit

TO THE EDITOR: Many drugs, dietary supplements, and foods are known to interact with warfarin. Most warfarin–food interactions are related with the vitamin K content of nutrients (e.g., vegetables), interfering with its therapeutic safety and efficacy. The mango (Mangifera indica) is an Anacardiaceae native to southern Asia. The mango is one of the most common orchard or backyard trees in Puerto Rico. The fruit is commercially grown in 4 municipalities on the island and harvested between March and November, peaking during the months of May and July.1 Mango fruit comes in a variety of sizes and shapes. Much of the varieties cultivated in Puerto Rico are oval, round, heart, or kidney-shaped, with its size fluctuating between a small melon to a large avocado. It is preferably consumed for its pleasant sweet flavor and high vitamin A, C, and fiber content. Mango possesses antiviral, antiparasitic, antitussive, laxative, and stomachic properties, among others.2-5 More recently, studies6,7 involving an aqueous extract of M. indica called Vimang have reported analgesic, antiinflammatory, and antioxidant activity. We report a possible interaction between mango fruit and warfarin. Case Reports. Thirteen male patients aged 56–85 years were found to have increased international normalized ratios (INRs) after mango fruit ingestion. Indication for chronic anticoagulation therapy varied among patients: atrial fibrillation (31%), recurrent deep-venous thrombosis (15%), heart valve replacement (31%), and others (23%). The majority of patients reported a daily mango intake of 1–3, 2–3, and 5–6 mangos 2 days to 1 month prior to the anticoagulation clinic appointment. No other factors for increased INR (e.g., confusion about warfarin dose, changes in other medications or diet, heart failure decompensation, alcohol intake) were identified on interview. The average INR increase in these patients was 38%. The difference between the INR at baseline and after mango intake was statistically significant (p < 0.001). No bleeding episodes resulted from the supratherapeutic INR found after mango ingestion. After identification of mango fruit as a possible cause of supratherapeutic INR, patients were instructed to stop mango ingestion for 2 weeks. The average measured INR in the 13 patients decreased by 17.7% after mango fruit was discontinued (Table 1). Patients denied changes in their drug regimen and reported a consistency in the intake of vitamin K–containing food, as well as good compliance with all other medications. These patients also denied the use of health-food supplements and vitamins during this period. Rechallenge with mango fruit was performed in 2 of the 13 patients (Table 2). Patients were told to eat the same amount of mango fruit they were eating before the increase in the INR was observed. Although the INR value increased after rechallenge, these 2 patients reported less mango ingestion than previously taken (2 mangos daily and 3 mangos in 1 week vs. 6 mangos daily and 1–2 mangos per day, respectively). After a MEDLINE search (1966–August 2001) no other case reports of a drug–food interaction between warfarin and mango fruit were found in the literature. Other possible causes for increased INR were ruled out before identifying mango fruit as the only recent dietary change in the patients’ regimen. Discussion. The vitamin content of a medium-sized mango (130 g without seed) is: vitamin A 8061 IU, vitamin C 57 mg, vitamin B6 0.28 mg, vitamin B1 0.12 mg, and folate 29 μg, among others.8 Although the exact mechanism for this interaction is unknown, there are literature reports9 suggesting that concomitant administration of warfarin and vitamin A can cause an increased anticoagulant effect when large doses of vitamin A are given. Vitamin A has several important functions in the body. It is known to play an essential role in the function of the retina, growth and differentiation of epithelial tissue, and is also required for growth of bone, reproduction, and embryonic development. Although the term vitamin A has been used to denote specific chemical compounds, like retinol, it has also been used for compounds with the biological properties of retinol.10 Yamazaki and Shimada11 investigated the effects of retinoic acid and retinol in the xenobiotic oxidations catalyzed by human cytochrome P450 enzymes. That study showed that retinol and retinoid acid were strong inhibitors for xenobiotic oxidations catalyzed by recombinant CYP2C19, the hepatic enzyme responsible for the metabolism (7-hydroxylation) of the warfarin R-isomer. Inhibition of CYP2C19 would lead to a moderate increase in warfarin concentrations