The effect was first discovered accidentally in 1989, when a test of drug interactions with alcohol used grapefruit juice to
hide the taste of the ethanol.[5][6] A 2005 medical review advised patients to avoid all citrus juices until further research clarifies the risks.[7] It was reported in 2008 that similar effects had been observed with apple juice.[2][8][9]
One whole grapefruit, or a small glass (200 mL, 6.8 US fl oz) of grapefruit juice, can cause drug overdose toxicity.[1] Fruit consumed three days before the medicine can still have an effect.[10] The relative risks of different types of citrus fruit have not been systematically studied.[1] Affected drugs typically have an
auxiliary label saying "Do not take with grapefruit" on the container, and the interaction is elaborated upon in the package insert.[11] People are also advised to ask their
physician or
pharmacist about drug interactions.[11]
The effects are caused by
furanocoumarins (and, to a lesser extent,
flavonoids).[12] These chemicals inhibit key
drug metabolizingenzymes, such as
cytochrome P450 3A4 (CYP3A4). CYP3A4 is a metabolizing enzyme for almost 50% of drugs, and is found in the liver and small intestinal epithelial cells.[13] As a result, many drugs are affected. Inhibition of enzymes can have two different effects, depending on whether the drug is either
In the first instance, inhibition of drug-metabolizing enzymes results in elevated concentrations of an active drug in the body, which may cause adverse effects.[11] Conversely, if the medication is a
prodrug, it needs to be metabolised to be converted to the
active drug. Compromising its metabolism lowers concentrations of the active drug, reducing its therapeutic effect, and risking therapeutic failure.
Low drug concentrations can also be caused when the fruit suppresses drug absorption from the intestine.[14]
History
The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989 by a group led by
pharmacologist David Bailey. Their first published clinical report on grapefruit drug interactions was in 1991.[5]
Organic derivatives of furanocoumarin interfere with liver and
intestinal enzyme CYP3A4 and may be responsible for the effects of grapefruit on the enzyme.[19] Cytochrome isoforms affected by grapefruit components also include
CYP1A2,
CYP2C9, and
CYP2D6.[20][21][22][23][24] Drugs metabolized by these enzymes may have interactions with citrus chemicals.
When drugs are taken orally, they enter the gut lumen to be absorbed in the small intestine and sometimes, in the stomach. In order for drugs to be absorbed, they must pass through the epithelial cells that line the lumen wall before they can enter the hepatic portal circulation to be distributed systemically in blood circulation. Drugs are metabolized by drug-specific
metabolizing enzymes in the epithelial cells. Metabolizing enzymes transform these drugs into metabolites. The primary purpose for drug metabolism is to detoxify, inactivate, solubilize and eliminate these drugs.[25][verification needed] As a result, the amount of the drug in its original form that reaches systemic circulation is reduced due to this first-pass metabolism.
Many drugs are affected by consumption of citrus juice. When the metabolizing enzyme is inhibited, less of the drug will be metabolized by it in the epithelial cells.[13] 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 effect and toxicity. Citrus juice inhibits the enzyme only within the
intestines if consumed in small amounts.[medical citation needed] When larger amounts are consumed they may also inhibit the enzyme in the liver. The hepatic enzyme inhibition may cause an additional increase in potency and a prolonged metabolic half-life (prolonged metabolic half-life for all ways of drug administration).[26] The degree of the effect varies widely between individuals and between samples of juice, and therefore cannot be accounted for a priori.
Grapefruit–drug interactions that affect the pre-systemic metabolism (i.e., the metabolism that occurs before the drug enters the blood) of drugs have a different duration of action than interactions that work by other mechanisms, such as on absorption, discussed below.[13]
The location of the inhibition occurs in the lining of the intestines, not within the liver.[29] The effects last because grapefruit-mediated inhibition of drug metabolizing enzymes, like
CYP3A4, is irreversible;[29] that is, once the grapefruit has "broken" the enzyme, the intestinal cells must produce more of the enzyme to restore their capacity to metabolize drugs that the enzyme is used to metabolize.[13] It takes around 24 hours to regain 50% of the cell's baseline enzyme activity and it can take 72 hours for the enzyme activity to completely return to baseline. For this reason, simply separating citrus consumption and medications taken daily does not avoid the drug interaction.[10]
Absorption interactions
For medications that interact due to inhibition of OATP (organic anion-transporting polypeptides), a relative short period of time is needed to avoid this interaction, and a 4-hour interval between grapefruit consumption and the medication should suffice.[13][27] For drugs recently sold on the market, drugs have information pages (monographs) that provide information on any potential interaction between a medication and grapefruit juice.[13] Because there is a growing number of medications that are known to interact with citrus,[1] patients should consult a pharmacist or physician before consuming citrus while taking their medications.
Affected fruit
Grapefruit is not the only
citrus fruit that can interact with medications.[1][2][3][4] One medical review advised patients to avoid all citrus.[7]
There are three ways to test if a fruit interacts with drugs:
Test a fruit chemically for the presence of the interacting polyphenol compounds
Test a fruit genetically for the genes needed to make the interacting polyphenol compounds[30]
The first approach involves risk to trial volunteers. The first and second approaches have another problem: the same fruit
cultivar could be tested twice with different results. Depending on growing and processing conditions, concentrations of the interacting polyphenol compounds can vary dramatically.[31][better source needed] The third approach is hampered by a paucity of knowledge of the genes in question.[30]
Citrus genetics and interactions
A descendant of citrus cultivars that cannot produce the problematic polyphenol compounds would presumably also lack the genes to produce them. Many citrus cultivars are hybrids of a small number of ancestral species, which have now been fully genetically sequenced.[32][33]
Many traditional citrus groups, such as true sweet oranges and lemons, seem to be
bud sports, mutant descendants of a single hybrid ancestor.[34] In theory, cultivars in a bud sport group would be either all safe or all problematic. Nonetheless, new citrus varieties arriving on the market are increasingly likely to be sexually created hybrids, not asexually created sports.
The ancestry of a hybrid cultivar may not be known. Even if it is known, it is not possible to be certain that a cultivar will not interact with drugs on the basis of taxonomy, as it is not known which ancestors lack the capacity to make the problematic polyphenol compounds. Nonetheless, many of the citrus cultivars known to be problematic seem to be closely related.
Ancestral species
Pomelo (the Asian fruit that was crossed with an orange to produce grapefruit) contains high amounts of furanocoumarin derivatives.
Grapefruit relatives and other varieties of pomelo have variable amounts of furanocoumarin.[7][2][35][36]
The
Dancy cultivar has a small amount of pomelo ancestry,[33] but is genetically close to a non-hybrid
true mandarin (unlike most commercial mandarins, which may have much more extensive hybridization). Eight Dancy fruits, all picked at one time from one tree, have been blended and tested for furanocoumarins; none were detectable.[35]
Tests on some tangelos (hybrids of mandarins/tangerines and pomelo or grapefruit) have not shown significant amounts of furanocoumarin; these studies were also conducted on eight fruit all picked at one time from one tree.[35]
Common lemons are the product of orange/citron hybridization, and hence have pomelo ancestry, and although
Key limes are papeda/citron hybrids, the more commercially prevalent
Persian limes and similar varieties are crosses of the Key lime with lemons, and hence likewise have pomelo ancestry.[32][33] These limes can also inhibit drug metabolism.[37] Other less-common citrus species also referred to as lemons or limes are genetically distinct from the more common varieties, with different proportions of pomelo ancestry.[32]
Inaccurate labeling
Marketing classifications often do not correspond to taxonomic ones. The "Ambersweet" cultivar is classified and sold as an orange, but does not descend from the same common ancestor as sweet oranges; it has grapefruit, orange, and mandarin ancestry. Fruits are often sold as mandarin,
tangerine, or
satsuma (which may be synonyms[38]). Fruit sold under these names include many that are, like Sunbursts and
Murcotts, hybrids with grapefruit ancestry.[35][39][40] The diversity of fruits called limes is remarkable; some, like the
Spanish lime and
Wild lime, are not even citrus fruit.
In some countries, citrus fruit must be labelled with the name of a registered cultivar. Juice is often not so labelled. Some medical literature also names the cultivar tested.
Other fruit and vegetables
The discovery that flavonoids are responsible for some interactions make it plausible that other fruit and vegetables are affected.[27]
Pomegranate juice inhibits the action of the drug metabolizing enzymes
CYP2C9 and
CYP3A4.[42] As of 2014[update], however, the currently available literature does not appear to indicate a clinically relevant impact of pomegranate juice on drugs that are metabolized by CYP2C9 and CYP3A4.[42]
Researchers have identified over 85 drugs with which grapefruit is known to have an adverse reaction.[43][1] According to a review done by the
Canadian Medical Association,[1] there is an increase in the number of potential drugs that can interact with grapefruit juice, and of the number of fruit types that can interact with those drugs. From 2008 to 2012, the number of drugs known to potentially interact with grapefruit, with risk of harmful or even dangerous effects (gastrointestinal bleeding,
nephrotoxicity), increased from 17 to 43.[1]
Traits
The interaction between citrus and medication depends on the individual drug, and not the class of the drug. Drugs that interact usually share three common features: they are taken orally, normally only a small amount enters systemic blood circulation, and they are metabolized by CYP3A4.[1] The effects on the CYP3A4 in the liver could in principle cause interactions with non-oral drugs,[citation needed] and non-CYP3A4-mediated effects also exist.[27]
Cytochrome isoforms affected by grapefruit components include
CYP3A4,
CYP1A2,
CYP2C9, and
CYP2D6.[20] Drugs that are metabolized by these enzymes may have interactions with components of grapefruit.
An easy way to tell if a medication may be affected by grapefruit juice is by researching whether another known CYP3A4 inhibitor drug is already contraindicated with the active drug of the medication in question. Examples of such known CYP3A4
inhibitors include
cisapride (Propulsid),[44]erythromycin,
itraconazole (Sporanox),
ketoconazole (Nizoral), and
mibefradil (Posicor).[45]
Incomplete list of affected drugs
By enzyme
Drugs that interact with grapefruit compounds at CYP3A4 include
Research has been done on the interaction between amphetamines and CYP2D6 enzyme, and researchers concluded that some parts of substrate molecules contribute to the binding of the enzyme.[57]
Other interactions
Additional drugs found to be affected by grapefruit juice include, but are not limited to
Amlodipine: Grapefruit increases the available amount of the drug in the blood stream, leading to an unpredictable increase in antihypertensive effects.
Acetaminophen/paracetamol (Tylenol) concentrations were found to be increased in
murine blood by white and pink grapefruit juice, with the white juice acting faster.[61] "The bioavailability of paracetamol was significantly reduced following multiple GFJ administration" in mice and rats. This suggests that repeated intake of grapefruit juice reduces the efficacy and bioavailability of acetaminophen/paracetamol in comparison with a single dose of grapefruit juice, which conversely increases the efficacy and bioavailability of acetaminophen/paracetamol.[62][63]
Buspirone (Buspar): Grapefruit juice increased peak and AUC plasma concentrations of buspirone 4.3- and 9.2
-fold, respectively, in a randomized, 2-phase, ten-subject
crossover study.[65]
Codeine is a prodrug that produces its analgesic properties following metabolism to morphine entirely by CYP2D6.[66]
Ciclosporin (cyclosporine, Neoral): Blood levels of ciclosporin are increased if taken with grapefruit juice, orange juice, or apple juice.[8] A plausible mechanism involves the combined inhibition of enteric CYP3A4 and MDR1, which potentially leads to serious adverse events (e.g., nephrotoxicity). Blood levels of
tacrolimus (Prograf) can also be equally affected for the same reason as ciclosporin, as both drugs are calcineurin inhibitors.[67]
Exemestane,
aromasin, and by extension all estrogen-like compounds and
aromatase inhibitors that mimic estrogen in function will be increased in effect, causing increased estrogen retention and increased drug retention.[69]
Etoposide interferes with grapefruit, orange, and apple juices.[8]
Fexofenadine (Allegra) concentrations are decreased rather than increased as is the case with most grapefruit–drug interactions.[70][71]
Imatinib (Gleevec): Although no formal studies with imatinib and grapefruit juice have been conducted, the fact that grapefruit juice is a known inhibitor of the CYP 3A4 suggests that co-administration may lead to increased imatinib plasma concentrations. Likewise, although no formal studies were conducted, co-administration of imatinib with another specific type of citrus juice called
Seville orange juice (SOJ) may lead to increased imatinib plasma concentrations via inhibition of the CYP3A isoenzymes. Seville orange juice is not usually consumed as a juice because of its sour taste, but it is found in marmalade and other jams. Seville orange juice has been reported to be a possible inhibitor of CYP3A enzymes without affecting MDR1 when taken concomitantly with ciclosporin.[73]
Ketamine: After drinking 200 mL of grapefruit juice daily for five days, the overall absorption of orally ingested ketamine was three-fold compared to a control group of a clinical trial. The peak blood ketamine concentration was over two-fold.[74]
Levothyroxine (Eltroxin, Levoxyl, Synthroid): "Grapefruit juice may slightly delay the absorption of levothyroxine, but it seems to have only a minor effect on its bioavailability."[clarification needed][75]
Oxycodone: grapefruit juice enhances the exposure to oral oxycodone. And a randomized, controlled trial 12 healthy volunteers ingested 200 mL of either grapefruit juice or water three times daily for five days. On the fourth day 10 mg of oxycodone hydrochloride were administered orally. Analgesic and behavioral effects were reported for 12 hours and plasma samples were analyzed for oxycodone metabolites for 48 hours. Grapefruit juice and increased the mean area under the oxycodone concentration-time curve (AUC(0-∞)) by 1.7 fold, the peak plasma concentration by 1.5-fold and the half-life of oxycodone by 1.2-fold as compared to water. The metabolite-to-parent ratios of noroxycodone and noroxymorphone decreased by 44% and 45% respectively. Oxymorphone AUC(0-∞) increased by 1.6-fold but the metabolite-to-parent ratio remained unchanged.[78]
Tamoxifen (Nolvadex): Tamoxifen is metabolized by CYP2D6 into its active metabolite 4-hydroxytamoxifen. Grapefruit juice may potentially reduce the effectiveness of tamoxifen.[80]
Trazodone (Desyrel): Little or no interaction with grapefruit juice.[81]
^
abcdeSaito, Mitsuo; Hirata-Koizumi, Mutsuko; Matsumoto, Mariko; Urano, Tsutomu; Hasegawa, Ryuichi (2005). "Undesirable effects of citrus juice on the pharmacokinetics of drugs: focus on recent studies". Drug Safety. 28 (8): 677–694.
doi:
10.2165/00002018-200528080-00003.
PMID16048354.
S2CID23222717.
^
abcGreenblatt DJ, von Moltke LL, Harmatz JS, et al. (August 2003). "Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice". Clinical Pharmacology and Therapeutics. 74 (2): 121–9.
doi:
10.1016/S0009-9236(03)00118-8.
PMID12891222.
S2CID21070191.
^
abcdefPirmohamed, Munir (12 January 2013). "Drug-grapefruit juice interactions: Two mechanisms are clear but individual responses vary". BMJ. 346 (7890): 9.
doi:
10.1136/bmj.f1.
PMID23297175.
S2CID5581600.
^
abEdwards, D. J.; Bernier, S. M. (1996). "Naringin and naringenin are not the primary CYP3A inhibitors in grapefruit juice". Life Sciences. 59 (13): 1025–1030.
doi:
10.1016/0024-3205(96)00417-1.
PMID8809221.
^Veronese ML, Gillen LP, Burke JP, Dorval EP, Hauck WW, Pequignot E, Waldman SA, Greenberg HE (August 2003). "Exposure-dependent inhibition of intestinal and hepatic CYP3A4 in vivo by grapefruit juice". Journal of Clinical Pharmacology. 43 (8): 831–9.
doi:
10.1177/0091270003256059.
PMID12953340.
S2CID6513161.{{
cite journal}}: CS1 maint: date and year (
link) CS1 maint: multiple names: authors list (
link)
^
abTassaneeyakul W, Guo LQ, Fukuda K, Ohta T, Yamazoe Y (June 2000). "Inhibition selectivity of grapefruit juice components on human cytochromes P450". Archives of Biochemistry and Biophysics. 378 (2): 356–63.
doi:
10.1006/abbi.2000.1835.
PMID10860553.
^Bressler R (November 2006). "Grapefruit juice and drug interactions. Exploring mechanisms of this interaction and potential toxicity for certain drugs". Geriatrics. 61 (11): 12–8.
PMID17112309.
^Veronese ML, Gillen LP, Burke JP, et al. (August 2003). "Exposure-dependent inhibition of intestinal and hepatic CYP3A4 in vivo by grapefruit juice". Journal of Clinical Pharmacology. 43 (8): 831–9.
doi:
10.1177/0091270003256059.
PMID12953340.
S2CID6513161.
^Lundahl J, Regårdh CG, Edgar B, Johnsson G (1995). "Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subjects". European Journal of Clinical Pharmacology. 49 (1–2): 61–7.
doi:
10.1007/BF00192360.
PMID8751023.
S2CID178579.
^
abGreenblatt, DJ; Patki, KC; von Moltke, LL; Shader, RI (2001). "Drug interactions with grapefruit juice: an update". J Clin Psychopharmacol. 21 (4): 357–9.
doi:
10.1097/00004714-200108000-00001.
PMID11476118.
^
abChen, Chunxian; Yu, Qibin; Wei, Xu; Cancalon, Paul F.; Gmitter Jr., Fred G.; Belzile, F. (October 2014). "Identification of genes associated with low furanocoumarin content in grapefruit". Genome. 57 (10): 537–545.
doi:
10.1139/gen-2014-0164.
PMID25756876.
^Musmul, A.; Cingi, M. Ipek; Boydaĝ, B. S.; Aktan, Yasemın; Özdemir, Murat (1998). "Interaction between grapefruit juice and diazepam in humans". European Journal of Drug Metabolism and Pharmacokinetics. 23 (1): 55–59.
doi:
10.1007/BF03189827.
PMID9625273.
S2CID9055484.
^Sugimoto K, Araki N, Ohmori M, et al. (March 2006). "Interaction between grapefruit juice and hypnotic drugs: comparison of triazolam and quazepam". European Journal of Clinical Pharmacology. 62 (3): 209–15.
doi:
10.1007/s00228-005-0071-1.
PMID16416305.
S2CID32616279.
^Lee AJ, Chan WK, Harralson AF, Buffum J, Bui BC (November 1999). "The effects of grapefruit juice on sertraline metabolism: an in vitro and in vivo study". Clinical Therapeutics. 21 (11): 1890–9.
doi:
10.1016/S0149-2918(00)86737-5.
PMID10890261.
^
abLilja JJ, Kivistö KT, Neuvonen PJ (August 1999). "Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin". Clinical Pharmacology and Therapeutics. 66 (2): 118–27.
doi:
10.1053/cp.1999.v66.100453001.
PMID10460065.
S2CID8103490.
^Jetter A, Kinzig-Schippers M, Walchner-Bonjean M, et al. (January 2002). "Effects of grapefruit juice on the pharmacokinetics of sildenafil". Clinical Pharmacology and Therapeutics. 71 (1): 21–9.
doi:
10.1067/mcp.2002.121236.
PMID11823754.
S2CID40447204.
^Dasgupta A, Reyes MA, Risin SA, Actor JK (December 2008). "Interaction of white and pink grapefruit juice with acetaminophen (paracetamol) in vivo in mice". Journal of Medicinal Food. 11 (4): 795–8.
doi:
10.1089/jmf.2008.0059.
PMID19053875.
^Qinna, Nidal A.; Ismail, Obbei A.; Alhussainy, Tawfiq M.; Idkaidek, Nasir M.; Arafat, Tawfiq A. (1 April 2016). "Evidence of reduced oral bioavailability of paracetamol in rats following multiple ingestion of grapefruit juice". European Journal of Drug Metabolism and Pharmacokinetics. 41 (2): 187–195.
doi:
10.1007/s13318-014-0251-4.
PMID25547640.
S2CID18180270.
^Samojlik, I.; Rasković, A.; Daković-Svajcer, K.; Mikov, M.; Jakovljević, V. (1 July 1999). "The effect of paracetamol on peritoneal reflex after single and multiple grapefruit ingestion". Experimental and Toxicologic Pathology. 51 (4–5): 418–420.
doi:
10.1016/S0940-2993(99)80032-3.
PMID10445408.
^Burnett, Bruce (1 September 2014).
"Exemestane (Aromasin)". Macmillan Cancer Support. Retrieved 17 July 2017.
^Dresser GK, Kim RB, Bailey DG (March 2005). "Effect of grapefruit juice volume on the reduction of fexofenadine bioavailability: possible role of organic anion transporting polypeptides". Clinical Pharmacology and Therapeutics. 77 (3): 170–7.
doi:
10.1016/j.clpt.2004.10.005.
PMID15735611.
S2CID24716662.
^Peltoniemi, Marko A.; Saari, Teijo I.; Hagelberg, Nora M.; Laine, Kari; Neuvonen, Pertti J.; Olkkola, Klaus T. (June 2012). "S-ketamine concentrations are greatly increased by grapefruit juice". European Journal of Clinical Pharmacology. 68 (6): 979–986.
doi:
10.1007/s00228-012-1214-9.
ISSN1432-1041.
PMID22286159.
S2CID15742712.
^Benmebarek M, Devaud C, Gex-Fabry M, et al. (July 2004). "Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone". Clinical Pharmacology and Therapeutics. 76 (1): 55–63.
doi:
10.1016/j.clpt.2004.03.007.
PMID15229464.
S2CID25693476.