CME
`
`Review
`
`CMAJ
`
`Grapefruit–medication interactions: Forbidden fruit
`or avoidable consequences?
`
`David G. Bailey BScPhm PhD, George Dresser MD PhD, J. Malcolm O. Arnold MB BCh MD
`
`O ur research group discovered the inter-
`
`action between grapefruit and certain
`medications more than 20 years ago.1–3
`Currently, more than 85 drugs, most of which
`are available in Canada, are known or predicted
`to interact with grapefruit. This interaction en -
`hances systemic drug concentration through
`impaired drug metabolism.
`Many of the drugs that interact with grape-
`fruit are highly prescribed and are essential for
`the treatment of important or common medical
`conditions. Recently, however, a disturbing trend
`has been seen. Between 2008 and 2012, the
`number of medications with the potential to
`interact with grapefruit and cause serious ad -
`verse effects (i.e., torsade de pointes, rhabdomy-
`olysis, myelotoxicity, respiratory depression,
`gastrointestinal bleeding, nephrotoxicity) has
`increased from 17 to 43, representing an average
`rate of increase exceeding 6 drugs per year. This
`increase is a result of the introduction of new
`chemical entities and formulations.
`This review identifies the key scientific con-
`cepts and clinical implications of grapefruit–
`drug interactions relevant to medical practice.
`We focus on grapefruit because it is the most
`widely examined, but other citrus fruits may
`have similar consequences. It was recently found
`that grapefruit and certain other citrus juices act
`by an additional mechanism to cause diminished
`systemic concentration of certain drugs by in -
`hibiting drug transporters.4 However, we will
`focus on the most well-known and well-studied
`interaction: that of interference in the activity of
`the cytochrome P450 3A4 (CYP3A4) enzyme. A
`summary of the evidence used in this review,
`which comes mainly from randomized con-
`trolled trials, is found in Box 1.
`
`What are the key scientific concepts
`of grapefruit–drug interactions?
`
`The actions of drugs are terminated through sev-
`eral biological mechanisms. The most important
`
`Competing interests: None
`declared.
`
`This article has been peer
`reviewed.
`
`Correspondence to:
`David G. Bailey,
`david.bailey@lhsc.on.ca
`
`CMAJ 2013. DOI:10.1503
`/cmaj.120951
`
`is drug metabolism involving oxidation by en -
`zymes belonging to the cytochrome P450 super-
`family. Cytochrome P450 3A4 is particularly
`essential, because it is involved in the bioinacti-
`vation of about 50% of all drugs.5 CYP3A4 is
`located in epithelial cells (enterocytes) lining the
`small intestines and colon, and in the parenchy-
`mal cells of the liver (hepatocytes) (Figure 1).
`Consequently, orally administered drugs can be
`metabolized twice before reaching the systemic
`circulation. Thus, the percentage of drug
`absorbed unchanged (oral bioavailability) can be
`markedly attenuated. For example, the oral
`bioavailability of the antihypertensive drug
`felodipine is normally reduced to 15% of the oral
`dose.6 In other words, felodipine has low innate
`bioavailability. For this reason, it is subject to a
`potentially dramatic increase in systemic expo-
`sure and associated higher risk of overdose with
`grapefruit as a result of diminished CYP3A4
`activity, primarily in the small intestine rather
`than in the liver.
`The chemicals in grapefruit involved in this
`interaction are the furanocoumarins.7 Fura-
`nocoumarins are metabolized by CYP3A4 to
`reactive intermediates that bond covalently to the
`active site of the enzyme, causing irreversible
`inactivation (mechanism-based inhibition).8 Con-
`
`Key points
`• Currently, more than 85 drugs have the possibility of interacting with
`grapefruit; of these drugs, 43 have interactions that can result in
`serious adverse effects.
`• Drugs that interact with grapefruit have all of the following
`characteristics: they are administered orally, they have very low to
`intermediate absolute bioavailability, and they are metabolized by the
`cytochrome P450 3A4 enzyme (CYP3A4).
`• All sources of grapefruit and certain related citrus fruits can irreversibly
`inhibit CYP3A4 in the gastrointestinal tract; to prevent this interaction,
`affected drugs should not be consumed with any of these fruits during
`the treatment period, or noninteracting alternative medications should
`be prescribed.
`• Older patients have the greatest possibility of ingesting grapefruit and
`interacting medications and are the most vulnerable to the adverse
`clinical consequences.
`
`© 2013 Canadian Medical Association or its licensors
`
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`
`sequently, CYP3A4 activity in the small intestine
`is impaired until de novo synthesis returns the
`enzyme to its previous level. This mechanism
`explains the important clinical effects on drug
`pharmacokinetics, specifically the peak plasma
`drug concentration (Cmax) and the area under the
`drug concentration–time curve (AUC). These
`key parameters of oral bioavailability are in -
`creased, whereas systemic elimination half-life is
`unaltered. The pharmacokinetics of intraven -
`ously administered drugs are unchanged.9,10
`Because these chemicals are innate to grape-
`fruit, all forms of the fruit (freshly squeezed
`juice, frozen concentrate and whole fruit) have
`the po tential to reduce the activity of CYP3A4.
`One whole grapefruit or 200 mL of grapefruit
`juice is sufficient to cause clinically relevant
`increased systemic drug concentration and sub-
`sequent adverse effects.11,12 Seville oranges,
`(often used in marmalades), limes and pomelos
`also produce this interaction.13–15 Varieties of
`sweet orange, such as navel or valencia, do not
`contain furanocoumarins and do not produce
`this interaction.2
`
`What determines which drugs are
`affected?
`
`The interaction between medications and grape-
`fruit is drug-specific and is not a class effect.
`Medications currently documented or predicted
`to have augmented oral bioavailability with
`grapefruit are shown in Table 1 and Appendix 1
`(available at www .cmaj .ca /lookup /suppl /doi: 10.
`1503 /cmaj .120951 / -/ DC1). Af fected drugs pos-
`sess 3 essential characteristics: they have an oral
`route of administration, they have very low
`(< 10%) to intermediate (> 30%–70%) intrinsic
`oral bioavailability, and they are metabolized by
`CYP3A4. These criteria can often be found in
`the product monograph or prescribing informa-
`tion (under “clinical pharmacology”) for a drug,
`
`Box 1: Evidence used in this review
`
`We conducted a comprehensive search of the PubMed database for all
`available scientifically valid evidence using the keyword “grapefruit” and the
`following additional terms: “drug,” “drug interaction,” “pharmacokinetics,”
`“cytochrome P450,” “CYP3A4,” “case report” or “review.” In addition, we
`obtained product monographs and prescribing information for drugs recently
`introduced (i.e., in the last 4 yr) to the Canadian market. We assessed the
`following sections of these documents for relevant information: “Summary
`Product Information,” “Warnings and Precautions,” “Contraindications,”
`“Adverse Reactions,” “Drug Interactions” and “Action and Clinical
`Pharmacology.” We identified 190 relevant publications (161 articles from
`PubMed; 29 product monographs or prescribing information sheets). Most of
`the information was from randomized controlled clinical trials (n = 102). The
`measured outcome from these studies was change in drug pharmacokinetics,
`and this was used to assess the potential for adverse clinical consequences.
`
`310
`
`CMAJ, March 5, 2013, 185(4)
`
`particularly for recently marketed drugs, and
`enable the prediction of whether an interaction
`might occur. In principle, this would assist prac-
`titioners in formulating ap propriate management
`strategies without exposing patients to poten-
`tially harmful combinations.
`
`What determines the clinical
`significance of the interaction?
`
`The clinical significance of any particular inter-
`action depends on the seriousness of the dose-
`related drug toxicity and the extent to which the
`systemic drug concentration increases. The latter
`relies on multiple factors that include the innate
`oral bioavailability of the interacting drug, the
`circumstances under which the grapefruit or
`other citrus fruit is consumed and the vulnerabil-
`ity of the patient to the interaction.
`
`Oral bioavailability
`The lower innate oral bioavailability of the drug,
`the greater the possible increase in systemic drug
`concentration. Grapefruit-interacting drugs can
`be separated into the 4 categories of very low
`(< 10%), low (10%–30%), intermediate (> 30%–
`70%) and high (> 70%) absolute bioavailability.
`Drugs with very low bioavailability are the most
`likely to interact with grapefruit in a way that
`substantially alters their pharmacokinetics (i.e.,
`analogous to consuming many doses of the drug
`alone). Conversely, drugs with high bioavailabil-
`ity have a marginally clinically relevant increase
`in systemic drug concentration.
`
`Circumstances of grapefruit consumption
`Although some pharmacokinetic studies have
`tested a higher than usual amount of grapefruit
`juice to determine the maximum effect, this should
`not be interpreted to mean that a relevant pharma-
`cokinetic interaction will only occur with high lev-
`els of consumption. Indeed, a single usual amount
`(i.e., 200–250 mL juice or a whole grapefruit) has
`sufficient potency to cause a pertinent pharmacoki-
`netic interaction.8,11,12 For example, felodipine com-
`bined with such a quantity of grapefruit had an
`average systemic drug concentration that was 3-
`fold that seen with water.8,11 With twice the amount
`of grapefruit, there was only a modestly greater
`increase in the systemic concentration of felodip-
`ine, showing that a near-maximal pharmacokinetic
`interaction had already occurred with the con-
`sumption of the single quantity.11 With repeated
`ingestion of grapefruit (250 mL of juice, 3 times/d
`for 6 d), a single dose of felodipine increased to 5
`times the systemic concentration seen with water,
`suggesting that frequent consumption of a usual
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`quantity daily augmented the pharmacokinetic
`effect moreso than the lone quantity.8
`The interval between the ingestion of grape-
`fruit and the adminstration of the interacting drug
`has some effect on pharmacokinetics. For exam-
`ple, a single glass (200 mL) of grapefruit juice
`ingested within 4 hours before felodipine pro-
`duced the maximal pharmacokinetic interaction.16
`Thereafter, an increased interval between ingest-
`ing the 2 substances slowly decreased the size of
`the effect — an interval of 10 hours produced an
`effect that was 50% of the maximum, and an
`interval of 24 hours produced an effect that was
`25% of the maximum.16 Thus, a modest solitary
`quantity of grapefruit can have sufficient duration
`of action to affect interacting drugs that are
`administered once daily at any time during the
`dosing interval. Furthermore, repeated ingestion
`of grapefruit (200 mL of juice, 3 times/d for 7 d)
`doubled the size of the interaction for 24 hours,
`consistent with a cumulative inhibitory action.17
`Theoretically, the batch, type (i.e., white or
`pink) and storage conditions of grapefruit could
`possibly influence the size of the interaction.
`However, to our knowledge, these aspects have
`not been systematically studied.
`
`Patient vulnerability
`Patient vulnerability to this pharmacokinetic
`interaction varies markedly. For example, individ-
`
`ual systemic felodipine concentrations with a sin-
`gle serving of grapefruit juice (250 mL) ranged
`from 0 to 8-fold that seen with water.8 Individual
`biopsies of the small intestine showed that higher
`CYP3A4 levels before ingesting grapefruit juice
`resulted in greater decrease in enzyme levels and
`greater increase in oral drug bioavailability after
`consumption of the juice. Accordingly, patients
`with elevated levels of CYP3A4 in the small
`intestine appear to be at increased risk for this
`interaction. It is impractical to routinely deter-
`mine enterocyte CYP3A4 content in clinical
`practice. However, patients with substantial
`intestinal levels of CYP3A4 could require a
`higher dose of a grapefrui t-interactive drug to
`achieve adequate systemic concentration. Thus,
`this is a possible means of identifying patients at
`greater risk before exposure to an interacting
`combination for medications routinely titrated to
`therapeutic effect.
`Despite current science from well-conducted
`clinical studies, there remains the key practical
`issue of the frequency of adverse outcomes from
`this interaction occurring in routine clinical
`practice. Because multiple factors likely need to
`combine to achieve a marked increase in sys-
`temic drug concentration, it is reasonable to
`state that just ex posure to any interacting combi-
`nation would not be sufficient to elicit a clini-
`cally important change in drug response in all, if
`
`2) Hepatocytes of the liver
`
`Drug
`100%
`
`15%
`
`15%
`
`CYP3A4
`
`30%
`
`2
`
`1) Enterocytes of the small intestine
`
`100%
`
`100%
`
`1
`
`CYP3A4
`
`30%
`
`Lumen
`
`Sinusoid
`
`Christine Kenny
`
`Figure 1: Sequential first-pass elimination of a drug, such as felodipine, through metabolism in enterocytes
`of the small intestine, then hepatocytes of the liver. The percentages of the initial dose that are available
`before and after passage through the gut wall and liver are shown. Although felodipine is 100% absorbed
`from the gastrointestinal tract, its bioavailability is only 15% after oral administration. CYP3A4 =
`cytochrome P450 enzyme 3A4.
`
`CMAJ, March 5, 2013, 185(4)
`
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`not most, cases. However, important toxic
`events have been documented for grapefruit–
`drug interactions (Ta ble 2).18–26 These case
`reports uniformly cited the circumstance of a
`patient whose therapeutic dose of a susceptible
`drug was stabilized, who subsequently showed
`serious toxicity that occurred after several days
`
`of simultaneous intake of the drug and grape-
`fruit in a normal or high quantity.
`But how big a problem are such interactions?
`Unless health care professionals are aware of the
`possibility that the adverse event they are seeing
`might have an origin in the recent addition of
`grapefruit to the patient’s diet, it is very unlikely
`
`Table 1 (part 1 of 2): Selected drugs that interact with grapefruit, associated oral bioavailability, adverse event(s), predicted risk
`and possible alternative agents
`
`Interacting drugs
`
`Anticancer agents
`Crizotinib
`
`Dasatinib
`
`Erlotinib
`Everolimus
`Lapatinib
`
`Nilotinib
`
`Pazopanib
`
`Sunitinib
`
`Vandetanib
`
`Venurafenib
`
`Anti-infective agents
`Erythromycin
`Halofantrine
`Maraviroc
`Primaquine
`Quinine
`Rilpivirine
`Antilipemic agents
`Atorvastatin
`
`Innate oral
`bioavailability*
`
`
`Intermediate
`
`Not known
`
`Intermediate
`Low
`Incomplete
`
`Intermediate
`
`Incomplete
`
`Not known
`
`Not known
`
`Not known
`
`
`Intermediate
`Low
`Low
`Intermediate
`Intermediate
`Not known
`
`Low
`
`Dose-related adverse event(s)
`
`
`Torsade de pointes,
`myelotoxicity
`Torsade de pointes,
`myelotoxicity
`Myelotoxicity
`Myelotoxicity, nephrotoxicity
`Torsade de pointes,
`myelotoxicity
`Torsade de pointes,
`myelotoxicity
`Torsade de pointes,
`myelotoxicity
`Torsade de pointes,
`myelotoxicity
`Torsade de pointes,
`myelotoxicity
`Torsade de pointes,
`myelotoxicity
`
`Torsade de pointes
`Torsade de pointes
`Postural hypotension, syncope
`Myelotoxicity
`Torsade de pointes
`Torsade de pointes
`
`Rhabdomyolysis
`
`Lovastatin
`
`Very low
`
`Rhabdomyolysis
`
`Simvastatin
`
`Very low
`
`Rhabdomyolysis
`
`Cardiovascular agents
`Amiodarone
`Apixaban
`Clopidogrel
`Dronedarone
`Eplerenone
`
`Felodipine
`
`Nifedipine
`
`
`Intermediate
`Intermediate
`Very low
`Low
`Intermediate
`
`Low
`
`Intermediate
`
`
`Torsade de pointes
`GI bleeding
`Loss of efficacy
`Torsade de pointes
`Hyperkalemia, serious
`arrhythmias
`Hypotension, peripheral
`edema
`Hypotension, peripheral
`edema
`
`312
`
`CMAJ, March 5, 2013, 185(4)
`
`Predicted
`interaction risk†
`
`Potential alternative
`agent(s)‡
`
`
`High
`
`High
`
`High
`High
`High
`
`High
`
`High
`
`High
`
`High
`
`High
`
`
`High
`Very high
`Very high
`High
`High
`High
`
`High
`
`Very high
`
`Very high
`
`
`High
`High
`High
`Very high
`High
`
`
`
`
`Imatinib
`
`
`
`
`
`Imatinib
`
`Sorafenib
`
`Sorafenib
`
`
`
`
`
`
`Clarithromycin
`Doxycycline
`Enfuvirtide
`Doxycycline
`Doxycycline
`Nevirapine
`
`Pravastatin, rosuvastatin,
`fluvastatin
`Pravastatin, rosuvastatin,
`fluvastatin
`Pravastatin, rosuvastatin,
`fluvastatin
`
`Sotalol
`Warfarin
`Acetylsalicylic acid
`Sotalol
`Spironolactone
`
`Intermediate
`
`Amlodipine
`
`Intermediate
`
`Amlodipine
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`
`that they will investigate it. In addition, the
`patient may not volunteer this information. Thus,
`we contend that there remains a lack of knowl-
`edge about this interaction in the general health
`care community. Consequently, current data are
`not available to provide an absolute or even
`
`approximate number representing the true inci-
`dence of grapefruit–drug interactions in routine
`practice. Nonetheless, there are certain situations
`in which this interaction has a predictably greater
`likelihood of producing particularly adverse clini-
`cal results.
`
`Table 1 (part 2 of 2): Selected drugs that interact with grapefruit, associated oral bioavailability, adverse event(s), predicted risk
`and possible alternative agents
`
`Innate oral
`bioavailability*
`
`
`
`
`
`Dose-related adverse event(s)
`
`Predicted
`interaction risk†
`
`Potential alternative
`agent(s)‡
`
`
`
`
`
`Intermediate
`Intermediate
`High
`
`
`Warfarin
`Acetylsalicyclic acid
`
`
`High
`High
`High
`High
`Very high
`Very high
`
`High
`High
`
`High
`
`Intermediate
`High
`
`
`Very high
`
`High
`High
`High
`High
`
`Intermediate
`
`Intermediate
`
`Intermediate
`Intermediate
`
`Intermediate
`
`
`Hydromorphone, morphine
`Oxazepam, tamazepam
`
`Hydromorphone, morphine
`Hydromorphone, morphine
`Haloperidol, risperidone
`olanzapine
`
`Hydromorphone, morphine
`Haloperidol, risperidone,
`olanzapine
`Haloperidol, risperidone,
`olanzapine
`Alprazolam, lorazepam
`Haloperidol, risperidone
`olanzapine
`
`Metoclopramide
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Interacting drugs
`
`Cardiovascular agents
`(continued)
`Quinidine
`Rivaroxaban
`Ticagrelor
`
`CNS agents
`Alfentanil (oral)
`Buspirone
`Dextromethorphan
`Fentanyl (oral)
`Ketamine (oral)
`Lurasidone
`
`Oxycodone
`Pimozide
`
`Quetiapine
`
`Triazolam
`Ziprasidone
`
`High
`High
`Intermediate
`
`
`Intermediate
`Very low
`Very low
`Intermediate
`Low
`Low
`
`Intermediate
`Intermediate
`
`Torsade de pointes
`GI bleeding
`GI or kidney bleeding
`
`
`Respiratory depression
`Dizziness, sedation
`Hallucinations, somnolence
`Respiratory depression
`Respiratory depression
`Torsade de pointes,
`orthostatic hypotension,
`syncope
`Respiratory depression
`Torsade de pointes
`
`Very low
`
`Dizziness, somnolence
`
`Intermediate
`Intermediate
`
`Sedation
`Torsade de pointes
`
`Gastrointestinal agents
`Domperidone
`Immunosuppressants
`Cyclosporine
`Everolimus
`Sirolimus
`Tacrolimus
`Urinary tract agents
`Darifenacin
`
`
`Low
`
`Low
`Low
`Low
`Low
`
`Low
`
`Fesoterodine
`
`Intermediate
`
`Solifenacin
`Silodosin
`
`Tamsulosin
`
`High
`Intermediate
`
`Intermediate
`
`
`Torsade de pointes
`
`Nephrotoxicity
`Myelotoxicity, nephrotoxicity
`Myelotoxicity, nephrotoxicity
`Nephrotoxicity
`
`Urinary retention,
`constipation
`Urinary retention,
`constipation
`Torsade de pointes
`Postural hypotension,
`dizziness
`Postural hypotension,
`dizziness
`
`Note: CNS = central nervous system, GI = gastrointestinal.
`*Population average: very low < 10%, low >10%–30%, intermediate >30%–70%, high > 70%.
`†Based on the seriousness of the adverse effect and adjusted for the innate oral bioavailability of the drug, which is used to determine the potential increase in
`systemic drug concentration. For older patients, particularly the elderly, it is recommended that grapefruit or other citrus fruits be contraindicated for drugs in the
`very high or high category, or that a suggested alternative noninteracting drug be employed when available.
`‡Commonly prescribed drugs (Top 100 prescribed in 2011 in Canada) with the same therapeutic indication that have no or minor pharmacokinetic interaction with
`grapefruit or other citrus fruits.
`
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`Who is at higher risk
`of grapefruit–drug interactions?
`
`Although patient vulnerability is largely un known,
`people older than 45 years are the prime purchasers
`of grapefruit and receive the most prescriptions for
`drugs.27,28 Because of the size of this population,
`substantial exposure to this interaction is likely. In
`addition, a pronounced pharmacokinetic interaction
`has been shown to occur in patients older than
`70 years.29 Furthermore, older adults can have de -
`creased capacity to compensate for excessive sys-
`temic drug concentrations. For example, felodipine
`(which normally lowers blood pressure) does not
`cause a compensating increase in heart rate in older
`adults when ingested with grapefruit, but does in
`young and middle-aged people, likely because of
`attenuated baroreceptor sensitivity associated with
`age.29 Consequently, older people appear to be an
`especially vulnerable population for grapefruit–
`drug interactions.
`The predicted interaction risk for grapefruit-
`interacting drugs (Table 1, Appendix 1) (i.e., very
`high, high, intermediate, low) can assist clinicians
`in prescribing drugs for vulnerable patients and
`determining whether grapefruit or other citrus fruits
`should be contraindicated during pharmacotherapy,
`or whether an alternative therapy can be used.
`
`What are examples of important
`grapefruit–drug interactions?
`
`Examples of grapefruit–drug interactions were
`selected to illustrate documented pharmacoki-
`
`Table 2: Case reports of serious adverse events related to grapefruit–drug
`interaction18–26
`
`Drug
`
`Amount of grapefruit consumed
`
`Amiodarone18
`
`Juice, 1–1.5 L/d on a regular basis
`
`Serious adverse
`event
`
`Torsade de
`pointes
`
`
`Complete heart
`block
`Rhabdomyolysis
`
`
`Nephrotoxicity
`
`Myelotoxicity
`Venous
`thrombosis
`
`Quinine in tonic
`water19
`Verapamil20
`
`Atorvastatin21,22
`
`Juice, high volume during
`preceding days
`Juice, high volume during
`preceding days
`Juice, 1–2 glasses/d for 5 d; juice
`from fresh grapefruit daily for
`2 mo
`Whole fruit, 1 fruit/d for 2 wk
`Marmalade, 1.5 kg eaten during
`preceding 1 wk
`Colchicine25
`Juice, 1 L/d for preceding 2 mo
`Ethinylestradiol26 Whole fruit, 1 fruit/d for breakfast
`for preceding 3 d
`
`Simvastatin23
`Tacrolimus24
`
`314
`
`CMAJ, March 5, 2013, 185(4)
`
`netic changes for which clinical outcomes are
`considered serious. These effects include torsade
`de pointes, rhabdomyolysis, nephrotoxicity and
`breast cancer.
`
`Torsade de pointes
`Torsade de pointes and risk of sudden death can
`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 h relative to drug administration) corre-
`sponding to 180% of that with water; the AUC was
`150% of that with water.30 The combination was
`also reported to markedly prolong the corrected QT
`interval and to cause ventricular ar rhythmias,
`including torsade de pointes, in clinical practice.18
`Dronedarone, the chemical analog of amiodarone,
`was associated with reports of ventricular arrhyth-
`mia, cardiac arrest and torsade de pointes in clinical
`practice.31 Dronedarone with grapefruit juice (300
`mL, 3 times/d) resulted in a systemic drug concen-
`tration that was 300% of that of a control.32
`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 that
`with water, and an AUC that was 129% of that
`with water.33 Sunitinib, another tyrosine kinase
`inhibitor, had a mean bioavailability with grape-
`fruit consumption (200 mL, 3 times/d for 3 d)
`that was 111% of that compared with the level
`seen when grapefruit is not consumed.34 Although
`the pharmacokinetic interaction was weaker with
`sunitinib, the potential seriousness of the adverse
`effect and concern for interpatient variability
`would still warrant the avoidance of grapefruit.
`
`Rhabdomyolysis
`Rhabdomyolysis is the consequence of profound
`damage to skeletal muscle tissue, the release of
`large quantities of proteins, such as myoglobin,
`into the blood and acute renal failure. The active
`forms of all statins can produce this toxicity at
`excessive systemic concentrations.35
`Simvastatin with grapefruit juice at high vol-
`ume (400 mL, 3 times/d for 3 d) had an AUC that
`was 700% of that for water; at a more usual
`amount of juice (200 mL, once daily for 3 d), the
`AUC was 330% of that with water.36,37 Rhab-
`domyolysis was also reported after 10 days con-
`comitant consumption of fresh grapefruit.23
`Lovastatin with grapefruit juice at a high level of
`consumption (400 mL, 3 times/d for 3 d) caused
`an AUC that was 500% of that with water.38 Ator-
`vastatin, the most frequently prescribed drug in
`Canada in 2011, had an AUC with grapefruit
`juice (250–400 mL, 3 times/d for 2–4 d) that
`ranged from 180% to 250% of that with water.39–41
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`Rhabdomyolysis has also been reported with
`grapefruit ingested at usual amounts (Ta -
`ble 2).21–23 Thus, this adverse outcome with cer-
`tain statins can occur with the ingestion of much
`less grapefruit than was previously ex pressed by
`the US Food and Drug Administration.42
`However, taking atorvastatin in the evening
`and drinking grapefruit juice in the morning
`(300 mL/d from a specific lot prepared by the
`Florida Department of Citrus) resulted in drug
`serum concentrations that were 119%–126% of
`those seen with no consumption of grapefruit,
`with no evidence of skeletal muscle toxicity (e.g.,
`elevated creatine phosphokinase, myalgia).43 In
`addition, pravastatin does not produce a pharma-
`cokinetic interaction with grapefruit,39,40 rosuvas-
`tatin is eliminated unchanged,35 and fluvastatin is
`metabolized by an enzyme (cytochrome P450
`2C9) that is not affected by grapefruit.35 Although
`staggering the ingestion of atorvastatin and grape-
`fruit may reduce risk, substituting pravastatin,
`rosuvastatin or fluvastatin, or eliminating grape-
`fruit juice from the diet, appears more preferable.
`
`Nephrotoxicity
`Nephrotoxicity can occur with the calcineurin
`inhibitors cyclosporine and tacrolimus, which are
`vital in preventing organ rejection after transplan-
`tation. Both of these 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 serving of 250 mL) produced a mean oral
`bioavailability that was 162% of that with water.10
`One of the 9 patients involved in this study had
`systemic drug availability increased to 670%. In
`addition, a case report showed cyclosporine con-
`centration to be increased to 600% with grape-
`fruit.44 Taking tac ro limus after ingesting grapefruit
`juice (250 mL, 4 times/d for 3 d) resulted in a
`1000% higher trough blood concentration, causing
`profound inhibition of calcineurin phosphatase in a
`recipient of a liver transplant.45 Moreover, taking
`tacrolimus after consuming a large amount of
`grapefruit marmalade during the previous week
`caused a 500% greater blood concentration of the
`drug and acute renal dysfunction.24
`
`Breast cancer
`Based on increased oral bioavailability of estro-
`gens (ethinylestradiol and 17-β-estradiol) with
`grapefruit juice, 2 large epidemiologic studies
`assessed the risk of breast cancer.46,47 The initial
`investigation found higher risk (relative risk
`1.30, 95% confidence interval 1.06–1.58) in
`women postmenopause who were taking estro-
`gens and consuming one-quarter grapefruit or
`more per day compared with women not eating
`
`grapefruit.48 However, a follow-up study involv-
`ing the same population found no such associa-
`tion.49 Thus, there is controversy over the risk of
`breast cancer in women postmenopause receiv-
`ing estrogen therapy and consuming grapefruit.
`
`Gaps in knowledge
`
`Although much effort has been expended to pro-
`vide a complete list of currently known and pre-
`dicted drugs that will interact with grapefruit, the
`absence of a drug from Table 1 and Appendix 1
`should not be interpreted to mean that it lacks
`this interaction. The few case reports presented
`in this review should not be considered as a use-
`ful index of the frequency of occurrence of seri-
`ous grapefruit–drug interactions in general prac-
`tice, as these are likely underreported.
`
`Conclusion
`
`Grapefruit and certain other citrus fruits represent
`examples of foods generally considered to be
`healthful, but with the potential for a pharmacoki-
`netic interaction causing greatly enhanced oral drug
`bioavailability. The current trend of increasing
`numbers of newly marketed grapefruit-affected
`drugs possessing substantial adverse clinical effects
`necessitates an understanding of this interaction
`and the application of this knowledge for the safe
`and effective use of drugs in general practice.
`
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