Black and Blue and Purple: Pomegranate and Coumadin

By Russell H. Greenfield, MD, Editor.

Synopsis: Studies on the effects of pomegranate juice on CYP-mediated drug metabolism have yielded inconsistent results, but this recently published case report raises the specter of interaction between the juice and warfarin, a drug whose narrow therapeutic window and potential for significant complications are well known.

Source: Komperda KE. Potential interaction between pomegranate juice and warfarin. Pharmacotherapy 2009; 29:1002-1006.

The author describes the case of a 64-year-old woman with a history of pulmonary embolism and deep vein thrombosis referred to an anticoagulation clinic for care. She had been on a stable drug regimen, and her use of supplements, including fish oils and a multivitamin, had not changed in a long time. She had been taking warfarin for approximately 4 years as directed by her primary care physician, using a stable dose of 4 mg/d for the prior 9 months except for a brief period of time 4 months before presenting to the clinic, when it was noted that her International Normalized Ratio (INR; typically deemed to be therapeutic between 2.0-3.0 while on warfarin) was fluctuating. A short series of warfarin dosage changes occurred before she was returned to the 4 mg/d dose.

The patient was present at a clinic educational session where she learned of the potential impact of certain foods on warfarin, as well as concerns about the use of cranberry juice while on the medication. At her clinic visit one week earlier, the patient's INR was 2.2 and was deemed therapeutic. After the educational session, she reported to the clinic physician that she had been drinking pomegranate juice 2-3 times a week for a number of months. The staff pharmacologist identified data suggesting a potential inhibition of CYP3A4 and CYP2C9 and recommended she stop drinking the juice. One week later, having had no pomegranate juice for 10 days, her INR was subtherapeutic at 1.7 in the face of no other medication changes and no missed warfarin doses. She required an increase in the dosage of warfarin to maintain a therapeutic INR.

The author forthrightly states there are limitations to her conclusions, including lack of a re-challenge of the patient with pomegranate juice (unethical) and the fact she was on other medications, albeit at stable doses.

Commentary

Case reports are rarely covered in the pages of Alternative Medicine Alert, chosen only when concern about a widespread or generally accepted intervention is raised. Such are the circumstances with this case report, though the intervention in question is largely a patient-initiated one.

As noted in Dr. Kiefer's review article, "Imported Fruits: Drink Their Juices?" (see August 2009 issue of Alternative Medicine Alert), pomegranate juice is perhaps the only one of the heavily marketed fruit juices (think açai and mangosteen, among others) associated with compelling supportive data for a potential health benefit from its ingestion. Widely touted potential anticancer, antioxidant, and cardiovascular health effects have created significant consumer demand for the often pricey drink, and physicians have had little reason for concern apart from the drink's sugar content. Years ago the same could be said for grapefruit juice, until it was discovered that drinking the juice could interfere with CYP3A4-metabolized drugs. Of late, concerns have been raised about cranberry juice and cytochrome P450 inhibition (CYP), though the data are contradictory. Now comes word of a possible interaction between pomegranate juice and warfarin, a drug whose therapeutic window is notoriously narrow.

In the case report at hand, the patient suffered no untoward consequences. In fact, it appears her INR was therapeutic because of her drinking pomegranate juice. The warfarin dose employed was likely too low to attain the desired therapeutic effect. The concern grows out of the potential for a patient to unknowingly augment warfarin's effects by drinking pomegranate juice, thereby creating a supertherapeutic INR and risking hemorrhagic complications.

As is often quoted, "What is natural is not synonymous with what is safe," at least not in all circumstances. It seems important to keep in mind the potential inhibitory effects of pomegranate juice on CYP activity for patients on CYP-metabolized drugs, especially warfarin, until more is known.