Grapefruit Interactions with Medications

Between 2008 and 2012, the number of medications with the potential to interact with grapefruit and cause serious adverse effects ( torsade de pointes , rhabdomyolysis, myelotoxicity, respiratory depression, gastrointestinal bleeding, nephrotoxicity) has increased, from 17 to 43, which represents an average increase rate of more than 6 medications/year. This increase is due to the introduction of new chemical entities and formulations.

The authors have focused on grapefruit because it is the most widely examined, but there are other citrus fruits that may have similar consequences. It has been proven that grapefruit and some other citrus juices act by an additional mechanism to cause a decrease in the systemic concentration of certain drugs, by inhibiting the drug transporter.

Drug actions take place through several biological mechanisms. The most important is drug metabolism that involves oxidation by enzymes belonging to the cytochrome P450 superfamily. Cytochrome P450 3A4 (CPY3A4) is particularly essential because it is involved in the bioinactivation of almost 50% of drugs. CYP3A4 is found in the epithelial cells (enterocytes) that line the small intestine and colon, and in the liver parenchyma cells (hepatocytes).

Consequently, orally administered medications can be metabolized twice before reaching the systemic circulation. Thus, the percentage of drugs absorbed unchanged (oral bioavailability) may be markedly attenuated.

For example, the oral bioavailability of the antihypertensive drug felodipine is typically reduced to 15% of the oral dose. In other words, felodipine has low innate bioavailability. For this reason, during systemic exposure there is an increased risk of overdose with grapefruit intake, as a result of decreased CYP3A4 activity, primarily in the small intestine (rather than the liver).

The chemicals involved in this interaction with grapefruit are furanocoumarins. Furanocoumarins are metabolized to reactive intermediates by CYP3A4, binding covalently to the active site of the enzyme, causing irreversible inactivation (mechanism based on inhibition).

Consequently, CYP3A4 activity in the small intestine deteriorates until de novo synthesis returns the enzyme to its previous level. This mechanism explains the important clinical effects on the pharmacokinetics of the drug, specifically its peak plasma concentration (Cmax) and the plasma concentration of a drug over a defined time interval (AUC: area under the curve). These key parameters of oral bioavailability are increased while the systemic elimination half-life remains unchanged. The pharmacokinetics of drugs administered intravenously do not change.

Because these chemicals are innate to grapefruit, all forms of the fruit (fresh-squeezed juice, frozen concentrate, and whole fruit) have the potential to reduce CYP3A4 activity.

One whole grapefruit or 200 ml of its juice is sufficient to clinically cause a significant increase in the systemic concentration of the drug and its subsequent adverse effects. 

Seville oranges (often used in jams), limes and grapefruits also produce this interaction. Sweet orange varieties, such as navel (navel orange) or valencia oranges, do not contain furanocoumarins and do not produce this interaction.

The interaction between the drug and grapefruit is drug-specific and is not a class effect.

The affected drugs have 3 essential characteristics : they are orally administered, they intrinsically have very low (<10%) to intermediate (>30%–70%) oral bioavailability and are metabolized by CYP3A4.

These criteria can often be found in the product monograph or package insert (under “Clinical Pharmacology”), especially for recently marketed drugs, allowing the possibility of an interaction to be predicted. In principle, this would help professionals in formulating appropriate management strategies, without exposing patients to potentially harmful risks.

The clinical significance of any particular interaction depends on the severity of the dose-related toxicity of the drugs and the degree to which the systemic concentration of the drug is increased. The latter depends on multiple factors including the innate oral bioavailability of the interacting drug, the circumstances under which grapefruit or other citrus fruits are consumed, and the patient’s vulnerability to the interaction.

The lower the innate oral bioavailability of the drug, the greater the potential increase in systemic drug concentration.

Drugs that interact with grapefruit can be separated into 4 absolute bioavailability categories: very low (<10%), low (10%–30%), intermediate (>30%–70%), and high (>70%).

Drugs with very low bioavailability are those most likely to interact with grapefruit, such that their pharmacokinetics are substantially altered (i.e., as if many doses of the drug were taken alone). In contrast, drugs with high bioavailability have a clinically insignificant increase in systemic drug concentration.

Although some pharmacokinetic studies have tested a higher amount of grapefruit than is usually involved in determining maximal effect, this should not be interpreted to mean that a significant pharmacokinetic effect will only occur if the level of grapefruit consumption is high.

In fact, a single typical amount (200 to 250 ml of juice or a whole grapefruit) has sufficient potency to cause a relevant pharmacokinetic interaction.

For example, felodipine combined with such an amount of grapefruit had a mean systemic drug concentration that was 3 times higher than that observed with water ingestion. With double the amount of grapefruit, there was only a modest increase in the systemic concentration of felodipine, showing that the pharmacokinetic action is almost maximal.

The interaction had already occurred with the consumption of the grapefruit unit. With repeated ingestion of grapefruit (250 ml of juice, 3 times/day) for 6 days), the single dose of felodipine increased to 5 times the systemic concentration observed with water, suggesting that frequent consumption of a daily amount usual increased the pharmacokinetic effect, rather than just the quantity.

The interval between grapefruit ingestion and administration of the interacting drug has some effect on pharmacokinetics. For example, a single glass (200 mL) of grapefruit juice ingested within 4 hours prior to the peak pharmacokinetic interaction of felodipine. Thereafter, a longer interval between ingestion of the 2 substances slowly decreased the size of the effect. The 10-hour interval produced an effect that was 50% of the maximum, and a 24-hour interval produced an effect that was 25%. of the maximum.

Thus, a modest amount of a single grapefruit may have a sufficiently long-lasting action to affect interacting drugs, administered once/day, at any time during the dosing interval. On the other hand, repeated ingestion of grapefruit (200 ml of juice, 3 times/day for 7 days) doubled the size of the interaction over 24 hours, consistent with a cumulative inhibitory action.

Theoretically, it is possible that batch processing, type (white or pink grapefruit), and storage conditions of grapefruit could influence the size of the interaction. However, to the best of our knowledge, these aspects have not been systematically studied.

The patient’s vulnerability to this pharmacokinetic interaction varies markedly. For example, individual systemic concentrations of felodipine with a serving of grapefruit juice (250 ml) ranged from 0 to 8 times that seen with water.

A biopsy of the small intestine showed that higher levels of CYP3A4 before ingesting grapefruit juice resulted in a more pronounced decrease in enzymes and a greater increase in oral drug bioavailability after consumption of the juice. Consequently, patients with elevated levels of CYP3A4 in the small intestine appear to be at increased risk for this interaction. It is not practical to routinely determine the CYP3A4 content of enterocytes in clinical practice.

However, patients with significant intestinal levels of CYP3A4 may require a higher dose of a drug that interacts with grapefruit to achieve an adequate systemic concentration. Thus, this is a possible means of identifying patients at highest risk, prior to exposure to an interaction with medications typically titrated for a therapeutic effect.

Despite current knowledge from well-conducted clinical trial research, the key question remains as to how frequently the adverse effects of this interaction occur in routine clinical practice. Because the combination of multiple factors is likely to be necessary to achieve a marked increase in systemic drug concentration, it is reasonable to state that simple exposure to any interactive combination would not be sufficient to cause a significant change in clinical evaluation, in response to all medications, if not in most cases. However, important toxic substance events have been documented due to drug interactions with grapefruit.

These case reports uniformly cited the circumstance of a patient whose therapeutic dose of a susceptible drug was stabilized, and who subsequently showed severe toxicity occurring after several days of simultaneous ingestion of the drug and grapefruit in normal or high amounts. But what is the magnitude of the problem of such interactions?

Unless healthcare professionals are aware of the possibility that the adverse event the patient is experiencing may have an origin in the recent addition of grapefruit to the diet, it is very unlikely that they will investigate it, other than the patient You cannot volunteer this information. Thus, the authors maintain that there is still a lack of knowledge about this interaction in health care in the general community.

Consequently, the current data are not sufficient to provide an absolute figure or even the approximate number that represents the actual incidence of grapefruit-drug interactions in routine practice. However, there are certain situations in which this interaction is more predictably likely to produce clinical effects, particularly adverse outcomes.

Although patient vulnerability is largely unknown, people >45 years of age are the primary buyers of grapefruit and receive the largest number of medication prescriptions.

Due to the size of this population, substantial exposure to this interaction is likely. A pronounced pharmacokinetic interaction has also been demonstrated in patients >70 years of age. On the other hand, older adults may have a greater capacity to compensate for excess systemic drug concentrations.

For example, felodipine (which normally lowers blood pressure) does not cause a compensatory increase in heart rate in older adults when taken with grapefruit, but does cause a compensatory increase in heart rate in older adults when taken with grapefruit, but it does in young and middle-aged people, probably due to the attenuated sensitivity of the age-associated baroreceptors.

Consequently, older people appear to be a particularly vulnerable population to grapefruit–drug interactions. The predicted interaction risk for grapefruit-drug interaction (i.e., very high, high, intermediate, low) may assist physicians in prescribing medications to vulnerable patients, and determining whether grapefruit or other citrus fruits should be used. be contraindicated during pharmacotherapy, or whether alternative therapy can be used.

Examples selected to illustrate documented pharmacokinetic changes that have serious clinical outcomes are: torsade de pointes , rhabdomyolysis, nephrotoxicity, and breast cancer.

> Torsade de pointes

Torsade de pointes and risk of sudden death may occur with excessive prolongation of the corrected QT interval. The antiarrhythmic agent amiodarone had a mean Cmax with grapefruit juice (300 ml at 0, 3 and 9 hours after drug administration) corresponding to 180% of that observed with water; The AUCs were 150% of the AUCs with water. The combination has also been reported to markedly prolong the corrected QT interval and in clinical practice cause ventricular arrhythmias, including torsade de pointes .

Dronedarone, the chemical analog of amiodarone, was associated with ventricular arrhythmia, cardiac arrest, and torsade de pointes in clinical practice. Dronedarone with grapefruit juice (300 ml, 3 times/day) resulted in a systemic drug concentration 300% higher than that of a control. Torsade de pointes can also occur with certain anticancer agents.

The tyrosine kinase inhibitor nilotinib had a mean Cmax with a single glass of grapefruit juice (480 mL) that was 160% of the Cmax taken with water, and an AUC that was 129% of the AUC with water. Sunitinib, another tyrosine kinase inhibitor, had an average bioavailability with the consumption of grapefruit (200 ml, 3 times/day for 3 days) 111% the bioavailability without having consumed grapefruit. Although the pharmacokinetic interaction was weaker with sunitinib, the potential severity of adverse effects and concerns about interpatient variability would still justify avoiding grapefruit.

> Rhabdomyolysis

Rhabdomyolysis is the consequence of deep damage to skeletal muscle tissue, with the release of large amounts of proteins into the blood, such as myoglobin, and acute kidney failure. At excessive systemic concentrations, the active forms of all statins can produce this toxicity. Simvastatin with large volume grapefruit juice (400 mL, 3 times/day for 3 days) had an AUC that was 700% of the AUC for water; with a more usual amount of juice (200 ml, once/day for 3 days) the AUC was 330% of that for water.

Rhabdomyolysis was also reported after 10 days of concomitant fresh grapefruit consumption. Lovastatin with grapefruit juice at a high intake level (400 mL, 3 times/day for 3 days) caused an AUC that was 500% of the AUC of water. Atorvastatin had an AUC with grapefruit juice (250–400 mL, 3 times/day for 2–4 days) that ranged from 180% to 250% of that with water.

Rhabdomyolysis has also been reported with grapefruit ingested in routine amounts. Therefore, this adverse outcome with certain statins may occur with the ingestion of much less grapefruit than previously expressed by the US Food and Drug Administration. However, taking atorvastatin at night and drinking grapefruit juice in the morning (300 ml/d from a specific lot prepared by the Florida Department of Citrus) resulted in serum drug concentrations of 119% to 126% of those observed without grapefruit consumption, with no evidence of skeletal muscle toxicity ( e.g., elevated creatine phosphokinase, myalgia).

On the other hand, pravastatin does not cause a pharmacokinetic interaction with grapefruit; rosuvastatin is eliminated unchanged and fluvastatin is metabolized by an enzyme (CYP450 2C9) that is not affected by grapefruit. To reduce the risk, instead of replacing the medication, the authors believe it is advisable to eliminate the ingestion of grapefruit juice.

> Nephrotoxicity

Nephrotoxicity can occur following ingestion of calcineurin inhibitors, cyclosporine and tacrolimus, which are vital in preventing organ rejection after transplantation. Both drugs have a narrow range of therapeutic blood concentrations (i.e., below which they lack sufficient efficacy and above which they cause toxicity).

Cyclosporine with grapefruit juice (single 250 ml serving) produced a mean oral bioavailability of 162% that of water. In 1 of the 9 patients involved in this study, systemic medication availability increased to 670%. Furthermore, a case report showed that the concentration of cyclosporine increased to 600% with grapefruit.

Ingestion of tacrolimus after ingesting grapefruit juice (250 mL, 4 times/day for 3 days) resulted in a 1,000% higher blood trough concentration, resulting in profound calcineurin phosphatase inhibition in the transplant recipient. of liver. On the other hand, ingestion of tacrolimus after consuming a large amount of grapefruit jam during the previous week caused a 500% higher blood concentration of the drug and acute kidney dysfunction.

> Breast cancer

Two large epidemiological studies evaluated the risk of breast cancer with increased oral bioavailability of estrogens (ethinyl estradiol and 17-β-estradiol) with grapefruit juice.

Initially, the research found greater risk in postmenopausal women who were taking estrogen and consuming a quarter of a grapefruit or more/day compared to women who did not eat grapefruit. However, a follow-up study involving the same population found no such association. Therefore, there is controversy about the risk of breast cancer in postmenopausal women who receive estrogen therapy and consume grapefruit.

Although many efforts have been made to provide a complete list of currently known and anticipated medications that would interact with grapefruit, the absence of a medication on the aforementioned list should not be interpreted as lacking this interaction.

The few case reports presented in this review should not be considered a useful index of the frequency of occurrence of serious grapefruit-drug interactions in general practice, as they are likely to be under-reported.

Grapefruit and some other citrus fruits represent examples of foods generally considered healthy, but with the potential for a pharmacokinetic interaction that results in increased bioavailability of the oral drug.

The current trend of adding to the list recently marketed drugs that are affected by grapefruit ingestion, and that have substantial adverse clinical effects, requires more knowledge of this interaction and the intention to apply this knowledge for the safety and effective use of medications. in general practice.