Learn about the dangers of grapefruit juice interacting with drugs.
Grapefruit Juice Interacting with Drugs
Our bodies have a remarkable ability to process foreign compounds. Consider the massive number of medications that have been introduced in the past fifty years. These pharmaceutical agents have many diverse actions such as treating cancer, menopausal symptoms, infections, inflammation, pain, anxiety, seizures, high blood pressure, and high cholesterol, just to name a few. It’s a wonder that chemicals designed in a laboratory could have such powerful and pervasive biochemical effects on our physiology. And it is perhaps equally wondrous that we manufacture an elaborate set of enzymes that allows us to take drugs in precise doses over extended periods of time without developing intolerable side effects. These enzymes accomplish this feat by metabolizing the drugs so that they can be eliminated from our bloodstream and tissues before they become toxic.
There is only one catch to this elegant garbage disposal system—it is prone to clogging. In modern cultures, human beings typically eat a complex diet that includes a wide variety of foods and spices. In addition, the trend toward medical self-care has led us to consume a growing number of herbal medicines. Foods and herbs contain a vast array of naturally occurring chemicals—too many to count—that are also processed by the very same enzymes that metabolize drugs, hormones, and toxins. This massive influx of chemicals burdens the disposal system, placing it at risk of overloading. As a consequence, the more new drugs we introduce into our bodies, the more likely we are to encounter significant interactions between these drugs, the foods we eat, and botanical medicines.
The Case of Grapefruit Juice and Drugs
A case in point is grapefruit, an extremely popular and nutritious food. Surveys have shown that up to 21 percent of all households in the United States purchase grapefruit juice. For most consumers, this is probably a very good thing—there are substances in grapefruit that appear to help prevent both cancer and heart disease. However, grapefruit juice also has a unique property: It can raise the blood levels of numerous prescription medications. Because grapefruit juice is usually consumed with breakfast—the same time that many people take their medications—this increases the likelihood of a significant effect. Depending on the condition being treated and the relative safety of the drug involved, this interaction could potentially be a problem . . . or, it could also be a benefit.
Almost ten years ago, a medical study was conducted to investigate the effect of alcohol on the absorption of a blood pressure medicine called felodipine. As part of the study, grapefruit juice was added to mask the taste of the alcohol. Much to the investigators’ surprise, it was discovered that the addition of grapefruit juice markedly enhanced the absorption of felodipine and raised its concentration in the bloodstream. In the years that followed, a similar effect was found with numerous other medications, and extensive research was conducted to find out exactly how this interaction occurred.
A central component of the body’s drug detoxification system is a family of enzymes called the cytochrome P450, or CYP450. These enzymes are found throughout the body but are especially concentrated in the liver and the walls of the intestines. The role of these CYP450 enzymes is to alter the chemical structure of a drug (or hormone or toxin) so that it can be more rapidly eliminated. When certain CYP450s are blocked or inhibited, the effect is to slow down the elimination of that substance, thus raising its level in the blood.
Grapefruit juice has been shown to inhibit a very specific enzyme, the CYP3A4. In the intestinal walls, this enzyme makes up 70 percent of all of the CYP450s, and this is precisely where grapefruit juice exerts its effect. In studies where purified grapefruit juice was given intravenously, it did not influence the blood levels of simultaneously administered medications. These studies confirmed that the juice had to be taken by mouth for it to impact drug metabolism. Further research found that a single, 200-ml cup of juice (about 7 fluid ounces) was sufficient to inhibit the CYP3A4 enzyme by almost 50 percent for a full twenty-four hours. Drinking a glass of grapefruit juice every day for several weeks may reduce this effect slightly (to about 30 percent inhibition), but this is still significant.
Grapefruit and the Affected Drugs
The reason it has been important to gather this information in so much detail is that CYP3A4 is a crucial enzyme for the detoxification of many important drugs, possibly up to 50 percent of all pharmaceutical agents. Anything that interferes with its function can potentially amplify the activity of these drugs. The list of drugs impacted is long but includes cyclosporine and tacrolimus, immune-suppressing drugs used for organ transplant patients; estrogens and oral contraceptives; certain calcium channel blockers, used to treat hypertension; several benzodiazepines, tranquilizers used to treat anxiety; many of the statins, used to treat high cholesterol; loratadine, an antihistamine; methadone, used to treat heroin addiction; sildenafil, used to treat erectile dysfunction; sertraline, an antidepressant; carbamazepine, an anti-seizure medicine; and saquinavir, used to treat HIV infection.
As mentioned earlier, the interaction between these drugs and grapefruit juice could be seen as a boon or bane depending on the circumstances. For example, drinking a glass of the juice at the same time as taking the drug sildenafil (Viagra) has allowed some people to cut the dose of their medication in half while still getting the same therapeutic effect. In an attempt to cut the cost of the drug, many doctors have been actively recommending this practice to their patients. In contrast, trying this procedure with cyclosporine could be extremely risky because the drug has a high degree of toxicity, especially when its blood levels are excessively elevated.
Part of the problem with intentionally using grapefruit juice as a “booster” to lower the therapeutic dose of certain medications is that it is still not known which specific components of grapefruit inhibit intestinal CYP3A4. Similar to what is often found with botanical medicines, recent studies indicate that it is probably a specific combination of ingredients that is responsible. (This explains why orange juice, which contains many of the same chemicals as grapefruit, does not have the same effect.) Because grapefruit juice is not a standardized product, the active ingredients—and the effect on drug metabolism—can vary from batch to batch. Another issue is that people have different amounts of CYP3A4 in their intestines. Those with lower amounts of the enzyme are less susceptible to influence by grapefruit.
The complexities of this situation have led some doctors to recommend that grapefruit juice be avoided by patients taking any of the medications listed above. Rumor has it that some hospitals have completely banned the juice from their kitchens. This reactionary stance might be an easy way out, but it risks losing something that is potentially of great value. Unfortunately, given the strong possibility that other foods and herbs will be discovered that can have similar effects to grapefruit, these kinds of policies could eventually lead to a long list of banned foods. In fact, one study found that 66 percent of twenty-one commonly used medicinal herbs were CYP3A4 inhibitors, including goldenseal (Hydrastis canadensis) and St. John’s wort (Hypericum perforatum). Other studies have suggested that purple grape (Vitis labrusca) and milk thistle (Silybum marianum) may also inhibit CYP3A4. Because these studies were done in a test tube, the implications are unclear; however, they do suggest the possibility that even more interactions will be discovered.
Certainly, before we can make positive use of the grapefruit/drug interaction, additional information is needed. When more is understood about the active ingredients, it may be possible to produce a standardized grapefruit product with consistent potency. Sophisticated laboratory testing is on the horizon, and someday this will be used to predict how an individual’s metabolism might be affected by drinking biologically active foods such as grapefruit or grape juice.
In the meantime, we simply have to accept the uncertainties inherent in our current medical knowledge. According to Brahma Singh, M.D., “Although there is a vast amount of literature, there is still no rational scientific basis to predict the effect of food for a particular chemical entity or a chemical class of therapeutic agents.” Perhaps we can take some comfort in knowing that our species has survived—and even thrived—despite dealing with these kinds of complexities for many thousands of years.
Robert Rountree, M.D., is a physician in private practice in Boulder, Colorado, where he practices integrative medicine. He is co-author of Smart Medicine for a Healthier Child (Avery, 1994) and Immunotics (Putnam, 2000), and is an Herb Research Foundation advisory board member.