Grapefruit and Medicines - Drug Interactions

Grapefruit is a citrus fruit with a thousand beneficial properties. It is rich in vitamin C, minerals, citric acid and pectins.

It is excellent in summer for slimming diets as it is refreshing and provides only a few calories (26Kcal / 100g). It has digestive, diuretic and purifying properties ... in short, it is a real panacea for health!
Despite all the beneficial properties of grapefruit, not everyone knows however that this fruit can interfere with some drugs, significantly affecting their biological activity through metabolic interactions.

Discovery

This information was made public as early as 1989, when by pure chance, grapefruit juice was used as an add-on to a placebo in a drug test in Canada.
In the placebo group with grapefruit juice, the plasma concentration of felodipine (a vasodilator drug used for hypertension) was unexpectedly high.
Since then, a myriad of research has started to confirm the "drug-grapefruit interaction. It was thus possible to discover that grapefruit interferes with numerous drugs including: statins, anti-rhythmics, immunosuppressive agents and calcium channel blockers (see table ).
There are, however, other classes of drugs that have not shown any toxic effect when taken with grapefruit juice, these drugs can therefore be used as an alternative therapy in those patients who show a high risk of drug interaction with grapefruit. Patients, however, they may choose to exclude grapefruit from their diet and consume other types of fruit, including other citrus fruits, in order to avoid a toxic interaction.

Table. Grapefruit-drug interactions and alternative therapies Drugs divided by classes Drugs that can potentially interact with grapefruit Effects of the interaction Alternative treatments Antiarrhythmics Amiodarone, disopyramide, quinidine Increased plasma levels of amiodarone may cause thyroid or lung toxicity, liver damage, QT prolongation, proarrhythmic disorders and bradycardia.
The increase in plasma levels of quinidine and disopyramide can be cardiotoxic and induce torsades de pointes. Digoxin, diltiazem, verapamil, beta blockers Calcium antagonists Felodipine, nicardipine, nifedipine, nimodipine, nisoldipine Increased plasma levels of these drugs can induce flushing, peripheral edema, headache, tachycardia, symptomatic hypotension and, in rare cases, myocardial infarction. Amlodipine, diltiazem, verapamil Statins Atorvastatin, lovastatin, simvastatin The increased plasma levels can cause headache, gastrointestinal disturbances, liver inflammation and myopathies (eg rhabdomyolysis). Fluvastatin, pravastatin, rosuvastatin
Fibrates, nicotinic acid, bile acid sequestrants Immunosop-pressors Ciclosporin, tacrolimus Increased adverse effects induced by these drugs.
Nephrotoxicity, hepatotoxicity and increased immunosuppressive effect. No alternatives are available Protease inhibitors Saquinavir The increase in plasma levels may cause an increased incidence of side effects, such as headache, fatigue, insomnia and anxiety. Amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir / ritonavir, nelfinavir, ritonavir

Mechanism of action:

Investigations carried out on grapefruit juice have shown that some components of this fruit, such as bergamottin and naringin (Fig. 1) are potent inhibitors of cytochrome P450 3A4 (CYP3A4).

Fig.1 Chemical structure

This enzyme, expressed in the intestine and in the liver, is the main actor responsible for the detoxification of the organism from about 50% of the currently existing drugs.

The interaction of the drug with grapefruit juice occurs mainly by inhibition of intestinal CYP3A4, which causes a slower disposal of the drug and its excessive permanence in the organism (Fig. 2). For this reason, overdose phenomena are frequent following the intake of grapefruit and the drug.

Since inhibition of CYP3A4 occurs in the intestine, drug-grapefruit juice interactions occur only with oral formulations. Studies carried out on drugs metabolised by hepatic CYP3A4, administered intravenously, have shown that grapefruit juice does not modify their plasma levels.

Fig. 2 Pre-systemic metabolism of felodipine by CYP3A4 on enterocytes and in the liver. CYP3A4 metabolizes the drug until its bioavailability is reduced by 15%. Grapefruit, on the other hand, by inhibiting the enzyme increases the bioavailability of the drug by 45%.

Quantity and duration of the effect

Intestinal levels of CYP3A4 can be reduced by 47% within a couple of hours of taking grapefruit.
Furthermore, it has been shown that drug interactions can also occur with the intake of modest quantities of grapefruit juice or fresh fruit (250 g).
This enzymatic inactivation can last for a long period (about 3 days), therefore it would be advisable avoid ingesting grapefruit products at least 72 hours before taking a drug.
However, there is a large biological variability of intestinal CYP3A4 expression (genetic polymorphism), consequently it is difficult to be able to predict with certainty, from one patient to another, a possible drug interaction involving grapefruit juice. In any case. , the higher the intestinal content of this enzyme, the greater the risk of toxic effects.

Side effects

Grapefruit, causing the "increase in plasma levels of some drugs, creates a condition of overdose. This" increased concentration of the drug in our body is responsible for possible mild side effects, such as: headache, fatigue, gastrointestinal disorders, but sometimes also effects serious collateral, such as: kidney disease and heart disease. A sensational case of grapefruit drug interaction occurred in the USA, when a 29-year-old man died prematurely following the simultaneous intake of Terfenadine (an antihistamine) and grapefruit juice. The drug was immediately removed from the market. Since some drug interactions can be particularly serious, pharmaceutical companies, manufacturers for example of cyclosporine and simvastatin, have decided to add special warnings on the package leaflet about the use of grapefruit products. in patients being treated with these drugs.

Recommendations

The intent of this article of mine is not to cause alarmism or discourage the consumption of grapefruit, but to inform. It is therefore sufficient not to consume grapefruits or their derivatives when taking certain drugs!
Although to date there are no definitive data on this, it would seem that other types of citrus fruits such as oranges also Seville and the mapo (a hybrid between grapefruit and tangerine) can interfere, similarly to grapefruit juice, with the metabolism of some drugs.
We can safely consume other citrus fruits such as: oranges, tangerines and lemons which instead have no effect on CYP3A4.

Bibliography

1. Bailey DG, Spence JD, Edgar B, Bayliff CD, Arnold JM. Ethanol enhances the hemodynamic effects of felodipine. Clin Invest Med. 1989;12:357–62.
2. Edwards DJ, Bellevue FH, Woster PM. Identification of 6 ', 7'-dihydroxybergamottin, a cytochrome P450, in grapefruit juice. Drug Metab Dispos. 1996; 24: 1287-1290.
3. Kuhnau J. The flavonoids: a class of semi-essential food components; their role in human nutrition. World Rev Nutr Diet. 1976; 24: 117–191
4. Dahan A, Altman H. Food-drug interaction: grapefruit juice augments drug bioavailabilitymechanism, extent and relevance. Eur J Clin Nutr 2004; 58: 1-9.
5. Dresser GK, Bailey DG. The effects of fruit juices on drug disposition: a new model for druginteractions. Eur J Clin Invest 2003; 33: 10-6.
6. Huang SM, et al. for the Center for Drug Evaluation and Research and Office of Regulatory Affairs, U.S. Food and Drug Administration. Drug interactions with herbal products and grapefruit juice: a conference report. Clin Pharmacol Ther 2004; 75: 1-12.

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