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-Only drugs specifically studied with grapefruit are included. Other CYP3A4 substrates might also interact-

Note: "AUC" refers to area under the plasma concentration vs. time curve and is an indicator of bioavailability

* Many of these interactions have been documented by observing serum concentration changes without alteration of the responses to the drugs. Because of this and the variability in these interactions, clinicians should consider the above listing as potential interactions and monitor patients accordingly. To avoid any potential interaction, have patients avoid eating grapefruit or drinking grapefruit juice while on these medications.

Background

Grapefruit juice has been shown to affect the metabolism of several drugs.^29,30 Included in the list of potential target drugs are diazepam, cisapride, cyclosporine, felodipine and other dihydropyridine calcium channel blockers, midazolam, nisoldipine, triazolam, saquinavir, lovastatin, and atorvastatin. The mechanism of the drug-drug interaction appears to primarily result from inhibition of CYP3A4 in the intestinal wall and is most important for drugs with high first pass metabolism.²⁹ Large amounts may also inhibit CYP450 in the liver.⁴⁸ Other mechanisms that might also be involved include inhibition of intestinal P-glycoprotein and organic anion transporting peptide (OATP).

P-glycoprotein is a drug transporter that is present at high levels in the intestinal mucosa.³⁸ It inhibits the absorption and increases the excretion of drugs. Researchers are now suggesting that grapefruit juice might be an inhibitor of P-glycoprotein, mainly in the gut.^39,40,49 There is very preliminary evidence that grapefruit might also inhibit the transporter OATP at the intestinal level.⁴¹ This transporter, unlike P-glycoprotein, transports substances into cells. More research is needed to determine the significance of the OATP interaction.

Several constituents of grapefruit juice have been implicated including the flavonoids naringin and naringenin, along with the furanocoumarins, bergapten and 6,7-dihydroxybergamottin.^29,31,42,43 Unfortunately, the content of these varies between different grapefruit juices and varieties of fruit, making it impossible to determine if one is safer than another.^32,43

How Long Does the Inhibition Last?

Takanaga et al (2000) performed a study to clarify how long grapefruit juice inhibits intestinal CYP3A4.³³ They used oral nisoldipine because it fits the characteristics of a drug that would be susceptible to this interaction. The study group included eight healthy subjects. None were taking any drugs that would affect CYP3A4, and two were smokers. Each subject underwent six trials, each separated by at least one week. The trials are described below:

1. Control: 10 mg nisoldipine with water
2. G0: 5 mg nisoldipine with 200 mL grapefruit juice
3. G14: 5 mg nisoldipine 14 hours after 7 days of TID grapefruit juice
4. G38: 5 mg nisoldipine 38 hours after 7 days of TID grapefruit juice
5. G72: 5 mg nisoldipine 72 hours after 7 days of TID grapefruit juice
6. G96: 5 mg nisoldipine 96 hours after 7 days of TID grapefruit juice

During the seven-day grapefruit juice administration, it was ingested at 9 a.m., 1 p.m., and 7 p.m. For G14-G96 the drug was ingested at the indicated number of hours after the last ingestion of grapefruit juice. Pharmacokinetics variables were determined after serum sampling for nisoldipine to determine Cmax, tmax, t1/2, and AUC. The pharmacodynamic impact was evaluated by monitoring heart rate and blood pressure for the maximal effect (Emax) and area under the effect (AUE) curve. Adverse effects were monitored by asking the subjects for spontaneous reports and open questioning.

Systolic and diastolic blood pressures were significantly decreased for eight hours after the dose in the G0 condition. The effects varied in the other study conditions. The systolic blood pressure was still significantly decreased in the G38 condition, and the diastolic AUE was still significantly decreased in the G72 condition. Adverse events were spontaneously reported in each treatment. Headaches were reported by three subjects in G0, two in G14, and one in G38.

The pharmacokinetics of nisoldipine were significantly altered by grapefruit juice. The plasma concentration was significantly elevated in the G0 to G72 groups. Cmax was significantly elevated in G0 and G14. In contrast, neither tmax nor t1/2 were significantly altered by grapefruit juice. The authors of this study concluded that it would be necessary to withhold grapefruit juice for at least three days before administration of this drug in order to avoid a drug interaction.

Commentary

The maximal impact of the first dose in this study agrees with a recent study looking at felodipine.³⁴ Near maximum inhibition of gut CYP3A4 occurs with just 200 mL⁴⁸ (less than a typical serving), and even lesser amounts can interact.⁴⁹

This study gives a clearer picture of the duration of the impact of grapefruit juice on CYP3A4 activity. The pharmacokinetic parameters appear to be affected for at least three days following ingestion, and could perhaps be longer in some patients.

In the Takanaga et al study, the pharmacodynamic impact did last up to 72 hours, but effects declined after ingestion as time went on and were much greater in the situation where the drug was taken with the grapefruit juice. Another study in healthy volunteers found that after a single 300 mL serving, half the gut enzymes had recovered after 23 hours.⁷⁶ This might be enough recovery to prevent a clinically significant interaction in some patients. But for others, it may take longer for normal metabolism to return. The only way to avoid this interaction is to advise patients to not ingest grapefruit juice.

Grapefruit juice does not normally inhibit the pharmacokinetics of medications administered intravenously. At usual doses it only affects enzymes in the gut wall. However, high consumption could inhibit liver CYP3A4 and prolong drug half-life.⁴⁸

In addition to grapefruit juice, many researchers are warning that the fruit itself could also cause problems. Several studies now indicate that the fruit should also be avoided in patients taking interacting drugs.^42-44 Health Canada is now advising consumers NOT to drink grapefruit juice or eat grapefruit in any form if they are taking medications that might interact, until they have talked to their doctor or pharmacist about the potential for side effects.³⁵

While sweet oranges and their juice do not appear to cause the same reaction, sour orange juice, such as that from Seville oranges, may have an effect similar to grapefruit juice. However, Seville orange juice is unpalatable, so Seville oranges are more often consumed as marmalade.⁴⁹ Preliminary research suggests lime juice might also have this effect.⁴⁵ Tangelos are a hybrid of grapefruit and may also interfere with drugs. Most other citrus fruits, such as lemons, citrons, naturally sweet oranges, and tangerines are considered safe.³⁵ There's no proof citrus or grapefruit-flavored sodas interact.⁷⁷

Most adverse events resulting from grapefruit interactions have been minor.⁵⁰ However, attempts to classify interactions as "mild," "moderate," or "severe" may be misleading. This is because the clinical significance of grapefruit juice interactions is likely to vary from patient-to-patient. Factors that may affect response include the patient's intestinal CYP3A4 content, age, and medical conditions.⁴⁸ For this reason, empiric dosage adjustment in an effort to avoid the interaction may not be effective. Instead, advise patients taking potentially interacting drugs to avoid grapefruit [Evidence level C; expert opinion].⁴⁹ If a patient insists on grapefruit, consider an alternative drug known not to interact.

Project Leaders in preparation of this Detail-Document: Melanie Cupp, Pharm.D., BCPS (January 2007 update), William A. Kehoe, Pharm.D., MA, FCCP, BCPS (original author)

Levels of Evidence

In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish.

Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65:251-8.