The “grapefruit effect” was discovered by accident in 1989. Researchers were investigating how a blood pressure medication would interact with alcohol, and to make the alcohol more palatable they added grapefruit juice – what your bartender would call a Greyhound (Bailey and colleagues. Clin Invest Med 1989;12:357-362). Much to the researchers’ surprise, many people experienced side effects, which were later attributed to very high medication levels in the blood stream. It seemed that grapefruit juice somehow blocked the breakdown of the blood pressure medication, so too much drug was circulating in the body.
To give a bit of background, most medications (and many other substances) are metabolized in the liver and intestine by a family of enzymes called the cytochrome P450 system. When you take a medication such as a TKI, certain cytochrome enzymes (called CYP3A4) bind to the TKI and eliminate it from the body.
When you take a second drug at the same time as your TKI, two different things can happen. Some drugs can induce CYP enzymes, which means that more enzymes are available to metabolize your medication. As a result, the medication is eliminated more quickly, and the drug levels you need to achieve a therapeutic effect aren’t reached. So the treatment will often be ineffective. An example of this is St. John’s wort, an alternative remedy for depression. It induces CYP3A4, so it should not be combined with your TKI.
The second thing that can happen is that your TKI and the second drug compete for the same enzymes. If the TKI can’t find any available enzymes, it won’t get broken down and will continue to circulate in your blood stream. So the drug levels go up, which increases the likelihood that you’ll experience medication-related side effects.
This is what happens with grapefruit juice. One study looked at the effect of combining Tasigna with grapefruit juice (Yin and colleagues. J Clin Pharmacol 2010;50:188-194). They found that peak drug levels of Tasigna increased by 60% with grapefruit juice. A similar effect is seen when grapefruit juice is combined with other TKIs, such as Gleevec and Sprycel.
You may think of grapefruit as a food rather than a drug in the conventional sense, but much of its popularity has been due to its reputation as a medicine. After it was introduced to Florida from the West Indies in the 1820s, grapefruit was used to treat colds, infections, rheumatism, weight loss, sleeplessness, nervousness, and a range of other complaints (Kiani & Imam. Nutr J 2007;6:33). It was considered a medicinal tonic but its effects were surprisingly potent. A single glass of grapefruit juice will interact with CYP3A4 for about three days (Greenblatt and colleagues. Clin Pharmacol Ther 2003;74:121-129). So you’ll need to forego your half grapefruit at breakfast if you’re taking a TKI.
Grapefruit may be the most potent juice when it comes to drug-metabolizing enzymes, but it’s not the only one that can have an effect on TKIs. Pomegranate juice will also interact with CYP3A4 enzymes in animals (Hidaka and colleagues. Drug Metab Dispos 2005;33:644-648). However, the evidence is mixed whether pomegranate juice will interact with medications in humans (Andrade C. J Clin Psychiatry 2014;75:e292-293; Srinivas NR. Eur J Drug Metab Pharmacokinet 2013;38:223-229).
Star fruit juice has been shown to increase drug levels about 30% so it’s prudent to avoid it if you’re taking a TKI (Hidaka and colleagues. Drug Metab Dispos 2006;34:343-345).
Another one to avoid is Seville orange juice, which is almost as potent as grapefruit juice in its effect on CYP3A4 enzymes in the liver and intestine (Malhotra and colleagues. Clin Pharmacol Ther 2001;69:14-23). Other types of orange juice, as well as apple juice, have the potential to alter drug metabolism by other mechanisms, although the significance of this finding isn’t known (Shirasaka and colleagues. Drug Metab Dispos 2013;41:615-621). The “apple juice effect” lasts about 4 hours.
Cranberry juice appears to have minimal effects on drug metabolism unless it’s consumed in large quantities – in the order of 1-2 litres a day (Srinivas SR. J Pharm Pharm Sci 2013;16:289-303). So moderation is the key.
For a list of drugs that interact with grapefruit juice, see Bailey and colleagues. Can Med Assoc J 2013;185:309-316; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3589309/pdf/1850309.pdf.
See Part 2 of this article on medications that can interact with your TKI.