grapefruit report

8/6/2019 Grapefruit Report

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Scientific/Medical Literature Evaluation Report

Health effects of Grapefruit and Grapefruit juice:as reported in peer-reviewed medical literature

July 27, 2010

This report aims to provide the California Grapefruit Growers Cooperative with a critical reviewof the medical/scientific literature concerning health issues (either positive or negative) associatedwith the consumption of grapefruit (GF) and grapefruit juice (GFJ).

Approach

This summary of the health aspects of consuming GF and GFJ (GF/J) is based on the literatureavailable in the U.S. National Library of Medicine online collection (PubMed). The literature review

was conducted from December 17, 2009 to July 1, 2010.

This review identifies areas of particular interest for GF/GFJ health effects including:

identification of the active ingredients in GF, with a brief discussion of benefits from vitaminsand antioxidants;

a brief discussion of GF drug interactions, considering the extent that clinical studies supportthe implications of laboratory studies;

a summary of the impact of GF consumption on cancer risk and treatment;

an overview of the effects of GF and GF derived chemicals on cardiovascular disease; the impact of GF consumption on weight loss and diabetes;

a report of GF effects on cellular flux of fatty acids and sugars;

miscellaneous other items of GF health effects worth mentioning.

Note: GF/GFJ interactions with drugs have been reviewed extensively, mostly from theperspective of what occurs in the laboratory, and therefore mightoccur clinically [for a discussion of invitro/clinical study discrepancies see: Farkas and Greenblatt (Farkas and Greenblatt, 2008). Ratherthan repeating the encyclopedic information collated in these reports, those sources deemed most

thorough and current have been referenced. This report aims to distinguish what has beendemonstrated viarobust clinical trials to actually occur in the human population, and to evaluate risksas well as potential health benefits. In addition, this report will propose areas to study to extendinsight into the health benefits of GF consumption.


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1) Physiologically active chemicals in GF/J

A. Pharmacological

Major pharmacologically active compounds in GF/Jinclude the furanocoumarins, bergamottin and 6',7'-dihydroxybergamottin, and the flavonoids, naringin andnaringenin (Mertens-Talcott et al., 2006; Strauch et al., 2009).The figure (right) pictures these (from Strauch et al., 2009).More detailed and additional structures, such as hesperetin,can be found on p. 15 of Fraga (CG Fraga, 2010). It isimportant to note that any fruit or vegetable contains up to10,000 different chemicals (phytochemicals or chemicalsnaturally occurring in plants), in addition to the well-knownnutrients and fiber. Many phytochemicals have not beencharacterized, nor have their physiological properties beendetermined. In other words, the chemicals in the figure areknown because research has focused on them, but this shouldnot be interpreted as these are the only possible bioactive

ingredients of GF/J. Similarly, all fruits, vegetables, and other foods have complex compositions ofphytochemicals, whose physiological significance have not been investigated at all, or have beenstudied only in a preliminary fashion.

A few facts to note about the impact of the known active chemicals in GF/J, according to arecent review (Strauch et al., 2009):

1) these chemicals are effective right after consuming GF/J and have maximum effects for ~4hr with total loss of the effects within 3 days;

2) repeated intake (e.g. daily) does not increase the impact.

It is also worthy to mention that the amounts of these compounds vary not only with the type o

GF/J, but the exact handling of the fruit.Some pertinent facts: Naringenin has a lethal dose (LD50) >5000 mg/kg. The naringin

concentration in GF (from 6685 juice samples) in (ppm): mean 412 149; minimum 6; maximum2115. In ripe fruit ~ 5 mmol/GF and 7 mol/g. Concentration after hand squeezing has been reportedas 115 to 384 mg/l (~0.5 mM). One-time consumption of 20 oz (a rather large amount) GFJ results inpeak plasma naringenin of 6 M. Naringenin content of a medium sized GF is ~78 mg/100g.Thesedata indicate that naringenin is relatively non-toxic and has a wide margin of safety in humans. Inaddition, these data need to be considered in evaluating claims about the biological effects ofnaringenin in the context of GF/J consumption.

The primary targets of these compounds include: the enzyme Cyp3A4, which degrades drugs

as they are absorbed into the intestinal cell, the influx transporters OATPs, which absorb drugs intothe intestinal cell, and possibly, but not necessarily the efflux transporters P-glycoprotein (MDR1) andMRP-2, which transport drugs from the intestinal cell into the body. The exact potential outcomedepends on the specific drug: a drug's blood concentration may be decreased by inhibiting one orboth transporters, or increased by inhibiting Cyp3A4, or an intermediate effect may occur, resulting inlittle change.

Many studies have been done in vitro (or not in a living animal) with pure compounds, not withactual GF/J. These studies are of uncertain clinical relevance. More relevant results stem from clinica


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trials that dose GF/J in amounts consumed as part of a "normal" diet. There are relatively few ofthese studies, and most study pharmacokinetics, not pharmacodynamics (defined below). Relativelyfew epidemiology (or the study of the frequency and distribution of disease in human populations) andcase studies have been reported. Although much is known about what occurs chemically in the testtube, relatively little is known about the actual effects of GF/J on the actions of most drugs in humanpopulations. Currently, the existence of only a few epidemiology and case studies does not providesupport for a prevalent public health issue, and mayreflect the absence of a widespread public healthissue.

B. Nutrients

Rampersaud calculated the nutrient density (quantity of nutrients per calorie) of 100% fruit juices by 6 different methods, and concluded (by all methods) GF and orange juices outrankedpineapple, prune, grape and apple juice in nutrient composition, with apple juice being the leastnutrient dense (Rampersaud, 2007).GFJ is especially high in vitamin C and was higher than or equato other juices in vitamin A, thiamin (a B vitamin), and phosphorus. GFJ also is a good source ofpotassium. GFJ has comparatively fewer calories than other juices. Other studies had notedpreviously that GF was a good source of ascorbic acid, thiamin and other vitamins (Staroscik et al.,1980)

2) Clinical Evidence of GF/J interactions with prescription or OTC drugs

A. Introduction

To evaluate the possibility that GF/J commonly has effects (deleterious or beneficial) inhumans, one must have some insight into the scientific basis for conclusions, and the methods andprocedures to evaluate biological actions (efficacy and toxicity) of chemicals on human biology. Thebrief description that follows aims to explain the processes to evaluate the potential health impact ofchemicals in general.

B.In vitro studies

Investigation of chemicals' (drugs or toxicants) actions on biological processes often beginswith laboratory work in a test tube, i.e. in vitro(literally "in glass"). Effects of the chemical are testedon specific proteins or other components isolated from cells or produced by recombinant DNAtechnology (e.g. enzymes, receptors). In vitro also refers to work done with sub-cellular fractionsprepared from tissues or cells. A more complex approach test effects on intact cells growing in culturedishes. Data obtained from any of these approaches may inform what might happen in a livingorganism (model animal or human), but not what will occur. Reasons for uncertainty may include

experimental design that does not faithfully reflect the actual conditions of exposure to the chemical(e.g. using higher concentrations than ingested by humans, or giving the chemical in a form that is noused therapeutically), or the simplicity of these models. (The simplicity of these models has bothadvantages and disadvantages.)

C.In vivo studies with model animals or humans

A more sophisticated (and complicated) approach relies on animal models, such as rats, mice,or primates, i.e. in vivo models (literally "in life"). This allows a more realistic evaluation of a


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chemical's impact, because chemicals do not arrive at a specific site (cell, enzyme or genetic matter)inside a living organism without first undergoing absorption into the system and distributionthroughout the animal, all the while being subjected to chemical modification by the animal/subject(metabolism). In addition, animal/human stores (e.g. in fat or liver) and/or secretes (e.g., urine, sweatfeces, exhalation) ingested chemicals, in their intact forms or after modification. These dietaryingested chemicals include nutrients, toxicants, and tens of thousands of phytochemicals. The actuaoutcome of these processes depends on the route of administration (e.g. oral, intravenousintramuscular, subcutaneous, etc.), the amount administered/eaten, and the actual form or vehicle

used to dissolve/administer the chemical. The process of absorption, distribution, metabolism andexcretion is known as pharmacokinetics. The biological action of any chemical is referred to aspharmacodynamics. The pharmacodynamics of any chemical depends on its route of dosingpharmacokinetics, size of the dose, species dosed, and the precise genetics, weight, activity, diet andhealth of the individual dosed.

It is important to note that different species are not always good predictors of each other'spharmacokinetics and pharmacodynamics. This is true even for rats and mice: the mouse is not asmall rat! It can be especially problematic when trying to extrapolate from a rodent to the human.

For example, GFJ enhanced bioavailability of talinolol, (a beta-blocker that relieveshypertension and angina), in rats, but reduced its absorption in humans. This was explained by the

differential effects of naringin on the uptake transporter OATP1A2 in humans vs. the efflux transporterMDR1a in rats (Shirasaka et al., 2010). This illustrates the limited application of rodent studies tohumans with respect to GF/J. The rat does not seem to be a good model for studying thepharmacokinetic effects and thus the pharmacodynamic effects of GF/J on drug action in humans.

D.Laboratory (in vitro) studies of GF/J and their chemical constituents

A vast literature exists that describes the inhibition of the intestinal enzyme that catalyzes thedegradation of a wide spectrum of drugs (Cyp3A4). For a thorough review see Mertens-Talcott(Mertens-Talcott et al., 2006) and the University of Florida Drug Interaction Center web site(http://www.druginteractioncenter.org/). The first resource reports pharmacokinetic and

pharmacodynamic effects of GF/J consumption on many classes of drugs, and reveals relatively fewreports of serious pharmacodynamic effects with normal consumption (see Appendix). The secondresource provides a searchable index of drug-GF/J interactions. For the reasons mentioned abovethis synopsis will focus on known interactions in humans (see Appendix).

E.Human studies

The most reliable assessment of a chemical's actions on humans are data obtained fromstudies in humans. (This may seem obvious, but it is lacking in many studies of GF/J components).These data can be obtained in several ways. Case reports communicate observations of cliniciansas they encounter "events" while treating patients. They are not meant to be exhaustive or definitivestudies, but may simply report a single observation, as a warning. Clinical trials are studies plannedaccording to defined protocols to determine the impact of drugs (pharmacokinetics and/opharmacodynamics) and/or other interventions. The most significant involve large numbers ofpatients (thousands) over many years. Epidemiology reports retrospective data. In other wordsepidemiologists "mine" the literature and interpret the existing data in an attempt to deduce issues ofpublic health concern. A review of these type of human studies is included (below) for GF/J.


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Key issues to remember about evaluating the effects of chemical on human health include:

New drugs are not introduced into clinical practice until undergoing several phases of study(in vitro, animal models, and clinical trials).

Well-planned, long-term, large-scale, double-blind clinical trials are the "gold standard" ofchemical action in humans.

In other words, these types of studies are required as a part of evaluating the impact of anychemical on human health.

Clinical trials. The vast majority of clinical trials concerning GF/J include three inherent designaspects that limit ability to extrapolate the effects of GF/J consumption on the health of humans: 1)they were exceedingly small, some with less than 10 patients per group; 2) they relied on largeramounts of GFJ, unlikely to represent realistic consumption; 3) they analyzed pharmacokinetics, bunot pharmacodynamics. To be clear, not all studies used unrealistic large amounts of GFJ, but manydid.

In a recent trial, a total of 32 patients, divided into 3 different groups were each given 1 liter ofpink GFJ, i.e. ~34 ounces, or a 2 ounces over 1 quart (Piccirillo et al., 2008). And even with this largedose, the conclusion stated : "The potential proarrhythmic actions of pink grapefruit juicemight beoconcern in patients withmajormyocardial structural disorders (emphasis added)". In other words, the

study provided no evidence that a healthy human would suffer adverse effects. In fact, the authorsnoted "Because we studied a small sample, wecannot(emphasis added) definitively conclude thasubjects with a known structural cardiomyopathy should avoid drinking large amounts of pinkgrapefruit juice".

The studies that dosed amounts of GFJ more likely to be consumed, i.e. 250 to 300 ml (8.5 to10.1 ounces) focused on pharmacokinetics, not pharmacodynamics. As a result, they can determinethe degree that GF/J or the constituent tested (naringin, bergamottin) alters serum levels of variousdrugs (fexofenadine, nicotine), but not how this affects therapeutic effects. The studies were smal(number of patients per group) for clinical studies that are intended to apply to the general humanpopulation.

Pharmacodynamic studies of drug GF/J interactions in humans are limited. The review byMertens-Talcott et. al provides a recent compilation of drugs inhibited by GF/J with 9 tables(Appendix) providing details of many experiments and summarizing 204 references (Mertens-Talcottet al., 2006). This review provides detailed information about specific drugs that can be used as areference, when addressing an explicit question.

Notably, no pharmacodynamic changes and/or adverse effects were reported for a variety ofdrug classes when regular strength or fresh squeezed grapefruit juice was administered to humans,and in some, but not all cases, when double strength GFJ was dosed.

Drugs classes for which GF/J do not have pharmacodynamiceffects in humans, or have minimaeffects, or for which clinically relevant effects have not been confirmed include:

antiallergics;

antibiotics;

anticoagulants;

antitumor drugs;

female hormones;

HIV protease inhibitor;


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immunosuppressants;

over the counter drugs;

statins (despite pharmacokinetic effects for some).

Drug classes for which some members may have clinically relevant interactions with GF/J include:

antimalarials (Halofantrine, but not Qunidine or Quinine);

beta-blockers;

sedatives-hypnotics (pharmacokinetic changes for some; no interactions with others).

A drug classes for which pharmacodynamics upon GF/J should be considered:

antiarrhythmics.

Note: for drugs that interact, multiple substitutes may be available that seem not to be affectedpharmacodynamically by GF/J.

The conclusion of the article for statins, one of the most common classes of drugs used in the US

and one that has received a great deal of attention relative to GF/J illustrates the foregoing points:"Overall, the changes in pharmacokinetics (AUC or area under the curve) of statins by far exceededthe extent of pharmacodynamic changes". In other words, even when GF/J changes the amounts ofstatins absorbed, this does not imply a serious impact on the medical effects of statins.

The article by Mertens-Talcott et. alnotes that conscientiousness in prescribing drugs is always agood idea, but "...overcautious overreaction leading to complete avoidance of citrus products seemunreasonable, especially because these contain significant amounts of antioxidant phytochemicalswith significant health benefits. Further research is needed extending across more drugs fograpefruit, citrus fruits other than grapefruit, and other food products in general. Further clinicaresearch will have to be conducted to conclusively determine the...clinical relevance of these

interactions.A recent Wall Street Journal article actually supports the conclusions that widespread negative

interactions between GF/J and drugs have not been proven and are not limited to GF/J, but alsoillustrates the nature of the problem for GF growers. The article, written by Shirley S. Wang, wasentitled "When Food and Pills Clash: Fresh Concerns on How Diet and Medicines Interact, FromPepper to Pomegranate" and had an illustration with a bold title: "Bad Pairings", and a lesseremphasized subheading: "Potential problems could result from combining these foods and drugs"(emphasis added). Although a casual reading of this article, and especially the illustration, mightseem to support avoiding GF/J, as well as a host of healthy (fish with omega-3 fatty acids, leafygreens, a low fat diet) or popular foods (licorice, chocolate, meat), a critical reading suggests littlecause for alarm. First, the use of two qualifiers ("potential" and "could") should alert the sophisticated

reader that the title "Bad Pairings" may be not represent the actual situation. More importantly, thearticle did note that "In general, diet will only interact with medications when a person is consumingexceptionally large portions of certain foods..." Scientists consulted for the article emphasized ageneral danger in overindulgenceof many items, including manyfood products. Patrick Stover notedthat "For every drug there is, there are unintended side effects. You should expect the same thingwhen taking nutrients at drug levels". Another scientist quoted cautioned about using "high-potency

juices...and drinking lots of wine". The term "drug levels" is imprecise, as are "high-potency" and "lotsof", but this illustrates the point that overdoing any good thing can be harmful, and that accuratescience demands caution in warning against excluding usual dietary items in amounts routinely


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consumed. For example, vitamin A is essential for life, but is toxic if ingested in excessive amounts,i.e. using "lots of" vitamin A will kill you, but so will going without vitamin A.

Clinical TrialNephrolithiasis (kidney stones) Trinchieri et al. concluded from a small scaleclinical trial (7 patients) using diluted GFJ that "Citrus fruit juices could represent a natural alternativeto potassium citrate in the management of nephrolithiasis" (Trinchieri et al., 2002). Goldfarb andAsplin (Goldfarb and Asplin, 2001) concluded that 240 ml (~8 ounces) of GFJ 3 times daily did notincrease lithogenicity (formation of calculi) and concluded that "The results do not demonstrate aneffect of grapefruit juice for increasing lithogenicity (or formation of kidney stones)". This was a short-term (7 days), small-scale (10 subjects) clinical trial.

Clinical StudyGF/J inhibits OATP1A2--A 2007 study demonstrated that GFJ (300 ml)reduced the plasma concentration (AUC, area under the curve) of the anti-allergy drug fexofenadinein humans (n = 12) by 50%. The significance of this study is to show that GF/J via some of itsingredients (naringin and hesperidin) can reduce drug uptake by OATP1A2 (aka OATP-A) but not byP-glycoprotein (Bailey et al., 2007). The authors concluded that naringin might be a safe probe forOATP1A2 involvement in drug uptake.

Epidemiology: introductionThere are very few epidemiological (prospective) studiesconcerning the impact of GFJ consumption on human health.

Epidemiology: breast cancer riskMonroe et al. concluded that "Grapefruit intake wassignificantly associated with an increased risk of breast cancer (relative risk = 1.30, 95% confidenceinterval 1.061.58) for subjects in the highest category of intake, that is, one-quarter grapefruit ormore per day, compared to non-consumers (Ptrend= 0.015)"and that "Grapefruit intake may increasethe risk of breast cancer among postmenopausal women"(Monroe et al., 2007). More recently, Kimet al., noted that the Monroe study was "...unable to examine grapefruit intake", and therefore theydid. They examined data from >77,000 women (about 10-fold more than the Monroe study), andfound "...no overall association with either grapefruit or grapefruit juice intake and breast cancer riskamong all women in the cohort, and among postmenopausal women only", but found "...a significandecrease in risk of breast cancer with greater intake of grapefruit in women who never used hormonetherapy"in contrast to the Monroe study (Kim et al., 2008). These discrepancies show the importance

of larger vs. smaller studies and reliable dietary data in prospective studies.Epidemiology: kidney stone formationBased on "a semiquantitative food frequency

questionnaire"the same data used above for the breast cancer risk studyCurran et al. (Curhan eal., 1996) concluded that "...the risk of stone formation increased by 35% (4-75%) for apple juice and37% (1-85%) for grapefruit juice". In a follow up study, Curran et al. (Curhan et al., 1998) found a "..44% (CI, 9% to 92%) increase in [kidney stone] risk [in women].... for each 240-mL serving ograpefruit juice consumed daily". These data need to be considered in context of clinical experimentsthat address the same issue. For example, the small clinical trial about renal stones (Trinchieri et al.2002) found no increase in nephrolithiasis.

Overall, current epidemiology studies seem insufficient to support adverse or beneficial healtheffects of GF/J, as they lack meta-analyses, i.e. analyses of several studies from several data basesto support a conclusion based on a broad spectrum of data and methods.

Case report. This early report (1996) observed a blood-pressure lowering interaction in asingle patient (63-year-od male) (Pisarik, 1996). This patient had a number of medical problems, inaddition to high blood pressure, which was not responding well to medication. He began to drink 6ounces of GFJ in the AM with his felodipine and terazosin on the advice of friends. His BP returned tonormal. He then worked with his physician to develop a drug regimen that included GFJ and anti-hypertensive medication to maintain an acceptable blood pressure.


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Case report. A women treated with a vitamin K antagonist who also had a "massiveabsorption of grapefruit juice" suffered a "severe" hemorrhage (Desmard et al., 2009).

Case report. A patient with suspected May-Thurner syndrome, i.e. compression of the lefcommon iliac vein, or deep venous thrombosis of the leg, was admitted to the hospital with a swollenand discolored leg (Grande et al., 2009). Her medications included levothroxine, drospirenone, andethinylestradiol. Although May-Thurner syndrome is a chronic condition, the authors "hypothesized"that the acute episode was initiated by a 1.5 hr car ride and "...her new diet" which includedgrapefruit. Her "new diet" was not described, other than it contained grapefruit, nor was the amount ograpefruit consumed mentioned. No assays were done to verify blood or urine levels of the activecomponents of grapefruit. She recovered fully after treatment. The case report was published in TheLancet. According to their instructions to authors, Lancet's case reports "...are intended to inform,entertain, and inspire"...and are aimed to "...the generalist, the family doctor...or the well informedmedical student".

To the best of our knowledge, there are no other case reports concerning GF/J or the majoractive constituents of GF/J--naringin, naringenin, and bergamottin.

F.Summary of studies with humans

The clinical literature has been summarized recently with respect to GF/J and nine other "fruit

beverages (Farkas and Greenblatt, 2008). The salient points, also supported by the literature cited inthis report, include:

1) not only GFJ, but orange and apple juice inhibit the OATP drug transporter (important fordrug absorption);

2) GF, lime, seville orange and pomelo juice interact with the intestinal drug metabolizingenzyme Cyp3A4 (important for drug inactivation during absorption after oral administration);

3) these interactions affect the pharmacokinetics of orally administered drugs, either bylessening amounts absorbed (OATP inhibition) or by decreasing amounts inactivated duringintestinal absorption (Cyp3A4 inhibitor);

4) the pharmacodynamic significance of these interactions is uncertain.

The article concluded: "Based on current reports from clinical trials, it appears that most in vitrointeractions between juices and prescription drugs are not clinically significant, but there areexceptions...more studies need to be carried out before specific conclusions can be made"

In short, studies in vitroand animal studies have an uneven record of accurately predicting thepharmacokinetic or pharmacodynamic effects of drugs, including GF/J, in humans. Case reports oftenlack significant details and, at best, may reflect only an individual's reaction that does not pertain tothe general population. To understand the health related impact of any chemical, including GF/J, inthe absence of consistent epidemiological data with meta-analysis, clinical studies focusing onpharmacodynamics are essential. The lack of epidemiological data (multiple observations of a clinicaissue correlated with a presumed cause) and case reports (initial observations of a clinical issue)

suggest that either a widespread problem does not exist or has gone unnoticed. Given the volume ofscientific literature since the confirmation of an interaction between GFJ and two drugs (felodipineand nifedipine) in 1991 (Bailey et al., 1991), after the accidental discovery of a drug GFJ interaction,one might argue that a serious and widespread problem would have been noticed, and revealed inmultiple case reports and epidemiological studies with consistent conclusions.

The issue for GF/J consumption: does clinical evidence reveal that normal intake of GF/J hascaused severe health issues in humans, or even mild but widespread health issues? The medicaliterature based on case studies, epidemiology, pharmacodynamic studies, and robust clinical studies


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has not revealed common and serious problems. Why is this, in light of the abundant in vitroevidenceconcerning the effects of GF/J furanocoumarins and flavonoids on intestinal proteins?

1) In vitro studies of enzyme or transporter inhibition are insufficient to predictpharmacokinetics and pharmacodynamics in intact organisms.

2) Naringin has different effects in some animal models (rat), than it does in humans.

3) Multiple transporters occur in the human intestine and study of their characteristics isincomplete (Hagenbuch and Meier, 2004) (Konig et al., 2006) (Seithel et al., 2008)(Klaassen and Aleksunes, 2010).

4) Pharmacokinetics are not identical with pharmacodynamics. As stated above, thepharmacodynamics of any chemical depends on route of dosing, pharmacokinetics, doseamount, and the genetics (allelic variants are common for OATP, e.g.), weight, activity, dietenvironment, and health of the individual dosed.

5) Physicians typically start a medication regiment with the lowest dose of a drug, andevaluate the outcome in a follow-up visit. At that time, the dose may be adjusted, or thedrug may be exchanged for another (more effective and/or without side effects noticed bythe individual). Many subjects (if not most) likely were ingesting GF/J prior to takingmedication: thus, GF/J effects would have been factored into the outcome. Also, side-

effects caused by drugs, and the individual's genetics and physiology, may be more of anissue in drug use than the potential exacerbation of a drug's effects by GF/J.

3. Grapefruit and cancer:

Currently, not a single review addresses whether GF/J has anti-tumor effects. Various activeingredients in GF/J, however, have been linked to (primarily) cancer protective effects. Theseingredients include vitamin C, limonoids, and, of particular interest, flavonoids found primarily in GF/Jsuch as naringin and naringenin. Epidemiological studies suggest that vitamin C can reduce variouscancers, although this claim has been controversial (Verrax and Calderon, 2008). Citrus limonoidsinhibit carcinogen induced neoplasia in several model systems (Silalahi, 2002). Limonoid glycosidesoccur in significant amounts in orange (320 ppm), lemon (82 ppm), and GF (190 ppm) juicesBecause vitamin C and limonoids are not specific to GF, we focused on the anti-neoplastic propertiesof GF and flavonoids. Citrus fruit flavonoids possess various antiproliferative activities (Benavente-Garcia and Castillo, 2008). This discussion will be limited to those particularly high in GF/J, such asnaringin and naringenin.

A. Breast Cancer

Several prospective studies have addressed the effects of GF on cancer risk. Monroe et al.(Monroe et al., 2007) found that GF intake (GFJ intake was not analyzed) increased breast cancerrisk among postmenopausal women in a multi ethnic cohort study, potentially by activating estrogenreceptors, but analysis of the Nurses Health Study showed no effect of GF/J intake on breast cancer

risk or estrogen levels among all women or among postmenopausal women (Kim et al., 2008)Grapefruit intake also had no effect on the risk of pre- or postmenopausal women to develop breastcancer in the European Prospective Investigation into Cancer and Nutrition study and no associationwas fond between GF intake and estradiol or estrogen levels in postmenopausal women (Spencer etal., 2009). In summary, GF consumption appears to have neither beneficial nor detrimental effects onbreast cancer risk based on these prospective studies. Several reports, however, describe anti-proliferative effects of GF derived compounds in animal and tissue culture models of breast cancer. Infemale Sprague-Dawley rats, the GF flavonoid naringin reduced the incidence of chemically induced


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breast cancers (So et al., 1996). Relevant to breast cancer and other ERalpha positive cancers, therelated flavonoid naringenin, also found in GF, can reduce ERalpha signaling by triggeringdepalmitoylation and reduced ERK signaling in cell lines (Galluzzo et al., 2008). Besides the inductionof ERalpha and beta dependent breast cancer cell apoptosis (Totta et al., 2004), other mechanisms,such as inhibition of cellular glucose uptake (Harmon and Patel, 2004) may also contribute tonaringenins anti proliferative properties.

B. Colon Cancer

GFJ intake reduced chemical DNA damage in rats (Miyata et al., 2002) and both GF and linoninreduced chemically induced aberrant crypt foci and enhanced tumor cell apoptosis (Vanamala et al.,2006).

C. Oral Cancer:

A 2008 study (Miller et al., 2008) in hamsters showed that flavonoids from GF (2.5% naringinnaringenin had less of an effect), but not other flavonoids (hesperetin, neohesperidin, tangeretin, andnobiletin) reduced oral carcinogenesis induced by 7,12-dimethylbenz[a]anthracene. In addition, oracancers also were inhibited by limonoids in GF and other citrus fruit (Miller et al., 1992).

Overall, the cancer literature provides few conclusive findings for the pro- or anti-cancer effects ofGF and GF derived compounds. However, results from colon and oral cancer models are

encouraging and may warrant further investigation.

4) Grapefruit and Cardiovascular Health

According to the Centers for Disease Control and Prevention, heart disease is the leading causeof death in the United States (CDC, 2010). GF/J contains compounds that may lower the risk ofcardiovascular disease by improving blood lipid profiles. The positive heart health effects seem to bemainly attributable to the compound naringin and its antioxidant capabilities and abilities to improvefactors involved in atherosclerosis. The selected studies mentioned below are just a few examples ofthe health benefits of grapefruit in decreasing cardiovascular disease risk. These studies wereselected because they are more recent, from groups that have published several papers on thesubject matter, and are representative of the evidence in the literature.

In a study with 57 human patients with pre-existing heart problems, eating one fresh red grapefruita day for 30 consecutive days improved serum cholesterol levels and lowered triglyceride levels(Gorinstein et al., 2006). In addition, after completion of the study, the serum antioxidant activity inpatients eating grapefruits vs. the control group was increased by 5%-36% depending on the assayused. The authors concluded that red grapefruit has high antioxidant potential (Gorinstein et al.,2006).

A laboratory study evaluated naringin and naringenin effects on progression of atherosclerosis inrabbits fed a high cholesterol diet (Lee et al., 2001). Naringin- and naringenin-supplemented rabbitsshowed lower expression of atherogenic factors. These atherogenic factors promote monocyte

adhesion and macrophage infiltration in aortic endothelium, thus clogging arteries (Lee et al., 2001)Improvements in metrics of heart health also have been reported in cholesterol-fed rats (Lee et al.,1999) and atherogenic mouse models (Mulvihill et al.). Other studies suggested naringenin lowersplasma cholesterol levels by reducing the expression and/or secretion of proteins involved inpackaging of lipids in the liver for secretion into plasma (Allister et al., 2005).

Overall, GF and its dominant flavonoid naringin seem to have benefits for heart health inlaboratory and human studies. The question remains whether the levels of naringin used in laboratorystudies are attainable by reasonable consumption of GF/J. A possible area of future research


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includes using naringin as a therapeutic to treat hypertriglyceridemia (as seen in apoA-V KO mice).Another possible area of research would investigate whether long-term GF/J consumption affectsvarious apolipoprotein expression levels and/or the lipoprotein profile (e.g. size of LDL particles) ofindividuals and/or laboratory animals.

5) Grapefruit and obesity/diabetes/metabolic syndrome

Weight loss diets containing GF, a.k.a. the Hollywood diet, have been popular since the 1930s.Popular belief attributes fat burning and weight loss properties to an unknown compound in GF.Overall, GF based diets are low calorie diets (800-1000 cal/day) that trigger weight loss regardless ofthe inclusion of GF. There are few controlled studies of the GF diets effectiveness. Several studies inhumans and animals, however, have indicated that GF may have promote weight loss and insulin-sensitivity.

A. Clinical studies

Few controlled studies have examined directly the effect of GF on weight loss, insulin sensitivity orthe metabolic syndrome. One study in 1990 found that taking a grapefruit pill (we were unable todetermine composition of these pills) over a six week period did not reduce body weight of obesesubjects relative to placebo controls (Sanders et al., 1990). The sole study that we could find that

investigated the effect of GF/J on weight and insulin sensitivity was done in 2006 by a group at theScripps Clinic in La Jolla California (Fujioka et al., 2006). For this study, 91 obese patients wererandomized into four groups: GF capsule + 7 oz apple juice (n = 24, 22 completed); placebo capsule+ apple juice (n = 22, 18 completed); placebo capsule + 8 oz GFJ (n = 21, 18 completed); placebocapsule + half a fresh GF (n = 24, 19 completed). Treatments were taken three times a day beforemeals for 12 weeks. The group that ate half a fresh grapefruit three times daily with a placebocapsule lost 1.6 kg (3.6 pounds). The grapefruit juice group lost 1.5 kg (3.3 pounds). The grapefruitcapsule group lost 1.1 kg (2.4 pounds), and the placebo group lost 0.3 kg (0.5) pounds. Whereas allGF containing groups lost more weight than the control, only the fresh grapefruit group hadstatistically significant weight loss compared with the placebo group (P = 0.048). Secondary analysisof those patients that were overweight and displayed signs of metabolic syndrome (defined by the

American Heart Association as having at least three of the following: elevated waist circumference:equal to or greater than 40 inches; elevated triglycerides: >150 mg/dL; reduced HDL (good)cholesterol: 130/85 mm Hg; elevated fasting glucose: >100mg/dL; all data for men) showed significantly more weight loss in the GF capsule, GFJ, and fresh GFgroups compared to the placebo group. The GF effect seemed to be limited to weight loss, as none ofthe interventions improved diastolic blood pressure, waist circumference, BMI, percent fat by bodyimpedance, triglycerides, cholesterol, high density lipoprotein cholesterol, low-density lipoproteincholesterol, aspartate aminotransferase, alanine aminotransferase, fasting glucose, 2-hour glucoseor fasting insulin. Also, the mechanism(s) by which GF administration before a meal reduced weightremains unknown.

B. GF scenteffects

Studies by a Japanese group found a surprising effect of olfactory stimulation by the scent of GFoil (particularly limonene) on lipolysis in white adipose tissue, activation of thermogenesis, andreduced feeding behavior in rats potentially mediated through the activation of the sympatheticnervous system (Niijima and Nagai, 2003; Shen et al., 2005). It is unclear if such aromatherapy wouldhave similar effects in species other than rats.


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C. GF effect on glycemic control and diabetes

A study with normal and diabetic rats (made diabetic through dosing streptozotocin) showed thaintragastric administration of naringenin (50 mg/kg for 5 days) reduced plasma glucose in bothgroups. Treatment degreased serum TG levels in diabetic animals but increased TG, cholesterol, andHDL levels in the normal rats (Ortiz-Andrade et al., 2008). The same group performed a toxicologicalevaluation of naringenin and found that its Medium Lethal Dose (LD50) is >5000 mg/kg. A similarstudy (Punithavathi et al., 2008) explored the effects of combined naringin and vitamin C treatment(low dose: 15 mg/kg, 25 mg/kg; high dose 30 mg/kg, 50 mg/kg respectively) for 21 days onstreptozotocin-induced diabetic rats. The high dose regiment showed significant anti-hyperglycemicand antioxidant effects.

Overall, results from the GF weight loss study are encouraging, but the study was small, did notaim to elucidate a mechanism of action, and showed no improvement of obesity associated disorders(other than weight loss itself). Thus, further studies with larger patient cohorts and study designsaimed at understanding and optimizing the GF effect are needed. The animal studies focusing on theeffects of naringin and naringenin on glucose levels in diabetic rats are interesting. Thenaringin/vitamin C study is particularly interesting, as both naringin and vitamin C occur naturally inGF/J. It is unclear what effects are due to naringin vs. vitamin C alone, and what the underlyingmechanisms are. Further, it would be more relevant to study the effects of GF and its active

components on high-fat diet induced insulin resistance.

6) Grapefruit and the uptake and efflux of glucose and lipids

Several studies have used animal and cell-based assays to determine the ability of GF andnaringenin to alter uptake or release of glucose and/or fatty acids. We found only one study thatdirectly addressed the fat burning effect of GF products that is sometimes quoted.

A) Effect on glucose metabolism

Treating with 100 M naringenin (but not naringin) reduced glucose release from a hepatoma cellline through mechanisms similar to metformin (lowered ATP), raising the possibility that naringenin

may have antidiabetic effects by suppressing hepatic glucose production (Purushotham et al., 2009)No in vivodata were presented in this study, however.

Treating genetically obese db/dbmice for 5 weeks with naringin supplementation (0.2 g/kg diet)significantly lowered serum glucose and lipid levels. This effect was at least in part attributed to adecrease in hepatic enzymes involved in glucose production (glucose-6-phosphatasephosphoenolpyruvate carboxykinase) and an increase in glucokinase levels, as well as a decrease inthe glucose transporter Glut2 (Jung et al., 2006).

The sole study that used GFJ found that dosing 3 ml/kg GFJ lowered fasting serum glucose levelsof normal non-diabetic rats (2.9 mM vs. 3.7 mM) (Owira and Ojewole, 2009). But no experiments withobese or diabetic animals were done.

In contrast to the animal studies that showed a lowering of serum glucose in response to naringin,a study using 3T3L1 adipocytes and naringenin found that higher doses (50100 M) of naringenininhibited Glut4 mediated glucose uptake, potentially by inhibiting PI3K. A more physiologicallyattainable concentration of naringenin (6 M) showed only a modest (20% reduction) effect (Harmonand Patel, 2003). The same group also reported an inhibitory effect of naringenin on glucose uptakeby MCF-7 breast cancer cells (Harmon and Patel, 2004).

In summary, there is cumulative evidence that GFJ components may reduce hepatic glucoseoutput, but studies with animal models more relevant to human type-2 diabetes are lacking.


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Reduction of hepatic glucose output would be beneficial in principal, simultaneous suppression ofglucose uptake by adipocytes (and potentially other tissues) might negate any effects. Given thepivotal role of PI3K in human development and physiology, it is questionable that normal consumptionof GF products would inhibit this enzyme or there would be ample clinical literature backing this claimFurther, the studies showing glucose uptake inhibition used fat cells and cancer cells. Muscle,however, is the principle sink for postprandial glucose. There are no studies reported that showalterations in muscle glucose uptake following GF consumption.

B) Effects on lipid uptake and efflux

A small clinical trial (10 volunteers per study arm) in 2008 measured the lipolytic effects of apolyphenolic extract from oranges and grapefruit marketed as SINETROL (Dallas et al., 2008). Tenoverweight volunteers were treated 12 weeks with either 1.4 g/day SINETROL or placebo. At the endthe SINETROL group had a 16% reduction in body fat, with an average weight loss of 5.2 kg (>11lbs). This study is interesting, but suffers limitations, including the complex composition of SINETROLand failure to measure blood glucose and insulin. The proposed mechanism for loss of fat was aninhibition of cAMP-phosphodiesterasean enzyme that suppresses fat mobilization (lipolysis) bylowering cAMP levels. Interestingly, another cell based study also found that naringenin may inhibitphosphodiesterases, raising cAMP levels and lipolysis rates (Orallo et al., 2005).

Other cell-based studies looking at the effect of GF components on fat cell differentiation and lipid

release are somewhat contradictory. Using 3T3 L1 adipocytes, Harmon and Harp (Harmon and Harp,2001) found that naringenin (1-100 M) lowered the proliferation rate of preadipocytes by ~40%, buthad no effect on fat cell differentiation or lipolysis. These data contrast with findings by Haze et al.who used primary rat adipocytes to show that GF oil (100 g/ml) reduced TG accumulation andexpression of differentiation markers (Haze et al.).

Overall, we conclude that the effects of GF components on adipocyte differentiation, as well as thepro-lipolytic effects of GF, warrant further investigation, particularly in the context of anti-diabetic andweight loss strategies.

7) Miscellaneous other health effects of GF

A) GF and bone quality

Two studies have started to address the effects of GF pulp and GFJ on bone quality usingorchidectomized rats as model systems (Deyhim et al., 2008a; Deyhim et al., 2008b). These studiesshowed that orchidectomized rats drinking GFJ (ad libitum instead of water) had improved antioxidantstatus and bone health (including increased density and mineral content, delayed femoral fracturesand decreased bone turnover rates) compared to rats drinking calorie matched sugar water. Similaresults were obtained using 5% GF pulp. The mechanism of action remains unclear, as does whetherGF consumption would have positive effects on human bone health.

8) Proposed future studies

Based on this review of the literature there are several exciting opportunities for future studies ofpotential GF/J health benefits.

A) GF and weight loss

Given the encouraging finding by the Scripps Clinic that GF consumption may cause weight lossand the perseverance of GF based weight loss diets, reproducing and understanding themechanisms of GF induced weight loss appears to be the most promising avenue to pursue. The


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most convincing evidence for an anti-obesity or even anti-diabetes effect of GF would emerge fromlarge clinical studies. Thus, a primary goal should be to generate new scientific data to provide theimpetus to justify these expensive trials. Key questions that should be addressed in animal and celculture model systems are:

Does GF/J or purified components induce weight loss in obese animals? To this end, geneticand diet induced models of obesity could be fed varying doses of GF or components.

What are the active ingredients in GF/J that cause weight loss? Identifying the active

compounds will be important to normalize for variations in GF composition, and might enhancethe commercial value of certain strains, or provide an expanded market for GF extracts.

How would GF cause weight loss? Providing a molecular mechanism of action for a GF anti-obesity effect would be a key motivator for additional clinical trials.

Will GF mediated weight loss improve diabetes and other obesity-related disorders? Weightloss is only the means to an end to improve health and particularly glucose homeostasis.

Does GF specifically reduce fat (vs. muscle mass, water, etc)? Several papers have indicatedthat GF may enhance the mobilization of fat from adipose tissue by elevating cAMP levels.

B) Cardiovascular benefits of GF/J

Hypertriglyceridemia is an independent risk factor for the development of atherosclerosis. A GFconsumption study in humans with pre-existing heart problems suggested GF lowers plasmatriglyceride levels (Gorinstein et al., 2006). Preliminary studies would further investigate themechanism by which GF/J improves triglyceride levels by using a hypertriglyceridemic mouse mode(such as apoA-V knockout mice). Researchers could use the main GF flavonoid, naringin, as atherapeutic to treat hypertriglyceridemia. Another possible area of research would investigate whetheGF/J consumption affects various apolipoprotein expression levels and/or the lipoprotein profile (e.gsize of LDL particles) of individuals and/or laboratory animals to further understand how GF/J and itsmain components improve plasma lipid parameters associated with heart disease.

C) Nutrigenomic aspects of GF/J

Based on its multiple active ingredients GF consumption would likely alter expression of manygenes throughout the body. Understanding what genes in what organs altered would enhanceunderstanding of potential health effects of GF consumption.


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Appendix:

1. Online resources:

The UF College of Pharmacy Center for Drug Interaction Research and Education(http://www.druginteractioncenter.org/) offers a wealth of information both for professionals and laypersons including a searchable list of drugs and their known interactions with GF/J (see also attachedlist).

Wikipedia (http://en.wikipedia.org/wiki/List_of_drugs_affected_by_grapefruit) offers a list ofdrug interactions and some additional information. It is not always a reliable source of scientificinformation, but is frequently consulted by the public.

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transfer protein expression and apolipoprotein B100 secretion by the citrus flavonoid naringenin and by insulin

involves activation of the mitogen-activated protein kinase pathway in hepatocytes. Diabetes 54, 1676-1683.

Bailey, D.G., Dresser, G.K., Leake, B.F., and Kim, R.B. (2007). Naringin is a major and selective clinicalinhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice. Clin Pharmacol Ther

81, 495-502.

Bailey, D.G., Spence, J.D., Munoz, C., and Arnold, J.M. (1991). Interaction of citrus juices with felodipine and

nifedipine. Lancet 337, 268-269.

Benavente-Garcia, O., and Castillo, J. (2008). Update on uses and properties of citrus flavonoids: new findingsin anticancer, cardiovascular, and anti-inflammatory activity. J Agric Food Chem 56, 6185-6205.

CDC (2010). Prevalence of abnormal lipid levels among youths --- United States, 1999-2006. MMWR Morb

Mortal Wkly Rep 59, 29-33.

CG Fraga, e. (2010). Plant phenolics and human health: biochemistry, nutrition and pharmacology. Wiley

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in women. Ann Intern Med 128, 534-540.

Dallas, C., Gerbi, A., Tenca, G., Juchaux, F., and Bernard, F.X. (2008). Lipolytic effect of a polyphenolic citrusdry extract of red orange, grapefruit, orange (SINETROL) in human body fat adipocytes. Mechanism of action

by inhibition of cAMP-phosphodiesterase (PDE). Phytomedicine 15, 783-792.

Desmard, M., Hellmann, R., Plantefeve, G., and Mentec, H. (2009). [Severe overdose in vitamin K antagonist

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Deyhim, F., Mandadi, K., Patil, B.S., and Faraji, B. (2008b). Grapefruit pulp increases antioxidant status and

improves bone quality in orchidectomized rats. Nutrition 24, 1039-1044.

Farkas, D., and Greenblatt, D.J. (2008). Influence of fruit juices on drug disposition: discrepancies between in

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Goldfarb, D.S., and Asplin, J.R. (2001). Effect of grapefruit juice on urinary lithogenicity. J Urol 166, 263-267.

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Miyata, M., Takano, H., Takahashi, K., Sasaki, Y.F., and Yamazoe, Y. (2002). Suppression of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced DNA damage in rat colon after grapefruit juice intake. Cancer

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Mulvihill, E.E., Assini, J.M., Sutherland, B.G., Dimattia, A.S., Khami, M., Koppes, J.B., Sawyez, C.G.

Whitman, S.C., and Huff, M.W. Naringenin decreases progression of atherosclerosis by improving dyslipidemia

in high-fat-fed low-density lipoprotein receptor-null mice. Arterioscler Thromb Vasc Biol 30, 742-748.

Niijima, A., and Nagai, K. (2003). Effect of olfactory stimulation with flavor of grapefruit oil and lemon oil onthe activity of sympathetic branch in the white adipose tissue of the epididymis. Exp Biol Med (Maywood) 2281190-1192.

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Ortiz-Andrade, R.R., Sanchez-Salgado, J.C., Navarrete-Vazquez, G., Webster, S.P., Binnie, M., Garcia-

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implications on extra-pancreatic glucose regulation. Diabetes Obes Metab 10, 1097-1104.

Owira, P.M., and Ojewole, J.A. (2009). Grapefruit juice improves glycemic control but exacerbates metformin-

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3. Purview of Literature Review:

1. Adeneye, A.A. (2008a). Hypoglycemic and hypolipidemic effects of methanol seed extract of Citrusparadisi Macfad (Rutaceae) in alloxan-induced diabetic Wistar rats. Nig Q J Hosp Med 18, 211-215.

2. Adeneye, A.A. (2008b). Methanol seed extract of Citrus paradisi Macfad lowers blood glucose, lipids andcardiovascular disease risk indices in normal Wistar rats. Nig Q J Hosp Med 18, 16-20.

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4. Allister, E.M., Borradaile, N.M., Edwards, J.Y., and Huff, M.W. (2005). Inhibition of microsomaltriglyceride transfer protein expression and apolipoprotein B100 secretion by the citrus flavonoid naringenin

and by insulin involves activation of the mitogen-activated protein kinase pathway in hepatocytes. Diabetes

54, 1676-1683.

5. Allister, E.M., Mulvihill, E.E., Barrett, P.H., Edwards, J.Y., Carter, L.P., and Huff, M.W. (2008). Inhibitionof apoB secretion from HepG2 cells by insulin is amplified by naringenin, independent of the insulin

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8. Bailey, D.G., Arnold, J.M., Munoz, C., and Spence, J.D. (1993a). Grapefruit juice--felodipine interaction:mechanism, predictability, and effect of naringin. Clin Pharmacol Ther 53, 637-642.

9. Bailey, D.G., Arnold, J.M., Strong, H.A., Munoz, C., and Spence, J.D. (1993b). Effect of grapefruit juiceand naringin on nisoldipine pharmacokinetics. Clin Pharmacol Ther 54, 589-594.

10.Bailey, D.G., Bend, J.R., Arnold, J.M., Tran, L.T., and Spence, J.D. (1996). Erythromycin-felodipineinteraction: magnitude, mechanism, and comparison with grapefruit juice. Clin Pharmacol Ther 60, 25-33.

11.Bailey, D.G., and Dresser, G.K. (2004). Interactions between grapefruit juice and cardiovascular drugs. AmJ Cardiovasc Drugs 4, 281-297.

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13.Bailey, D.G., Dresser, G.K., Kreeft, J.H., Munoz, C., Freeman, D.J., and Bend, J.R. (2000). Grapefruit-felodipine interaction: effect of unprocessed fruit and probable active ingredients. Clin Pharmacol Ther 68,

468-477.

14.Bailey, D.G., Dresser, G.K., Leake, B.F., and Kim, R.B. (2007). Naringin is a major and selective clinicalinhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice. Clin PharmacolTher 81, 495-502.

15.Bailey, D.G., Kreeft, J.H., Munoz, C., Freeman, D.J., and Bend, J.R. (1998a). Grapefruit juice-felodipineinteraction: effect of naringin and 6',7'-dihydroxybergamottin in humans. Clin Pharmacol Ther 64, 248-256.

16.Bailey, D.G., Malcolm, J., Arnold, O., and Spence, J.D. (1998b). Grapefruit juice-drug interactions. Br JClin Pharmacol 46, 101-110.

17.Bailey, D.G., Spence, J.D., Munoz, C., and Arnold, J.M. (1991). Interaction of citrus juices with felodipineand nifedipine. Lancet 337, 268-269.

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