In their study published in the August 1, 1998, issue of AJHP, Sullivan et al.1 found that daily ingestion, of 24 oz of grapefruit juice prepared from frozen concentrate had no effect on the response to warfarin by 10 patients receiving long-term therapy with the drug. Contrary to that finding, ingestion of grapefruit juice by a patient at our anticoagulation clinic may have led to a significant increase in the response to warfarin.
A 64-year-old man with atrial fibrillation began warfarin therapy in September 1995. Through April 1996, 50% of his International Normalized Ratios (INRs) were in the target range of 2-3.
The INR at the man's clinic appointment on April 11, 1996, was 6.29. He did not have any evidence of bleeding. Extensive questioning revealed no change in his health status,. no new medical diagnosis, and no new medication. The patient did reveal, however, that, 10 days before the appointment, he had started drinking about 1.5 L (50 oz) of ready-to-drink grapefruit juice (President's Choice, Sunfresh Ltd., Toronto, Ontario) daily. The patient was told not to take warfarin for two days and then to resume his usual regimen (55 mg/wk) for the next five days.
Upon being informed there was a possibility that the grapefruit juice had caused the elevated INR, he consented to stop drinking the juice.
One week later, the man's INR was 1.82. We told him to resume his previous warfarin regimen. Six of the next 10 INRs were in the target range; the highest value outside the target range was 3.24. The patient has not allowed us to rechallenge him with grapefruit juice.
To further explore this possible drug-juice interaction, I ingested sufficient warfarin to produce two consecutive INRs of 2-3 and then drank about 1.5 L of the patient’s brand of grapefruit juice daily. No clinically important changes in the INR occurred.
Grapefruit juice contains at least one substance known to inhibit the activity of cytochrome P-450 isoenzyme 3A4, the same isoenzyme that metabolizes (R)-warfarin. This is the less potent enantiomer of warfarin, according to in vitro data; however, it Is possible that, with ingestion of large volumes of grapefruit juice, sufficient (R)-warfarin could accumulate in vivo to contribute significantly to the anticoagulant effect of the marketed product, which is a racemic mixture.
Recent evidence suggests that grapefruit juice inhibits only the cytochrome enzymes in the gut wall; this finding explains why only drugs that undergo substantial first-pass metabolism in the liver are affected.2 Warfarin is not known to undergo this type of metabolism and thus is less likely to be affected by the juice. New factors that affect the response to warfarin are still being reported.3,4 It is possible that some unknown factor resulted in our patient's elevated INR; however, we could find no explanation other than his consumption of grapefruit juice.
1. Sullivan DM, Ford MA, Boyden 1W. Grapefruit juice and the response to warfarin. Am J Health-Syst Pharm. 1998; 55: 1581-3.
2. Bailey DG, Malcolm J, Arnold O et al. Grapefruit Juice-drug interactions. Br J Clin Pharmacol. 1998; 46:101-10.
3. Bartle WR, Ferland G. Fiddleheads and the International Normalized Ratio. N Engl J Med. 1998; 338:1550. Letter.
4. Shibata Y, Hashimoto H, Kurata C et al. Influence of physical activity on warfarin therapy. Thromb Haemost 1998; 80:203-4. Letter.
W. R. Bartle, Pharm.D., Education Coordinator and Senior Research Associate
Pharmacy Department and
Anticoagulation Clinic
Sunnybrook and Women's Health Sciences Centre
2075 Bayview Avenue
Toronto, Ontario M4N 3MS
Canada