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 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.39,40 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) recently 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
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. The maximal impact of the first dose in this study agrees with a recent study looking at felodipine.34
So we now have two important pieces of information. For drugs that are significantly impacted by this interaction, one glass (8 ounces or 250 mL) of
grapefruit juice is enough to cause the interaction, and following regular ingestion, the effect can last for up to three days following the last glass. Since most patients
take medications on a somewhat regular basis, it appears that the safest approach is to avoid grapefruit juice altogether.
It is important to note that the study of Takanaga et al was done in healthy
volunteers. 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. However, in patients who are taking the drug for diseases, these pharmacodynamic alterations could be more
risky. So it would be very difficult to say that these changes would not be important for real patients waiting to take their medication later in the day after ingesting
juice. The only way to avoid this interaction is to advise patients to not ingest grapefruit juice. Other alternatives, such as orange juice, may be more appropriate.
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.
42,43,44 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. 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.
