Herb-Drug Interactions: Grapefruit

2011

Citrus paradisi Macfad. (Rutaceae)

Synonym(s) and related species

Citrus paradisi Macfad.

Grapefruit is a hybrid of the Pummelo or Pomelo (Citrus maxima (Burm.) Merr) with the sweet orange (Citrus sinensis (L.) Osbeck).

Constituents

Grapefruit contains furanocoumarins including bergamottin, 6′,7′-dihydroxybergamottin, bergapten, bergaptol, geranyl-coumarin and paradisin A, flavonoid glycosides such as naringin and flavonoid aglycones galangin, kaempferol, morin, naringenin, quercetin and others.

The peel contains a volatile oil, mostly composed of limonene.

Note that some grapefruit seed extracts have been found to contain preservatives such as benzethonium chloride, triclosan and methyl-p-hydroxybenzoate, which might be present because of the methods of production.

Use and indications

Grapefruit is used as a source of flavonoids (citrus bioflavonoids), which are widely used for their supposed antioxidant effects, and are covered under flavonoids.

Grapefruit seed extracts are used for their antimicrobial properties, but there is some controversy that this might be due to preservative content rather than natural constituents. Grapefruit and grapefruit juice are commonly ingested as part of the diet, and the oil is used as a fragrance.

Pharmacokinetics

Most of the data on the pharmacokinetics of grapefruit relate to the juice, which are summarised below. Note that it should not be directly extrapolated to herbal medicines containing grapefruit, because some differences in interaction potential have been seen. For information on the pharmacokinetics of the flavonoid constituents of grapefruit, see under flavonoids, and for information on the furanocoumarin constituents of grapefruit, see under natural coumarins.

(a) Cytochrome P450 isoenzymes

Grapefruit juice has been found to irreversibly inhibit the cytochrome P450 isoenzyme CYP3A4, and to cause drug interactions in quantities as low as 200 mL. Several compounds present are known to have inhibitory effects on CYP3A4, CYP2D6 and CYP2C9 in vitro, with the most potent thought to be the furanocoumarins, particularly dihydroxybergamottin, and the flavonoids naringenin and quercetin. However, the exact constituents that are responsible for the well-established clinical interactions of grapefruit juice are still uncertain. Naringin is present in grapefruit, but absent from other citrus fruits which led to the suggestion that naringin is the active principle, but this was later refuted. Quercetin has been reported to inhibit CYP3A4 in vitro; however, a clinical study found that, unlike grapefruit juice, quercetin alone, given at a concentration 40 times that found in the grapefruit juice, had no significant effect on the metabolism of nifedipine by CYP3A4. Furanocoumarins may also contribute to the interactions of grapefruit juice, because furanocoumarin-free grapefruit juice did not interact with felodipine, in one study. Nevertheless, none of the furanocoumarins individually appears to have much effect, and it appears that the net effect of all the furanocoumarins present determines the clinical effect. The effect of grapefruit juice on CYP3A is thought to be mainly exerted on intestinal CYP3A rather than hepatic CYP3A, because drugs given intravenously tend to be affected only to a small extent.

(b) P-glycoprotein

Based on the results of in vitro and interaction studies, it is thought that some component of grapefruit juice inhibits the activity of P-glycoprotein. However, note that there is no significant interaction with digoxin, a substrate of P-glycoprotein.

(c) Organic anion-transporting potypeptide (OATP)

In vitro, grapefruit juice has been shown to inhibit the organic anion-transporting protein (OATP), as have the individual ingredients bergamottin, 6′,7′-dihydroxybergamottin, quercetin, naringin, naringenin and tangeretin. The inhibitory effect of naringin on OATP1A2 has also been confirmed in another in vitro study. Inhibition of this transporter protein results in a modest reduction in the bioavailability of drugs that are substrates for this transporter, such as fexofenadine.

Interactions overview

The vast majority of known drug interactions of grapefruit have been reported with grapefruit juice, which is not used as a medicine or dietary supplement. For this reason, these interactions are not included here in detail, but they are summarised in the table Summary of established drug interactions of grapefruit juice. While most clinically important interactions of grapefruit juice result in an increase in drug exposure, note that modest decreased exposure occurs with the beta blockers celiprolol and talinolol, and with the antihistamine, fexofenadine.

The interactions of grapefruit juice are probably also applicable to the consumption of the fresh fruit, as reported with carbamazepine and some calcium-channel blockers, such as felodipine. An interaction has also been reported with grapefruit marmalade and tacrolimus. However, grapefruit juice interactions cannot be directly extrapolated to other grapefruit products such as the citrus bioflavonoids. In general, bioflavonoids are unlikely to interact to the same extent as grapefruit juice, because usually the furanocou-marins are required for a significant interaction to occur. However, there is evidence that citrus bioflavonoids alone might have an important interaction with lovastatin and simvastatin. For interactions of individual bioflavonoids present in grapefruit supplements, see under flavonoids, and for the interaction of individual furanocoumarins, see under natural coumarins.

There is one report of grapefruit seed extract interacting with warfarin; however, this was shown be due to the preservative content rather than the grapefruit extract.

Summary of established drug interactions of grapefruit juice

Drug Effect on AUC Recommendation
Avoid grapefruit juice with these drugs
Gclosporin Increase of 23 to 85% (trough level) Because of the likely adverse consequences of these interactions, it is probably best to avoid concurrent grapefruit juice altogether
Felodipine* Increase of two- to threefold
Halofantrine 2.8-fold increase
Lovastatin, simvastatin 1.6 to 16-fold increase
Primaquine Up to twofold increase
Tacrolimus** Increase of 300% (trough level)
Drugs requiring caution with grapefruit juice intake
Amiodarone Increase of 50% Monitor the effects of concurrent use. Consider advising limiting the intake of grapefruit juice and/or reducing the dose of the drug. Bear in mind that variability in the constituents of grapefruit juice and variability in timing and amount of the juice consumed complicate management of these interactions
Atorvastatin 2.5-fold increase
Buspirone 9-fold increase
Carbamazepine* Increase of 40%
Celiprolol Decrease of 87%
D extro m eth o rp h an Fivefold increase
Ivabradine Twofold increase
Nicardipine, mfedipine,* nimodipine, nisoldipine* Up to twofold increase
Verapamil*** Increase of 40%
Drugs for which the interaction with grapefruit juice is usually of tittle practical importance
Benzodiazepines: These interactions are generally unlikely to be clinically relevant. Bear them in mind in the event of an unexpected response to treatment
– Diazepam 3.2-fold increase
– Oral Midazolam Increase of 52%
– Triazolam Increase of 50 to 150%
Digoxin Increase of 10%
Erythromycin Increase of 49%
Fexofenadine Decrease of up to 67%
Fluvoxamine Increase of 60%
Methyl prednisolone Increase of 75%
Praziquantel Increase of 90%
Saquinavir Increase of 50%
Sertraline Increase of 50% (trough level)
Sildenafil*** Increase of 25%
Talinolol Decrease of 44%

* Effect also seen with the fruit (grapefruit segments or grapefruit pulp).
** Effect also seen with excessive consumption of grapefruit marmalade.
*** Manufacturer actually advises avoidance of grapefruit juice with these drugs.

Grapefruit + Caffeine

For mention that grapefruit juice and one of its constituents naringin, a grapefruit flavonoid, had no effect on the metabolism of caffeine, see Flavonoids + Caffeine.

Grapefruit + Calcium-channel blockers

Grapefruit segments increase the exposure to nifedipine, nisoldipine and felodipine.

Clinical evidence

In a single-dose pharmacokinetic study in 12 healthy subjects, homogenised grapefruit segments or an extract from the segment-free parts increased the AUC of felodipine by 3.2-fold and 3.6-fold, respectively. This increase was the same or slightly greater than the increase seen with 250 mL of grapefruit juice. In another single-dose study in 8 healthy subjects, grapefruit pulp from one grapefruit increased the AUC of both nifedipine and nisoldipine by about 30%, and increased the maximum concentration of nifedipine and nisoldipine by about 40% and 50%, respectively, when the grapefruit was eaten 1 hour before taking the calcium-channel blocker. The authors noted that these increases were smaller than those previously seen with grapefruit juice.

Experimental evidence

Because these interactions are established, experimental data have not been sought.

Mechanism

Grapefruit appears to inhibit the activity of the cytochrome P450 isoenzymes CYP3A subfamily in the intestinal wall so that the first-pass metabolism of these calcium-channel blockers is reduced, thereby increasing their bioavailability and therefore their effects. Grapefruit juice is well established to have this effect.

One small clinical study suggests that quercetin is not involved in the interaction between grapefruit juice and nifedipine.

Importance and management

These interactions are established. It has been suggested that whole grapefruit should be avoided in patients taking felodipine. Given the data here, this would appear to be prudent advice. It has also been suggested that other products made from whole grapefruit such as marmalade should be avoided, although there is no published evidence that grapefruit marmalade may interact with calcium-channel blockers. However, an isolated case describes raised tacrolimus levels and toxicity associated with the excessive consumption of grapefruit marmalade. See Grapefruit + Tacrolimus, below.

For mention that furanocoumarin-free grapefruit juice had no consistent effect on felodipine pharmacokinetics, but also that no individual furanocoumarin tested had an effect as great as grapefruit juice, see Natural coumarins + Felodipine.

Some caution would also be appropriate with nifedipine and nisoldipine. There appears to be no specific information on a potential interaction between whole grapefruit and other calcium-channel blockers. However, it may be worth considering an interaction with grapefruit in any patient who complains of an otherwise unexplained increase in adverse effects with any of the calcium-channel blockers.

Grapefruit + Carbamazepine

A case of possible carbamazepine toxicity has been seen when a man taking carbamazepine started to eat grapefruit.

Clinical evidence

A 58-year-old man, taking carbamazepine 1 g daily for epilepsy developed visual disturbances with diplopia, and was found to have a carbamazepine level of 11 micrograms/mL (therapeutic range 4 to 10 micrograms/mL). Previous levels had not exceeded 5.4 micrograms/mL. The patient said that one month previously he had started to eat one whole grapefruit each day. The levels restabilised at 5.1 micrograms/mL after the carbamazepine dose was reduced to 800 mg daily.

Experimental evidence

No relevant data found.

Mechanism

The cytochrome P450 isoenzyme CYP3A4 is the main isoenzyme involved in the metabolism of carbamazepine. Components of grapefruit juice are known to inhibit CYP3A4, which in this case would lead to a reduction in the metabolism of carbamazepine, and therefore an increase in levels.

Importance and management

Evidence for an interaction between grapefruit and carbamazepine appears to be limited to one isolated case. In this report, the patient continued to eat grapefruit, and this was successfully managed by a reduction in the carbamazepine dose. However, it should be noted that intake of a set amount of grapefruit would need to be maintained for this approach to work, and carbamazepine dosage adjustment and monitoring of levels should be undertaken as appropriate. If monitoring is not practical, or regular intake of grapefruit is not desired, it may be prudent to avoid grapefruit.

Grapefruit + Fexofenadine

For mention that grapefruit juice and, to a lesser extent, naringin, a grapefruit flavonoid, modestly decrease the AUC of fexofenadine, see Flavonoids + Fexofenadine.

Grapefruit + Food

No interactions found. For mention that grapefruit juice and one of its constituents naringin, a grapefruit flavonoid, had no effect on the metabolism of caffeine, see Flavonoids + Caffeine.

Grapefruit + Herbal medicines

No interactions found. Note that naringin, a grapefruit flavonoid, and grapefruit juice do not alter the metabolism of caffeine, see Flavonoids + Caffeine, and so would be unlikely to interact with caffeine in caffeine-containing herbs.

Grapefruit + Tacrolimus

A case of tacrolimus toxicity has been seen when a man ate more than 1.5 kg of grapefruit marmalade during one week.

Clinical evidence

A 52-year-old man with a liver transplant, stabilised on tacrolimus 3 mg twice daily, began to feel anxious and febrile with continued trembling and blurred vision. Within 5 days he deteriorated and developed severe left chest pain. His tacrolimus whole blood level was found to be markedly raised to 55.4 micrograms/L from a previous therapeutic level (between 8 and 13 micrograms/L), and he had renal impairment (serum creatinine of 174 micromols/L). It transpired that during the week preceding the onset of symptoms he had eaten more than 1.5 kg of a home-made marmalade, which was made with more than 50% grapefruit.

Experimental evidence

No relevant data found.

Mechanism

It is well established that grapefruit juice increases levels of tacrolimus, and this case appears to show that this can occur with grapefruit marmalade. The process of making marmalade uses the whole fruit, and it appears that, whatever the active interacting constituents are, these are not destroyed by the long boiling.

Importance and management

This is the first case to show that a drug interaction can occur with grapefruit marmalade. As such, it requires confirmation by further study. Note that, in this case, the patient consumed an unusually large amount of marmalade (estimated 14 dessert spoonfuls (15 g) daily). More modest consumption (a spoonful of about 15 g daily) would appear unlikely to interact. Note that grapefruit juice is well established to interact with tacrolimus and combined use should be avoided.

Grapefruit + Warfarin

A rise in INR occurred in a couple taking warfarin who took a grapefruit seed extract product containing considerable amounts of the preservative benzethonium chloride for 3 days. One of them developed a minor haematoma.

Clinical evidence

A couple, both well stabilised on warfarin, took some drops of a grapefruit seed extract product (Estratto di Semillas di Pompelmo, Lakshmi, Italy) for 3 days. No more was taken, but after a further 3 days the woman developed a minor subcutaneous haematoma, and her INR was found to be 7.9. The man was found to have an INR of 5.1, with no evidence of bleeding.

Experimental evidence

See under Mechanism, below.

Mechanism

The product used was stated to contain grapefruit seed extract, glycerol and water. However, chemical analysis of this product revealed that it also contained considerable amounts (77 mg/mL) of the preservative, benzethonium chloride, and did not contain any significant amount of natural substances from grapefruit seeds. The constituents of two other commercial grapefruit seed products were similar on analysis (Citroseed and Citricidal).

Further, in vitro analysis showed that benzethonium chloride, and the three products, were potent inhibitors of the cytochrome P450 isoenzyme CYP2C9, suggesting that they could inhibit the metabolism of warfarin.

Importance and management

Data presented in this report, and other papers (one of which is cited as an example), suggest that the primary constituent of many grapefruit seed extract products appears to be the preservative benzethonium chloride. The evidence from the two cases, backed by in vitro data, suggests that this has the potential to interact with warfarin. On this basis, it would probably be prudent for patients taking warfarin to avoid grapefruit seed extract products, or for concurrent use to be monitored closely. Some caution might also be appropriate with other pharmaceutical preparations containing benzethonium chloride.