List of drugs affected by grapefruit

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File:Citrus paradisi (Grapefruit, pink).jpg

Sliced pink grapefruit

Grapefruit and grapefruit juice has the potential to interact with numerous drugs. A number of organic compounds with the most potent that were identified as furanocoumarin derivates interfere with the intestinal enzyme cytochrome P450 isoform CYP3A4 and are therefore primarily responsible for the interaction. However, bioactive compounds in grapefuit juice may also interfere with P-glycoprotein and organic anion transporting polypeptides (OATPs) either increasing or decreasing bioavailability of a number of drugs.

History

In 1989 a pharmacological study evaluated the possibility of an interaction between ethanol ingestion and medication with the dihydropyridine calcium channel blocker - felodipine. It was grapefruit juice that was used as a flavouring additive during the test. The results of study showed several-fold increase of felodipine concentrations compared to results obtained in other investigations of the drug. Additionally, there were lower blood pressure readings and more adverse effects compared to the group of subjects on felodipine alone. Further investigations revealed that grapefruit juice strikingly elevated felodipine bioavailability and could influence its other pharmacokinetic and pharmacodynamic properties.

Affected drugs

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The following drugs are affected by CYP3A4 inhibition with grapefruit compounds:

• The benzodiazepines triazolam, alprazolam and quazepam
• Ritonavir inhibits CYP3A4 preventing the metabolism of protease inhibitors

Additional drugs found to be affected by grapefruit juice include, but are not limited to:

Amiodarone

• Repeated doses of grapefruit juice markedly increase amiodarone levels. • Evaluated in controlled studies in healthy volunteers; increased AUC and Cmax

Management • Avoid grapefruit juice; other juices not known to interact. • If used in combination, monitor for adverse effects associated with increased serum levels of amiodarone (e.g., bradycardia, elevation of liver enzymes).

Atorvastatin

• Grapefruit juice may increase plasma levels of HMG CoA reductase inhibitors m.etabolized by CYP 3A4. • Atorvastatin appears to be affected to a lesser extent than lovastatin and simvastatin.

Management • Avoid consumption of grapefruit juice; other juices not known to interact. • Consider choosing a HMG CoA reductase inhibitor not m.etabolized by CYP 3A4 (e.g., pravastatin and fluvastatin). • If used in combination, monitor for adverse effects associated with increased serum levels of atorvastatin (e.g., myopathy, rhabdomyolysis).

Benzodiazepines

see diazepam, triazolam

Budesonide

• Substantial intake of grapefruit juice may increase systemic exposure to orally administered budesonide. • The bioavailability of orally administered budesonide was approximately doubled in male subjects taking 600 mL of concentrated grapefruit juice per day for 4 days.

Management • Avoid consumption of grapefruit juice; other juices not known to interact. • If used in combination, monitor for adverse effects associated with the use of glucocorticoids (e.g., hyperglycemia, Cushingoid features).

Buspirone

• Repeated doses of grapefruit juice markedly increase buspirone serum concentration.

Management • Avoid grapefruit juice; other juices not known to interact. • If used in combination, monitor for adverse effects associated with increased serum levels of buspirone (e.g., sedation and psychomotor impairment).

===Calcium Channel Blockers===, see felodipine, nifedipine, nimodipine

Carbamazepine

• May increase carbamazepine serum levels. • Evaluated in small controlled study of epileptic patients; increased AUC, peak and trough concentrations

Management • Avoid grapefruit juice; other juices not known to interact. • If used in combination, monitor for signs of carbamazepine toxicity (e.g., drowsiness, dizziness, headache, unsteadiness on the feet, diplopia, nausea, vomiting).

Carvedilol

• Can result in higher plasma levels of carvedilol due to reduced drug m.etabolism. • Evaluated in controlled studies; increased area under curve (AUC).

Management • Evidence of this interaction is limited. • If used in combination, monitor for adverse effects associated with increased serum levels of carvedilol (e.g., low blood pressure and bradycardia).

Clomipramine

• May increase clomipramine serum levels. • The interaction between grapefruit juice and other tricyclic antidepressants has not been established.

Management • Avoid consumption of grapefruit juice; other juices not known to interact. • If used in combination, monitor for adverse effects associated with increased serum levels of clomipramine (e.g., drowsiness, hypotension, respiratory depression, cardiovascular disturbances, anticholinergic effects, agitation).

Cyclosporine

• May increase plasma levels of cyclosporine. • Evaluated in controlled studies; increased AUC and increased plasma concentration.

Management • Avoid grapefruit juice; other juices not known to interact. • If used in combination, monitor for symptoms of toxicity (e.g., nephrotoxicity, hepatotoxicity, increased immunosuppression). • Monitor cyclosporine effect particularly when grapefruit juice is initiated, discontinued or the interval between drug and grapefruit juice ingestion changes. • Lower doses of cyclosporine may be required.

Diazepam

• May increase diazepam levels. • Evaluated in controlled studies in healthy volunteers; increased AUC and Cmax.

Management • Clinical importance is unknown. • It is likely that some patients would be adversely affected especially those in whom diazepam levels are likely to be elevated (e.g., older individuals, those with liver impairment or concurrent use of other cytochrome P450-inhibitors). • Avoid grapefruit juice; other juices not known to interact. • If used in combination, monitor for increased sedation.

Erythromycin

• Grapefruit juice may increase serum concentrations of erythromycin. • Evaluated in an open crossover study in six healthy subjects; increased Cmax and AUC.

Management • Avoid grapefruit juice; other juices not known to interact. • If used in combination, monitor for adverse effects that may be associated with erythromycin.

Ethinyl Estradiol

• Appears to increase serum concentrations of ethinyl estradiol. • Theoretically, grapefruit juice may affect the m.etabolism of other estrogens.

Management • Clinical significance is not established. • Avoid consumption of grapefruit juice; other juices not known to interact. • If used in combination, suggest maintaining a consistent interval between drug and grapefruit juice ingestion when possible.

Felodipine

• Can increase plasma levels and intensify the clinical effects of some 1,4-dihydropyridine calcium channel blockers. • Can significantly increase plasma felodipine levels. • May be affected to a greater extent than other dihydropyridine calcium channel blockers.

Management • Avoid grapefruit juice; other juices not known to interact. • If used in combination, monitor for adverse effects associated with increased serum concentrations of felodipine (e.g., decreased diastolic blood pressure, increased heart rate, flushing, headache and lightheadedness).

HMG CoA reductase inhibitors, see atorvastatin, lovastatin, simvastatin

Itraconazole=

• May decrease itraconazole serum levels. • Evaluated in controlled study in healthy volunteers; decreased AUC and Cmax. This effect has not been consistently shown in all studies. • May occur with ketoconazole but no data exists.

Management • Avoid consumption of grapefruit juice. • If used in combination, monitor patient for loss of efficacy.

Lovastatin

• Repeated doses may result in increased lovastatin serum concentrations. • Simvastatin appears to be similarly affected by grapefruit juice; however, atorvastatin is not as greatly affected.

Management • Avoid consumption of grapefruit juice; other juices not known to interact. • Consider choosing a HMG CoA reductase inhibitor not m.etabolized by CYP 3A4 (e.g., fluvastatin and pravastatin). • If used in combination, monitor for signs of adverse effects associated with increased serum concentrations of lovastatin (e.g., myopathy, rhabdomyolysis).

Methylprednisolone

• Grapefruit juice may increase serum concentrations and half-life of methylprednisolone. • Evaluated in a crossover study in ten healthy subjects; repeated administration of double-strength grapefruit juice increased AUC, Cmax and half-life of methylprednisolone. Clinical significance unknown. The effect on half-life shown in this study is likely a function of the large doses of grapefruit juice administered.

Management • Avoid grapefruit juice; other juices not known to interact. • If used in combination, monitor for adverse effects that may be associated with the use of corticosteroids (e.g., hyperglycemia, Cushingoid features).

Nifedipine

• May lead to increased serum levels of nifedipine. • Evaluated in single dose controlled studies in healthy volunteers.

Management • Avoid grapefruit juice; other juices not known to interact. • If used in combination, monitor for signs of adverse effects associated with increased serum concentrations of nifedipine (e.g., decreased diastolic blood pressure, increased heart rate, flushing, headache and lightheadedness).

Nimodipine

• May increase plasma concentrations of nimodipine. • Pharmacokinetics after a single dose of grapefruit juice are altered. • Pharmacodynamic effects may be augmented.

Management • Avoid grapefruit juice; other juices not known to interact. • If used in combination, monitor for increased hypotensive effect and side effects such as headache.

Pimozide

• Can result in elevated levels due to decreased drug m.etabolism. • Elevated levels may enhance the risk of QT prolongation.

Management • Avoid grapefruit juice; other juices not known to interact. • If used in combination, monitor for signs of adverse effects associated with increased serum levels of pimozide (e.g., torsades de pointes, extrapyramidal symptoms, hypotension).

Protease inhibitors

see saquinavir

Saquinavir

• Can increase absorption of saquinivir from hard gel capsules. Effect on soft gel capsules unknown, but may differ due to intrinsically better absorption from this formulation. • A decrease in AUC has been reported with indinavir; effect on ritonavir has not been studied.

Management • Clinical significance is unknown.

Sertraline

• Grapefruit juice may increase serum concentrations of sertraline. • Evaluated in an open controlled study in five patients being treated for depression with 50-75 mg/day of sertraline; increased the mean trough concentration of sertraline. No subject was withdrawn from the study due to adverse effects or mood changes. Clinical significance unknown.

Management • Avoid grapefruit juice; other juices not known to interact. • If used in combination, monitor for adverse effects associated with increased serum levels of sertraline (e.g., insomnia or somnolence, tremor, dizziness).

Simvastatin

• May increase simvastatin serum concentrations. • Lovastatin bioavailability is similarly increased by grapefruit juice; however, atorvastatin is not as greatly affected.

Management • Avoid consumption of grapefruit juice; other juices not known to interact. • Consider choosing a HMG CoA reductase inhibitor not m.etabolized by CYP 3A4 (e.g., fluvastatin and pravastatin). • If used in combination, monitor for signs of adverse effects associated with increased serum concentrations of simvastatin (e.g., myopathy, rhabdomyolysis).

Sirolimus

• Grapefruit juice may have the potential to increase sirolimus blood concentrations

Management • Avoid grapefruit juice; the manufacturer of Rapamune® specifically recommends taking Rapamune® with either water or orange juice. • If used in combination, monitor for increased blood concentrations and for adverse effects associated with increased serum concentrations of sirolimus (e.g., thrombocytopenia, hyperlipidemia)

Tacrolimus

• May have the potential to increase tacrolimus blood concentrations.

Management • Avoid grapefruit juice; other juices not known to interact. • If used in combination, monitor for increased blood levels and symptoms of toxicity (e.g., nephrotoxicity, hepatotoxicity, increased immunosuppression).

Triazolam

• May increase triazolam serum levels. • Evaluated in controlled studies in healthy volunteers; increased AUC and Cmax and small increase in psychomotor impairment.

Management • It is likely that some patients would be adversely affected especially those in whom triazolam levels are likely to be elevated (e.g., older individuals, those with liver impairment or concurrent use of other cytochrome P450-inhibitors). • Avoid grapefruit juice; other juices not known to interact. • If used in combination, monitor for increased sedation. Significant increase in drowsiness has been reported

• Statins such as atorvastatin, lovastatin, and simvastatin
• Dihydropyridines including felodipine (Plendil), nicardipine (Cardene), difedipine, nisoldipine (Sular), nitrendipine (Bayotensin)
• losartan (Cozaar)
• repaglinide (Prandin)
• verapamil (Calan SR, Covera HS, Isoptin SR, Verelan)
• Antiarrhythmics including amiodarone (Cordarone), quinidine (Quinidex, Cardioquin, Quinora), disopyramine (Norpace), propafenone (Rhythmol), and carvediol
• Antihistaminic terfenadine ,
• Cisapride which treat GERD
• The male impotence drugs sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra)
• The anti-migraine drugs ergotamine (Cafergot, Ergomar) and nimodipine (Nimotop)
• Fluvoxamine (Luvox, Faverin, Fevarin and Dumyrox)
• Codeine and Tramadol. It reduces the amount of codeine converted by CYP3A4 into norcodeine thus increasing the amount metabolised into morphine.^{[How to reference and link to summary or text]}
• cyclosporine. Blood levels of cyclosporine are increased if taken with grapefruit juice. A plausible mechanism involves the combined inhibition of enteric CYP3A4 and P-glycoprotein, which potentially leads to serious adverse events (eg, nephrotoxicity).
• oxycodone ^{[How to reference and link to summary or text]}
• Quetiapine (Seroquel, Ketipinor) ^{[How to reference and link to summary or text]}

Mechanism of the interaction

The CYP3A4 isoform of cytochrome P450 is located in both the liver and the enterocytes. Many oral drugs undergo first-pass (presystemic) metabolism by the enzyme. Several organic compounds found in grapefruit and specifically in grapefruit juice exert inhibitory action on drug metabolism by the enzyme. It has been established that a group of compounds called furanocoumarins are responsible for this interaction and not flavonoids as was previously reported The list of active furanocoumarins found in grapefruit juice includes: bergamottin, bergapten, bergaptol and 6',7'-dihydroxybergamottin.

This interaction is particularly dangerous when the drug in question has a low therapeutic index, so that a small increase in blood concentration can be the difference between therapeutic success and toxicity. Grapefruit juice only inhibits the enzyme within the intestines, not in the liver or elsewhere in the body, and does not impact injected drugs. The degree of the effect varies widely between individuals and between samples of juice, therefore it cannot be accounted for a priori.

Another mechanism of interaction is possibly through the P-glycoprotein (Pgp) that is localized in the apical brush border of the enterocytes. Pgp transports lipophilic molecules out of the enterocyte back into the intestinal lumen. Drugs that possess lipophilic properties are either metabolised by CYP3A4 or removed into the intestine by the Pgp transporter. Both the Pgp and CYP3A4 may act synergistically as a barrier to many orally administered drugs. Therefore their inhibition (both or alone) can markedly increase the bioavailability of a drug.

The interaction caused by grapefruit compounds lasts for up to 24 hours and its effect is the greatest when the juice is ingested with the drug or up to 4 hours before the drug.

The flavonoid existing in highest concentration in grapefruit juice is naringin, which in humans is metabolised to naringenin. Other flavonoids exist in grapefruit juice in lower concentrations as well. Orange juice does not contain naringin in as high a concentration, instead containing hesperetin. It is sometimes recommended as a substitute. Juice of limes and Seville oranges can also inhibit drug metabolism, however, as can apple juice with some drugs.

Drugs affected by grapefruit juice

Drug class	Major Interactions	Minor interactions
Calcium channel antagonists		Plendil Cardene (Nicardipine) Procardia (Nifedipine) Nimotop Sular DynaCirc
Statins (HMG-CoA reductatase inhibitors)	Mevacor (Lovastatin)	Lipitor Baycol (off the market)
Immunosuppressants		Sandimmune (Cyclosporine) Prograf Rapamune Mercaptopurine
Dissociatives		Dextromethorphan
Sedatives, hypnotics, and anxiolytics	Buspar	Halcion Versed Valium (Diazepam) Sonata (Zaleplon) Alprazolam
Other psychotropics		Tegretol (Carbamazepine) Desyrel Serzone Seroquel Fluvoxamine
Antihistamines	Seldane (off the market) Hismanal (off the market)	Claritin (Loratadine)
HIV protease inhibitors		Invirase Norvir Viracept Agenerase
Hormones		Ortho-Cept (Ethinyl estradiol) Depo-Medrol (Methylprednisolone)
Other drugs	Cordarone	Viagra Propulsid

External links

• Grapefruit-Drug Interaction Website by Canadian Pharmacist Dean Elbe, B.Sc.(Pharm.), BCPP
• USDA Database of Flavonoid content of food
• Food—Drug Interactions-Which Ones Really Matter? March 21, 2007
• Graedon's Guide to Grapefruit Interactions.PDF (34.6 KiB)