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Source: Kane GC, Lipsky JJ. Mayo Clin Proc 2000;75:933-942.
The American public is consuming grapefruit juice in great quantities with 14% of men drinking the juice at least weekly.1 Yet grapefruits, like prunes, have commonly been referred to as a "funny" fruit. Yet, there is nothing funny about the way grapefruit interacts with some drugs.
A possible drug interaction with grapefruit juice was first reported approximately 10 years ago when investigators at the University of Western Ontario were attempting to find an effective way of disguising the flavor of alcohol. They found that double-strength grapefruit juice best masked the taste of alcohol, but they also found the blood level of felodipine to be three times higher in those people who were taking that medication with alcohol that had been laced with grapefruit juice to mask the taste of the alcohol2 than were the blood levels in subjects who had taken the medication without grapefruit juice. Bailey and colleagues at the University of Western Ontario test- ed this serendipitous observation by measuring drug blood levels after giving the felodipine on one day with water and comparing the observed blood levels to those obtained the next day when felodipine was given with grapefruit juice—the drug blood levels were found to be up to four times higher when grapefruit juice was ingest- ed with the drug.3
The drug-food interaction observed when ingesting grapefruit juice appears to occur because of the inhibition by grapefruit juice of one of the intestinal cytochrome enzyme systems. The isoform known as cytochrome P- 450 3A4 (CYP3A4) is well known because of its frequent involvement with drug-drug interactions. The largest concentration of this family of heme-containing proteins is found in the endoplasmic reticulum of cells located throughout the body— especially in the liver and in the intestinal wall where they play a role in the oxidative biotransformation of numerous endogenous substances and xenobitics. Wide variations exist in the expression of this enzyme in the liver and intestines; however, it has now been clearly demonstrated that patients with the highest intestinal CYP 3A4 concentrations display the greatest untoward effects when they ingest grapefruit juice.4
Skeptical members of the medical community initially ignored the data; however, multiple studies have now clearly confirmed the interaction of grapefruit juice with felodipine as well as with other medications. The majority of the studies on pharmodynamic evaluations have been performed on relatively small numbers of healthy adult volunteers but more recently, an increasing number of case reports of adverse effects due to drug interactions of grapefruit juice with many medications have been published. These drugs are clearly tabulated in the Table.
An argument can be made that if a patient has been taking medication with grapefruit juice for some time without ill effect, it is probably safe to continue to do so; however, the variability in the level of interaction with different types of juice would suggest that this approach may not be entirely safe. For example, felodipine blood levels have been demonstrated to increase 300-500% when taken with grapefruit juice and such elevations have led to symptoms of flushing, lightheadedness, and fainting in otherwise healthy research subjects. Obviously, an elderly person with significant coronary artery disease or hypertension might even have more sig- nificant symptomatology. Each patient’s medical condi- tion should be individually considered and advice regard- ing the use of grapefruit juice should be based on the spe- cific medication involved; however, it would seem fool- hardy not to recommend to patients that they use water rather than grapefruit juice for the ingestion of any of the many drugs tabulated in the Table. These drugs should not be taken with grapefruit juice until the drug-grape- fruit juice interactions have been clarified. The spectrum of these drugs included many drug categories such as heart/high blood pressure agents, antihistamines, trans- plant rejection agents, cholesterol-lowering drugs, and other agents such as warfarin (Coumadin), cisapride (Propulsid), and even sildenafil (Viagra).
Table: Grapefruit and Drug Interactions*
|Verapamil (Calan, Isoptin)||No|
|HMG-CO inhibitors (statin)|
|Fluvastatin (Lescol)||? No|
|Pravastatin (Pravacol)||? No|
*This is a partial list—many other medications are being investigated.
For the practicing physician, it is important to recognize that regular strength grapefruit juice has as much as 80-90% of the untoward effect of double-strength grapefruit juice and, in fact, whole grapefruits have almost the same effect. Therefore, it behooves all physicians to caution their patients about the use of any strength grapefruit juice as a liquid vehicle for the ingestion of any drug, but especially for those listed in the Table. Also, it should be noted that most studies examining the grapefruit-drug interactions have used a single 8-oz glass of fresh or reconstituted grapefruit juice. These studies suggest that even a small amount of juice can cause a significant drug interaction and, therefore, these drugs should not be ingested within 24 hours after ingesting grapefruit juice or eating a significant amount of the fruit.
Dr. Karpman is Clinical Professor of Medicine, UCLA School of Medicine, Los Angeles, Calif.
1. Curhan GC, et al. Am J Epidemiol 1996;143:240-247.
2. Bailey DG, et al. Clin Invest Med 1989;12:357-362.
3. Bailey DG, et al. Lancet 1991;337:268-269.
4. Lown KS, et al. J Clin Invest 1997;99:2545-2553.