Grapefruit

Last Updated: September 28 2022

Grapefruit is a food product known for having a high level of bioactives, similar to the pomegranate. It does appear to be effective at reducing fat mass when a mixture of polyphenols are used, and may work nicely with caffeine.

Grapefruit is most often used for.



Don't miss out on the latest research

Become an Examine Insider for FREE to stay on top of the latest nutrition research, supplement myths, and more

    1.

    Source and Composition

    1.1

    Composition

    Grapfruit contains the following bioactives:

    • The polyphenol Naringenin[1] at approximately 32.64mg/100g fresh weight (pink grapefruit); also its glycoside (bound to carbohydrate storage form) Naringin
    • Hesperiden at approximately 0.35mg/100g, and its aglycone (without sugar) form Hesperitin; Hesperidin is technically called Hesperitin-7-rhamnoglucoside (attached to a rutinose sugar) and a molecule called neohesperidin is short for Hesperitin-7-b-neohesperidoside[2]
    • Nootkatone[3]
    • 6'7'-dihydroxybergamottin, the CYP3A4 inhibitor blamed for 'the grapefruit effect'[4] and other furanocoumarins such as Bergamottin and 5-methoxy-7 gernoxycoumarin[5]
    • Poncirin and Didymin[5]
    • Isosakuranetín and its glycoside, isosakuranetín-7-O-rutinoside (possible other glycosides)[6]
    • Apigenin and various glycosides[6]
    • Spermidine, a polyamine also found in some other vegetables and semen[7]
    • Quercetin, its related compound Isorhamnetin, and various glycosides[6]
    • Kaempferol and glycosides
    • Luteolin-7-O-neohesperidoside-4′-O-glucoside[6]
    • Two scopoletin glycosides[6]
    • Sinapic Acid, Ferulic Acid, and aromatic compounds[6]

    In general, when the bioactives of a 'Grapefruit' are referred to it tends to refer to the Naringenin class of flavonoids and the Hesperidin class of flavonoids. The furanocoumarin class (things related to Bergamottin in structure) may also be mentioned due to drug-drug interactions, and Nootkatone is both similar in actions to the former two classes and aromatic (tasty) and also deserves mention. These four classes are mostly unique to Grapefruit and more likely to be related to 'Grapefruit related effects', unlike stuff like Quercetin or Apigenin which are present in most plants

    When looking at the average phenolic content of grapefruit juice, one study noted that it ranged from 1173–2216mg/L and appeared to be greater than tangerine, sweet orange, and lemon juice on average.[6] Most of these polyphenols, particularily the ones unique to Grapefruit and listed first in the list, are localized more in the peel than in the juice.[8] Despite the higher content of bioflavonoids, grapefruit tends to be more bitter than the other fruits mentioned; partially due to having more neohesperidin than other fruits which confers a bitter taste (hesperidin is fairly tasteless)[2] and the peel is even more bitter due to a high limolin content.[5]

    One study using a lone grapefruit (to reduce variability of components) and subjecting segments to different processing techniques (juicing, hand squeezing, and blending the entire grapefruit with peel as the third group) noted that the blended juice (with peel) had 7-fold higher levels of naringin (160.79mg/100mL) relative to juiced (26.25) and hand-squeezed (22.51) and this trend of the peel-containing juice having more bioactives extends to poncirin and didymin; however, it also possessed a higher limonin content which confers a bitter taste, having 2.45mg/100mL relative to 0.14 and 0.09 with juiced and hand-squeezed grapefruit juice.[5]

    Oddly, handsqueezed juice had higher levels of 6'7'-dihydroxybergamottin (0.38mg/100mL) relative to juiced (0.10mg) and blended (0.20mg) although Bergamottin itself was highest in blended as was a third tested furanocoumarin, 5-methoxy-7 gernoxycoumarin.[5] Vitamin C was lower in the blended juice due to higher concentrations of other bioactives, and relatively higher in hand-squeezed and juiced.[5]

    Many of the unique bioactives of grapefruit are highest in the peel, and thus a pulpy juice is likely to hold more of these bioactives than is a juice made without the peel blended into it

    1.2

    Structure

    image

    Hesperidin (glycone) is tan or yellowish in color, and forms long needles when pure. Its melting point ranges from 258-262°C and is easily soluble in dilute alkali, slightly soluble in methanol and almost insoluble in acetone.[2] Its solubility in water is 1 in 50, and it has a habit of forming crystals similar to other glycosides of flavonoids; hesperidin is tasteless and odourless.[2]

    2.

    Pharmacokinetics

    2.1

    Enzymatic/Transporter Interactions

    Naringin seems to be able to inhibit Organic Anion-Transporting Polypeptide (OATP1A2)[9] and Grapefruit Juice in general also appears to inhibit the 2B1 isoform, OATP2B1.[10] Both of these transports absorb drugs from the intestines, and their inhibition may reduce systemic availability of the drugs.[9][10]

    2.2

    Grapefruit Effect

    The Grapefruit effect refers to the ability of Grapefruit juice and supplements to interact with a wide variety of pharmaceuticals, either enhancing or limiting their systemic availability. Due to altering the active dosage of the pharmaceutical, Grapefruit Juice is commonly contradindicted (to not be used alongside) many drugs.

    This is due to different bioactives, such as Naringin which can inhibit absorption of some drugs (via OATP inhibition) but more commonly 6'7'-dihydroxybergamottin, which inhibits CYP3A4; this latter enzyme metabolizes pharmaceuticals, and its inhibition results in less metabolism and thus higher circulating levels. Despite also being a CYP3A inhibit in vitro, the Quercetin content of Grapefruit appears to not be a significant concern.[11]

    3.

    Interactions with Obesity

    3.1

    Mechanisms

    A few compounds in Grapefruit act on AMPK (adenosine monophosphate kinase) to activate it and draw nutrients into tissue, including Nootkatone and Naringenin.

    Nootkanone appears to active AMPK and LKB1 in the liver (hepatocytes) and muscle (myocytes), which has been confirmed with oral feeding of 200mg/kg Nootkatone to rats within 30-60 minutes.[3] Nootkatone acts on the isoforms of AMPKα1 and AMPKα2 mostly, and is partly mediated in muscles by activation of CaMKK and intracellular calcium, and the calcium appears to act via AMPK isoforms as incubation Nootkatone in HeLa cells (lacking the other AMPK-like protein, LKB1) is fully calcium dependent.[3] Interestingly, these mechanisms are not dependent on reactive oxygen/nitrogen species.

    Naringenin appears to stimulate glucose uptake at 50uM concentration (without significant influence at 10uM and 20uM) to 141+/-5.5% of control, with most significant effects at 75uM (165+/-4.9%) and no further effects at 100uM and 150uM.[1] Naringenin appears to act via the insulin receptor, as aside from phosphorylating Akt Naringenin loses efficacy when the in vitro assay is saturated with insulin and the receptors occupied.[1] Naringenin did activate AMPK as well, unlike insulin, in a dose and time-dependent manner which is not mediated by the SIRT1 protein and its maximum efficacy (205+/-24%) was more potent than resveratrol (168+/-12%) which acts by similar mechanisms.

    Nootkatone does not appear to interact with PPARα nor PPARδ.[3]

    The mechanisms of Grapefruit polyphenols appear to be related to activating AMPK, which is a mechanism of producing ATP (cellular energy) and increasing the metabolic rate

    A blend of polyphenols known as SINETROL (anthocyanins, flavonoids and caffeine) appear to influence Phosphodiesterase (PDE) enzymes via inhibition, which in a whole-cell culture can influence AMPK activation in a similar manner as resveratrol.[12] When tested in vitro, this SINETROL mixture at 0.01% was able to inhibit an average of 97+/-1% of active PDE, while the same dose of caffeine inhibited 56+/-5% and two of the bioactives in SINETROL (Naringin and Cyanidin-3-Glucoside) inhibited 87+/-6% and 99+/-8% at the same concentration.[13] SINETROL by itself is able to increase free fatty acid release from fat cells in vitro, to about twice the level of Guarana (12% caffeine) but to lesser extents than theopylline and Isoproterenol; concentrations varied with these two making direct comparisons difficult.[13]

    It is possible that grapefruit polyphenols act on phosphodiesterase enzymes (PDEs) and inhibit them, which would increase activity of AMPK and increase glucose uptake into cells. A mechanistic chain somewhat similar to the wine polyphenol resveratrol

    3.2

    Interventions

    One study in rats using isolated Nootkatone noted an increase in measured VO2 and metabolic rate, without significantly influencing respiratory quotient (percentage of energy coming from lipids or glucose).[3] Elsewhere in this study, rats were fed Nootkatone at 0.1-0.3% of the diet by weight and the expected increase in diet-induced obesity was significantly attenuated (with high fat control being increase to 187% of baseline bodyweight and Nootkatone at 0.1, 0.2, and 0.3% of the diet reducing this increase to 162%, 160%, and 147%).[3]

    A human study using overweight/obese subjects that were otherwise healthy compared a control diet to a diet with a moderate amount of grapefruit (one half of a fresh Rio-Red grapefruit with each of three meals) for 6 weeks, and noted that grapefruit consumption was associated with modest weight loss (-0.61+/-2.23 kg) that came with a modest decrease in blood pressure (−3.21+/-10.13 mmHg) while no changes occurred in control.[14] Self-reported intake as assessed by 24-hour dietary recall did not differ between groups, and estimated intake of Naringenin and Hesperiden was 146.2mg and 1.57mg daily.[14] A later study in obese persons compared solid grapefruit with grapefruit juice and a third group with grapefruit capsules of 500mg extract (blinded) noted that over the course of 2 weeks that all groups were able to lose weight with 1.1kg (capsules) 1.5kg (juice) and 1.6kg (fruit).[15] The fruit was significantly more effective than placebo at weight loss while the other two groups trended towards being more effective, and this trend toward increased efficacy also appeared to hold for blood pressure (although did not reach statistical significance).[15]

    One study using a SINETROL mixture (grapefruit polyphenols, anthocyanins, caffeine) noted that this mixture, when taken by healthy overweight/obese persons at 1.4g daily (four capsules of 350mg) over 12 weeks had their BMI reduced by 2.2+/-0.9 points from a baseline status of 28.1+/-2.45, which was accompanied by a reduction of their body fat percentage from 30.7+/-1.9% to 29.0+/-0.8% at 4 weeks (5.4% reduction) and 25.9+/-1.0% (15.6% reduction) at 12 weeks; this study did not disclose any affiliations with the patent owners or producers of SINETROL.[13]

    Grapefruit polyphenols do appear to be effective at reducing bodyweight, reliably but not outright potently. The efficacy of grapefruit polyphenols in reducing body weight may be better if consumed via the grapefruit itself (possibly through fibers also acting) and appear to be synergistic with anthocyanins (blue-red pigments in fruits like berries)

    4.

    Interactions with Neurology

    4.1

    Depression

    Hesperidin, a flavonoid glycoside found in grapefruit, appears to have anti-depressant effects in mice when injected at doses of 0.3mg/kg and appears to be mediated by serotonergic mechanisms as it is inhibited by serotonin receptor antagonists and when serotonin synthesis is inhibited, and 0.1mg/kg is augmented with selective serotonin reuptake inhibitors (SSRIs).[16]

    4.2

    Neuroprotection

    In a study screening Traditional Chinese Medicine for bioactives, Naringenin was found to induce GRP78 (an endoplasmic reticulum protein) in a dose-dependent manner up to 3-fold luciferase activity at 0.2mM and showing statistically significant effects at 0.05mM; naringin and glycyrrhizic/glycerrhezic acids were all found to be inactive.[17] Subsequently, Naringenin was found to suppress protein aggregation in HeLa-tetQ97 cells and in cells expressing EGFP-polyQ97 (as GRP78 reduces aggregation[18]), suggesting Naringenin may be useful for neural diseases associated with polyglutamine aggregation.[17]

    5.

    Longevity

    Hesperidin, a flavonoid glycoside from Grapefruit, appears to be associated with increased longevity in yeast related to its anti-oxidant abilities.[19] This was observed to occur with 5uM and 10uM concentrations, and was not associated with Hesperitin (the aglycone of Hesperidin) implicating the sugar moiety on C-7 of hesperitin as critical to the observed effects; and the gene UTH1 (not present in humans) appears to be implicated in the yeast, although in vitro assays suggested induction of both SIRT1 and Superoxide Dismutase which may have relevance to humans.[19]

    Too preliminary to draw any conclusions

    6.

    Exercise and Performance

    One study in mice assessing swimming performance noted a 21% increase after Nootkatone administration at 0.2% of the diet, relative to control mice.[3]

    7.

    Cardiovascular Health

    7.1

    Blood Pressure

    Consumption of a half a small grapefruit thrice a day for 6 weeks is associated with a moderate drop in systolic blood pressure (-3.21+/-10.13 mmHg) with no influence on diastolic or heart rate.[14]

    7.2

    Blood Flow and Platelets

    Mechanistically, the Nootkatone component of grapefruit has been shown to inhibit platelet aggregation when it is isolated from the plant Cyperus Rotundus, and was able to significantly suppress thrombin and arachidonic-acid induced clotting at 30uM while needing 100uM to suppress collagen-induced clotting.[20] However, nootkatone in isolation was able to suppress platelet aggregation induced by collagen at 30mg/kg bodyweight oral ingestion in rats to a greater extent than aspirin at 30mg/kg, and of equal potency when nootkatone was dosed at 10mg/kg; Nootkatone appears to mediate most anti-platelet effects of Cyperus Rotundus ethanolic extract.[20] 30mg/kg Nootkatone also prolonged tail bleeding time in rats to the same degree as 50mg/kg Aspirin.[20]

    In one study comparing grape juice, orange juice, and grapefruit juice on platelet aggregation it was found that only grape juice was active.[21] 5-7.5mL/kg juice for 7-10 days in otherwise healthy persons, prior to a collagen-induced clotting test, noted that grape juice was associated with a significant 77% reduction in clotting while grapefruit was not significantly different than control.[21] These observed effects may be due to Nootkatone being localized to the peel of the grapefruit and being in ethanolic rather than water extracts,[22] both of which may preclude its exclusion in juice.

    Has the ability to reduce platelet aggregation with large potency via the Nootkatone component, but this has not yet been demonstrated in humans and the one study in humans (that may have not been designed to properly assess this question) had null results

    7.3

    Cholesterol

    One study using half a small grapfruit thrice a day with meals noted that the grapefruit group had reductions in lipoproteins and triglycerides, but control also had a reduction and this it was deemed insignificant.[14]

    A study conducted on the Grapefruit pectin (fiber component) noted that consumption of grapefruit pectin in a blinded manner for 16 weeks in person at risk for cardiovascular disease risk was associated with improvements in the lipid profile (7.6% reduction in total cholesterol and 10.8% LDL-C reductions).[23]

    8.

    Interactions with Glucose Metabolism

    8.1

    Interventions

    One intervention assessing 500mg Grapefruit capsules, grapefruit juice, and grapefruits themselves noted that after 12 weeks of supplementation that both the juice and fruit groups appears to improve insulin sensitivity in obese persons in response to an oral glucose tolerance test.[15]

    9.

    Inflammation and Immunology

    9.1

    Mechanisms

    Nootkatone, also a component of Cyperus rotundus, appears to be able to induce Heme-Oxygenase 1 induction (HO-1) and is one of the two most active components of Cuperus Rotundus in doing so (the other being valencene ).[24] This induction of HO-1 mediates suppression of iNOS induction by LPS in macrophages, and anti-inflammatory effects in the presence of pro-inflammatory stimuli, and this induction has been associated with less death from sepsis in mice (via HO-1 suppressing HMGB1 release).[24]

    10.

    Interactions with Hormones

    10.1

    Estrogen

    In ovariectomized women given 2mg of estrogen, grapefruit juice appeared to increase the kinetics of exogenous estrogen by interfering with estrogen metabolism.[25]

    11.

    Nutrient-Nutrient Interactions

    11.1

    Nicotine

    Nicotine appears to be metabolized into Cotinine via the enzyme CYP2A6, which grapefruit inhibits, and relative to consuming water alongside 2mg nicotine the consumption of grapefruit juice (large dose, 1L) can delay the Tmax (time to peak concentration) by an extra 8-47% while attenuating the Cmax (peak concentration), although renal clearance of nicotine is also enhanced and overall exposure (AUC) is unaffected.[26]

    11.2

    Xanthines

    Xanthine compounds, most notably caffeine and its metabolite theophylline (found in teas), are metabolized by the same general class of enzymes that Grapefruit components inhibit. In studies investigated the interactions between the two, theophylline may have its absorption reduced by grapefruit if coingested[27] although another study suggests that there is no significant difference between theophylline kinetics and theophylline kinetics under the influence of grapefruit juice.[28]

    Two studies conducted on the interaction of caffeine and grapefruit juice note no significant effects of grapefruit components on caffeine kinetics,[29] with a study measuring the increase in metabolic rate from caffeine finding that naringenin did not enhance it (from theoretically increasing exposure to caffeine, which naringenin also failed to accomplish at 100 and 200mg).[30]

    11.3

    SINETROL

    SINETROL is a mixture of grapefruit polyphenols (Narirutin, Naringin, Hesperidin, Neohesperidin) anthocyanins (Delphinidin-3-glucoside, Pelargonidin-3-Glucoside, Cyanidin-3-Glucoside, peonidin-3-glucoside, Malvidin-3-Glucoside) and caffeine, and appears to possess some synergistic components.

    In an assay for PDE inhibition, 0.01% of SINETROL is able to inhibit an equal amount of PDE as 0.01% Cyanidin-3-Glucoside despite having a much smaller concentration of Cyanidin-3-glucoside; the Naringen appears to be bioactive but to a lesser degree than Cyanidin-3-glucoside, but not enough to account for the discrepancy.[13]

    Grapefruit polyphenols and Anthocyanins appear to possess synergism in regards to PDE inhibition, but the exact molecules that are causative of this are not known

    11.4

    Diosmin

    A combination of Hesperidin (Hesperitin glycoside) and Diosmin (Diosmetin glycoside) in a 1:9 ratio (50mg and 450mg; respectively) is called Daflon500, and two capsules daily of Daflon has been associated with benefits in humans with chronic venous insufficiency and reducing related symptoms such as cramps and edema.[31]

    12.

    Safety and Toxicity

    12.1

    Drug interactions

    Grapefruit contains various chemicals known to reduce the metabolism of a wide variety of pharmaceutical drugs due to their inhibition of drug-metabolizing enzymes, primarily of the Cytochrome P450 superfamily as expressed in the intestines.[32] This can potentially lead to excessive and detrimental effects from these drugs. These enzymes include but aren’t limited to:

    Additionally, there are effects on organic anion-transporting polypeptide and p-glycoprotein, though these likely don’t account for most of most drug interactions.[39][40][41]

    The primary class of chemicals responsible are the furocoumarins, which are highly potent.[42][43] The most prevalent furocoumarins in grapefruit are bergaptol, bergamottin, and DHB, and interestingly, in commercial grapefruit juices, bergaptol is dominant, but in fresh-squeezed grapefruit juices, DHB is.[44]

    There is some effect of naringin and naringenin, which are present in a variety of citrus fruits, though their influence on CYP3A4 is minor when compared with the influence of furocoumarins.[45] [46]

    Hesperidin has demonstrated potential drug interactions, though the amount in grapefruit is unlikely to make it a major player.[2]

    There are also potential effects from BAS 100 and minor and limited effects from nootkatone.[47][36]

    Naturally occurring chemicals in grapefruit can cause negative drug interactions. It’s very important to talk to a doctor or pharmacist about the potential risks of combining grapefruit and your medications.

    12.2

    Other potential concerns

    Blood pressure

    Grapefruit may enhance the effect of nitrates on blood pressure by preventing reoxidation of nitrite to nitrate via cytochrome P450 3A4.[48] This might produce hypotension in those with already normal or low blood pressure, though evidence for this is lacking.

    Breast cancer

    P450 34A is involved in the metabolism of estrogens, and frequent consumption may increase levels of some estrogens.[49] One study found an increased risk of breast cancer, but another failed to.[50][51] Therefore, this risk is highly speculative and requires more research.

    References
    1.^Zygmunt K, Faubert B, MacNeil J, Tsiani ENaringenin, a citrus flavonoid, increases muscle cell glucose uptake via AMPKBiochem Biophys Res Commun.(2010 Jul 23)
    2.^Garg A, Garg S, Zaneveld LJ, Singla AKChemistry and pharmacology of the Citrus bioflavonoid hesperidinPhytother Res.(2001 Dec)
    3.^Murase T, Misawa K, Haramizu S, Minegishi Y, Hase TNootkatone, a characteristic constituent of grapefruit, stimulates energy metabolism and prevents diet-induced obesity by activating AMPKAm J Physiol Endocrinol Metab.(2010 Aug)
    4.^Kakar SM, Paine MF, Stewart PW, Watkins PB6'7'-Dihydroxybergamottin contributes to the grapefruit juice effectClin Pharmacol Ther.(2004 Jun)
    5.^Uckoo RM, Jayaprakasha GK, Balasubramaniam VM, Patil BSGrapefruit (Citrus paradisi Macfad) Phytochemicals Composition Is Modulated by Household Processing TechniquesJ Food Sci.(2012 Sep)
    7.^Zoumas-Morse C, Rock CL, Quintana EL, Neuhouser ML, Gerner EW, Meyskens FL JrDevelopment of a polyamine database for assessing dietary intakeJ Am Diet Assoc.(2007 Jun)
    11.^Rashid J, McKinstry C, Renwick AG, Dirnhuber M, Waller DG, George CFQuercetin, an in vitro inhibitor of CYP3A, does not contribute to the interaction between nifedipine and grapefruit juiceBr J Clin Pharmacol.(1993 Nov)
    12.^Park SJ, Ahmad F, Philp A, Baar K, Williams T, Luo H, Ke H, Rehmann H, Taussig R, Brown AL, Kim MK, Beaven MA, Burgin AB, Manganiello V, Chung JHResveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterasesCell.(2012 Feb 3)
    15.^Fujioka K, Greenway F, Sheard J, Ying YThe effects of grapefruit on weight and insulin resistance: relationship to the metabolic syndromeJ Med Food.(2006 Spring)
    16.^Souza LC, de Gomes MG, Goes AT, Del Fabbro L, Filho CB, Boeira SP, Jesse CREvidence for the involvement of the serotonergic 5-HT(1A) receptors in the antidepressant-like effect caused by hesperidin in miceProg Neuropsychopharmacol Biol Psychiatry.(2012 Sep 17)
    18.^Yamagishi N, Magara S, Tamura S, Saito Y, Hatayama TEndoplasmic reticulum chaperone GRP78 suppresses the aggregation of proteins containing expanded polyglutamine tractBiochem Biophys Res Commun.(2012 Jun 8)
    19.^Sun K, Xiang L, Ishihara S, Matsuura A, Sakagami Y, Qi JAnti-aging effects of hesperidin on Saccharomyces cerevisiae via inhibition of reactive oxygen species and UTH1 gene expressionBiosci Biotechnol Biochem.(2012)
    20.^Seo EJ, Lee DU, Kwak JH, Lee SM, Kim YS, Jung YSAntiplatelet effects of Cyperus rotundus and its component (+)-nootkatoneJ Ethnopharmacol.(2011 Apr 26)
    23.^Cerda JJ, Robbins FL, Burgin CW, Baumgartner TG, Rice RWThe effects of grapefruit pectin on patients at risk for coronary heart disease without altering diet or lifestyleClin Cardiol.(1988 Sep)
    24.^Tsoyi K, Jang HJ, Lee YS, Kim YM, Kim HJ, Seo HG, Lee JH, Kwak JH, Lee DU, Chang KC(+)-Nootkatone and (+)-valencene from rhizomes of Cyperus rotundus increase survival rates in septic mice due to heme oxygenase-1 inductionJ Ethnopharmacol.(2011 Oct 11)
    25.^Schubert W, Cullberg G, Edgar B, Hedner TInhibition of 17 beta-estradiol metabolism by grapefruit juice in ovariectomized womenMaturitas.(1994 Dec)
    26.^Hukkanen J, Jacob P 3rd, Benowitz NLEffect of grapefruit juice on cytochrome P450 2A6 and nicotine renal clearanceClin Pharmacol Ther.(2006 Nov)
    27.^Gupta MC, Garg SK, Badyal D, Malhotra S, Bhargava VKEffect of grapefruit juice on the pharmacokinetics of theophylline in healthy male volunteersMethods Find Exp Clin Pharmacol.(1999 Dec)
    28.^Fuhr U, Maier A, Keller A, Steinijans VW, Sauter R, Staib AHLacking effect of grapefruit juice on theophylline pharmacokineticsInt J Clin Pharmacol Ther.(1995 Jun)
    29.^Maish WA, Hampton EM, Whitsett TL, Shepard JD, Lovallo WRInfluence of grapefruit juice on caffeine pharmacokinetics and pharmacodynamicsPharmacotherapy.(1996 Nov-Dec)
    30.^Ballard TL, Halaweish FT, Stevermer CL, Agrawal P, Vukovich MDNaringin does not alter caffeine pharmacokinetics, energy expenditure, or cardiovascular haemodynamics in humans following caffeine consumptionClin Exp Pharmacol Physiol.(2006 Apr)
    31.^Guillot B, Guilhou JJ, de Champvallins M, Mallet C, Moccatti D, Pointel JPA long term treatment with a venotropic drug. Results on efficacy and safety of Daflon 500 mg in chronic venous insufficiencyInt Angiol.(1989 Oct-Dec)
    32.^David G Bailey, George Dresser, J Malcolm O ArnoldGrapefruit-medication interactions: forbidden fruit or avoidable consequences?CMAJ.(2013 Mar 5)
    35.^Janne Hukkanen, Peyton Jacob 3rd, Neal L BenowitzEffect of grapefruit juice on cytochrome P450 2A6 and nicotine renal clearanceClin Pharmacol Ther.(2006 Nov)
    36.^W Tassaneeyakul, L Q Guo, K Fukuda, T Ohta, Y YamazoeInhibition selectivity of grapefruit juice components on human cytochromes P450Arch Biochem Biophys.(2000 Jun 15)
    37.^Basavaraj Girennavar, Shibu M Poulose, Guddadarangavvanahally K Jayaprakasha, Narayan G Bhat, Bhimanagouda S PatilFurocoumarins from grapefruit juice and their effect on human CYP 3A4 and CYP 1B1 isoenzymesBioorg Med Chem.(2006 Apr 15)
    39.^Shimako Tanaka, Shinya Uchida, Sachiko Miyakawa, Naoki Inui, Kazuhiko Takeuchi, Hiroshi Watanabe, Noriyuki NamikiComparison of inhibitory duration of grapefruit juice on organic anion-transporting polypeptide and cytochrome P450 3A4Biol Pharm Bull.(2013)
    40.^Robert B Parker, C Ryan Yates, Judith E Soberman, S Casey LaizureEffects of grapefruit juice on intestinal P-glycoprotein: evaluation using digoxin in humansPharmacotherapy.(2003 Aug)
    41.^Grapefruit and drug interactionsPrescrire Int.(2012 Dec)
    42.^Andrea Dreiseitel, Peter Schreier, Anett Oehme, Sanja Locher, Goeran Hajak, Philipp G SandAnthocyanins and their metabolites are weak inhibitors of cytochrome P450 3A4Mol Nutr Food Res.(2008 Dec)
    43.^Anastasia Messer, Nicole Raquet, Christiane Lohr, Dieter SchrenkMajor furocoumarins in grapefruit juice II: phototoxicity, photogenotoxicity, and inhibitory potency vs. cytochrome P450 3A4 activityFood Chem Toxicol.(2012 Mar)
    44.^Anastasia Messer, Anna Nieborowski, Christian Strasser, Christiane Lohr, Dieter SchrenkMajor furocoumarins in grapefruit juice I: levels and urinary metabolite(s)Food Chem Toxicol.(2011 Dec)
    45.^Keishi Yamasaki, Daisuke Iohara, Yoko Oyama, Narumi Nishizaki, Seitaro Kawazu, Koji Nishi, Daisuke Kadowaki, Kazuaki Taguchi, Masaki Otagiri, Hakaru SeoProcessing grapefruit juice with γ-cyclodextrin attenuates its inhibitory effect on cytochrome P450 3A activityJ Pharm Pharmacol.(2020 Mar)
    47.^N F Smith, S D Baker, F J Gonzalez, J W Harris, W D Figg, A SparreboomModulation of erlotinib pharmacokinetics in mice by a novel cytochrome P450 3A4 inhibitor, BAS 100Br J Cancer.(2008 May 20)
    48.^Kevin O'Gallagher, Sarah Borg Cardona, Callum Hill, Ali Al-Saedi, Fawzia Shahed, Christopher N Floyd, Karen McNeill, Charlotte E Mills, Andrew J WebbGrapefruit juice enhances the systolic blood pressure-lowering effects of dietary nitrate-containing beetroot juiceBr J Clin Pharmacol.(2021 Feb)
    49.^Kristine R Monroe, Frank Z Stanczyk, Kathleen H Besinque, Malcolm C PikeThe effect of grapefruit intake on endogenous serum estrogen levels in postmenopausal womenNutr Cancer.(2013)
    51.^Elizabeth A Spencer, Timothy J Key, Paul N Appleby, Carla H van Gils, Anja Olsen, Anne Tjønneland, Françoise Clavel-Chapelon, Marie-Christine Boutron-Ruault, Marina Touillaud, Maria-José Sánchez, Sheila Bingham, Kay Tee Khaw, Nadia Slimani, Rudolf Kaaks, Elio RiboliProspective study of the association between grapefruit intake and risk of breast cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)Cancer Causes Control.(2009 Aug)