Grapefruit Info thread - AnabolicMinds.com

Grapefruit Info thread

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    Grapefruit Info thread


    What is a grapefruit?

    The grapefruit is a sub-tropical citrus tree grown for its fruit which was originally named the "forbidden fruit" of Barbados. (wiki)


    Grapefruit w/drug interactions

    Grapefruit can have a number of interactions with drugs, often increasing the effective potency of compounds. Grapefruit contains naringin, bergamottin and dihydroxybergamottin, which inhibit the cytochrome P450 isoform CYP3A4 in the intestine. It is via inhibition of this enzyme that grapefruit increases the effects of buspirone (Buspar), carbamazepine, several statin drugs (such as simvastatin), terfenadine, felodipine, nifedipine, verapamil, estradiol, tacrolimus, dextromethorphan (significant only at recreational doses), benzodiazepines, and ciclosporin.[10][11][12][13][14] The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989. However, the effect became well-publicized after being responsible for a number of deaths due to overdosing on medication. (wiki)


    Grapefruit on Nutrition

    Grapefruit is an excellent source of many nutrients and phytochemicals, for a healthy diet. Grapefruit is a good source of vitamin C,[8][16] pectin fiber,[17] and the pink and red hues contain the beneficial antioxidant lycopene.[8][18] Studies have shown grapefruit helps lower cholesterol[8][19] and there is evidence that the seeds have low levels of antioxidant properties.[20] Grapefruit forms a core part of the "grapefruit diet", the theory being that the fruit's low glycemic index is able to help the body's metabolism burn fat.[21]

    Grapefruit seed extract has been claimed to be a strong antimicrobial with proven activity against bacteria and fungi. However, studies have shown the efficacy of grapefruit seed extract as an antimicrobial is not demonstrated. Although GSE is promoted as a highly effective plant-based preservative by some natural personal care manufacturers, studies indicate the universal antimicrobial activity associated with GSE preparations is merely due to contamination with synthetic preservatives.[22][23][24][25][26]

    A 2007 study found a correlation between eating a quarter of grapefruit daily and a 30% increase in risk for breast cancer in post-menopausal women. The study points to the inhibition of CYP3A4 enzyme by grapefruit, which metabolizes estrogen. (wiki)


    Things in Grapefruit that i will focus on


    Narinigin

    Naringin is the major flavonoid glycoside in grapefruit and gives grapefruit juice its bitter taste. It is metabolized to the flavanone naringenin in humans. Both naringenin and hesperetin, which are the aglycones of naringin and hesperidin, occur naturally in citrus fruits.

    Narinigin exerts a variety of pharmacological effects such as antioxidant activity, blood lipid-lowering, anticarcinogenic activity, and inhibition of selected cytochrome P450 enzymes including CYP3A4 and CYP1A2, which may result in several drug interactions in-vitro. (wiki)

    Naringin is a citrus flavanoid commonly found in grapefruit, and is responsible for grapefruit's distinctive bitter taste. Most of us have heard how it's important to be careful consuming grapefruit juice along with certain medications -- studies reveal that naringininterferes with some digestive enzymes which can affect the metabolismand breakdown of these drugs. This can in effect lead to an inadvertantlyhigher dose of the drug, which may pose the threat of adverse reactions in some cases.

    However, naringin displays many other interesting properties, some of which make it suitable for inclusion into the ingredients list of many popular fat burners. (Akira finding)

    For one, there is some evidence that the effects and levels of caffeine can be extended when consumed with naringin. Since virtually 99% of thefat burners on the market contain caffeine (often derived from natural sourceslike Kola nut, Yerba mate, Green tea, and so on), and since caffeine doesexhibit thermogenic (fat burning) properties, naringin is an obvious "no brainer" way to improve and extend its effects. (Akira finding)

    Naringin has also been shown to exhibit cholesterol-lowering effects, which is always a good thing for dieters. It's also an aldose reductase inhibitor,which means it may also have a role to play battling retinal disease indiabetics. While naringin may not be the most "sexy" ingredient in your favorite fat burner,it is a worthwhile one. (Akira finding)

    bergamottin

    Bergamottin is a natural furanocoumarin found principally in grapefruit juice. It is also found in the oil of bergamot, from which it was first isolated and from which its name is derived. To a lesser extent, bergamottin is also present in the essential oils of other citrus fruits. Along with the chemically related compound 6’,7’-dihydroxybergamottin, it is believed to be responsible for the grapefruit juice effect in which the consumption of the juice affects the metabolism of a variety of pharmaceutical drugs. (wiki)

    Chemically, bergamottin and dihydroxybergamottin are linear furanocoumarins functionalized with side chains derived from geraniol. They are inhibitors of some isoforms of the cytochrome P450 enzyme, particularly CYP3A4. [2] This prevents oxidative metabolism of certain drugs by the enzyme, resulting in an elevated concentration of drug in the bloodstream. (wiki)

    Normally, the grapefruit juice effect is considered to be a negative interaction, and patients are often warned not to consume grapefruit or its juice when taking medication. However, some current research is focused on the potential benefits of cytochrome P450 inhibition.[3] Bergamottin, dihydroxybergamottin, or synthetic analogs may be developed as drugs that are targeted to increase the oral bioavailability of other drugs. Drugs that may have limited use because they are metabolized by CYP3A4 may become viable medications when taken with a CYP3A4 inhibitor because the dose required to achieve a necessary concentration in the blood would be lowered. (wiki)



    WHAT THIS ALL MEANS

    Naringin appears to interfere with the activity of several enzymes that are responsible for the breakdown of certain nutrients in the intestines, along with many types of drugs, resulting in higher levels of those substances in the blood. As such, naringin is used to enhance the effectiveness and increase the half-life of several supplements and related substances, such as caffeine.

    Most studies have shown that a dose of 25 milligrams of naringin is enough to increase the bioavailability and half-life of certain nutrients and/or drugs consumed with it.

    The main source of naringin is pure grapefruit juice. However, many types of grapefruit juice are either blended with other juices, or use grapefruits that have low naringin levels, to help remove bitterness and improve taste. Naringin supplements are also available, and are sold in pill, liquid and capsule form.

    What can happen if I take too much naringin? Are there any interactions I should be aware of? What precautions should I take?

    Because naringin can alter the metabolism of certain drugs so that they remain in the bloodstream longer, taking naringin supplements can result in higher-than-expected levels of those drugs in the blood, which may cause a variety of unwanted side-effects. As a result, patients should not take any drugs with naringin or grapefruit juice without first consulting a licensed health care provider. In addition, the effects of taking naringin and/or drinking grapefruit juice are cumulative; the more naringin that is ingested, the greater its interaction with certain drugs and other nutrients.

    Among the drugs known to be affected by naringin are calcium channel blockers; estrogen supplements; sedatives; high blood pressure medications; and cholesterol-lowering medications. As always, make sure to consult with a licensed health care provider before taking naringin or any other herbal remedy or dietary supplement.

    "Don't get too carried away with this. It can lead to dangerous, toxic levels of some drugs or possibly supplements (one example I think someone mentioned might be red yeast rice). I suggest you look into which ones have a bad interaction with grapefruit on your own if you are indeed taking any medication (bitterplacebo)."

    Jonny21 says it great "Grapefruit juice inhibits certain enzymes that metabolize chemicals therefore allowing more chemical to enter blood.

    Example:
    Prescribed dose of Lipitor is 10mg. Lipitor begins to get metabolized by cyp p450 3a isoenzyme in intestinal wall. Lets say for arguments sake that only 5mg makes it into bloodstream. Now, you drink some grapefruit juice which inhibits cyp p450 3a isoenzyme, and then take 10mg lipitor. Again for arguments sake, lets say the entire 10g makes it into the bloodstream. This can pose problems since it will allow for higher blood levels than expected, especially for blood pressure meds.

    The same enzyme metabolizes Testosterone so theoretically taking grapefruit juice prior to oral testosterone would increase chances of Test making into the bloodstream. That is if it makes it past the stomach."

    The potential for this type of drug interaction is enormous. Dr. David Bailey, stated in the September 3rd, 1998 issue of the Medical Tribune:

    "Sixty percent of drugs that are (commonly) prescribed are metabolized to some extent by this enzyme, CYP3A4 (Cytochrome P450 3A4). Many drugs undergo first-pass metabolism by CYP3A4. Hence, the inhibition of this enzyme in the gut causes plasma concentrations of these drugs to increase markedly after oral administration. The result can be significant. For example, taking one tablet of lovastatin (Mevacor) with a glass of grapefruit juice is the same as taking 12 to 15 tablets with a glass of water. Certain antihistamines, benzodiazepines, cyclosporin, caffeine, calcium antagonists and cisapride are among other drugs with which grapefruit interacts. So this interaction is very important and the list (of drugs) is going to continue to grow".

    I've read that the effects can be seen up to 72 hours after an 8oz glass of grapefruit juice. But that's a general statement for which I couldn't find any specific data on what thresh hold for the inhibition was used to say that the effects wouldn't be seen anymore.

    up to 72hours from one serving. translation. only need one serving per 2 days or every other day for something which can possibly provide such huge benefits.

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    bitterplacebo also posted not sure where from i think google finds

    I don't think you'll find a lengthy, definitive list of dietary supplements that interact dangerously with grapefruit. You can find some excellent lists of medications that interact, though, by simply asking google.

    The general rule to grapefruit is that it will interact with substances that have a low bioavailability and are metabolized by the CYP 3A4 enzyme, so you might be able to research a particular supplement to see if there is any harmful possibilities going from those two aspects.

    Otherwise, off the top of my head, I can only think of a few supplements that can be harmful with grapefruit.
    ___
    Red Yeast Rice - or anything containing statins which are meant to lower cholesterol and reduce risk of cardiovascular disease. The interaction with RYR increases the risk of myopathy.
    ___
    Designer Steroids - if you think of them as "supplements" they may interact badly with grapefruit in the case that they happen to be methylated, with significant androgenic activity. An increase in bioavailability/half-life from grapefruit here would put more stress/damage on the liver and possibly other organs.
    ___
    Caffeine - there might be some unpleasant CNS overstimulation if you all of a sudden start taking significant doses of caffeine in a short period of time. This would be like 300-400mg or more taken at once, depending on personal tolerances. So, really one can take smaller doses of caffeine when using grapefruit juice to get the desired effects. The lethal dose of caffeine is quite high, so I don't think we need to worry about it here. With grapefruit the LD.50 might be 50 cups of coffee instead of 100 for the average adult male.
    ___

    Considering the site where I'm posting, I guess I should post some non-supplemental things that could interact to give people some idea.

    ___
    SERMs may interact. Nolvadex is listed as possibly interacting, but the significance is unknown right now. I don't believe it's significant because Nolvadex has a high bioavailability to begin with, but other might want to think more about their choice to use grapefruit with a SERM.
    ___
    Cabergoline - it's a dopamine agonist, but might be used by some to try to control prolactin induced gynecomastia. Grapefruit can cause increased blood levels of cabergoline, and trust me, you don't want to mess around with overstimulating your dopamine receptors if you like mental stability.
    ___
    The Benzos - the breakdown of these will be slowed by grapefruit, and could potentially build to toxic levels.
    ___

    There's probably many other choices that are unhealthy, but few that are truly harmful, dangerous or fatal. I'm sure it would be easier to find information if it were the case that people were dying or being hospitalized for using grapefruit with dietary supplements.





    AND AGAIN BOTTOM LINE IS...


    Grapefruit juice and or its important abilities can be very beneficial and or possible harmfull when taken with many possible drugs. So ask your doctor or ask the boards but this is something to consider !!!!
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    stolen from an ubi post

    bergamottin, a major furanocoumarin in grapefruit juice, can be used to increase bioavailabilty of some compounds.

    Grapefruit seed extract has high anti-oxidant properties.

    I took this from pureliquidgold site.

    Grapefruit seed extract is being used successfully in humans and animals alike to fight many types of internal and external infections caused from parasites (single and multi-celled), viruses, bacteria, fungus and more!

    The greatest benefit is due to it's multipurpose (broad spectrum) effect. It is effective even if the causes of the infections are known, unknown or misdiagnosed. Grapefruit seed extract naturally detoxifies, enhances and supports the immune system.

    Grapefruit seed extract contains high levels of vitamin C and E, and bioflavonoids. The important substances have an antioxidant action and can neutralize free radicals that damage cells and cause a number of illnesses.

    Another important benefit of grapefruit seed extract is that it is helpful in alkalizing the blood. Alkalizing the body fluids (raising pH) is one of the single most important health regeneration benefits available as disease causing microforms (fungi, bacteria, virus etc.) cannot survive in an alkaline oxygenated environment. Though lemons, limes, and grapefruits are chemically acid, tests show that when they are metabolized in the body they actually have an alkalizing effect. They have very little sugar and they contain an abundance of oxygen. This is a plus for anyone fighting candida or any other disease. Conclusion: Eat more fresh vegetables and less processed foods as most all vegetables are alkaline forming in the body.

    Grapefruit seed extract is effective at very low concentrations. During 1989-90, an international research team (reported in the Journal of Orthomolecular Medicine, Volume 5, No. 3, USA, 1990) examined the effects of GSE and compared this with 30 effective antibiotics and 18 proven fungicides. GSE was found to perform as well as any and all of the tested agents. Without the harsh side effects. It is a natural alternative to strong antibiotics.

    Grapefruit seed extract is nontoxic. According to an independent laboratory testing "Acute Oral Toxicity", it would take at least 4,000 times the normal dose of gse to produce a 50% chance of poisoning (called LD50).

    Because grapefruit seed extract does not exhibit the harsh side effects and high cost of pharmaceuticals it is becoming the alternative health choice for naturopathic physicians, clinics and the general public.

    Internal uses include but not limited to : Digestive Upsets: Gastrointestinal Disorders, Diarrhea and Food Poisoning. Infections from: Parasites (single and multi-celled), Bacterial, Viral and Fungal. Candida Yeast Infections, Thrush and Chronic Fatigue. Oral Infections: Tooth Plaque, Gum Disorders, Breath Freshener and Mouthwash. Colds and Flu, Sore Throats, Strep Throat, Ear Inflammation / Pain, Gassiness, Sinusitis and much more!

    External uses include but not limited to: Acne, Athletes Foot, Nail Fungus Infections. Skin Infections: Fungal / Bacterial / Parasitic / Viral / Ringworm, Cuts / Wounds. Warts, Poison Ivy/Poison Oak, Rashes, Jock Itch, Shaving Itch, Dandruff, Cold Sores / Herpes, Head Lice, Chickenpox, Cracked Lips, Toothbrush Cleaning and much more!

    Physicians have observed that the herpes simplex virus becomes inactive just ten minutes after the application of grapefruit seed extract.

    So I don't see the seed extract to have the same effects as bergamottin.. but I also have another little tidbit of info for you, about this beneficial extract..

    It increases the shelf life of injectable oils... tremendously. It has amazing preservative qualities. 2% of the total volume, and you're golden.
    •   
       

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    Quote Originally Posted by nycste View Post
    bitterplacebo also posted not sure where from i think google finds
    Yes, the contraindications or other information can be found through simple searching. The only speculation I made was with the designer steroids. For them to cause issues, they have to be metabolized by the enzymes that grapefruit inhibits, and there's not a lot of clear information on this. In addition, a particular designer steroid with a low oral bioavailability would see the most issues with grapefruit interaction. This is also not clear, because most are not designed with methods to increase oral bioavailability. I believe this is what methylation does, allowing the drug to bypass the first enzyme systems that we mentioned and make it to the liver, but someone correct me if I'm wrong.
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    Clin Pharmacol Ther. 2005 Oct;78(4):441-3.
    Effects of grapefruit juice on the pharmacokinetics of sildenafil.Jetter A, Kinzig-Schippers M, Walchner-Bonjean M, Hering U, Bulitta J, Schreiner P, Sorgel F, Fuhr U.
    Institute for Pharmacology, Clinical Pharmacology, University of Koln, Germany. alexander.jetter@medizin.uni-koeln.de

    BACKGROUND AND OBJECTIVES: Because of extensive first-pass metabolism, oral bioavailability of sildenafil reaches only 40%. Formation of the primary metabolite, N -desmethylsildenafil, is mainly mediated by the cytochrome P450 enzyme CYP3A4. In this study we investigated the influence of grapefruit juice, containing inhibitors of intestinal CYP3A4, on the pharmacokinetics of sildenafil and N -desmethylsildenafil. METHODS: In a randomized crossover study, 24 healthy white male volunteers received single 50-mg doses of sildenafil. Two doses each of 250 ml grapefruit juice or water, respectively, were administered 1 hour before and together with the drug. Plasma concentrations of sildenafil and N -desmethylsildenafil were determined up to 24 hours post dose by use of liquid chromatography-tandem mass spectrometry (limit of quantification, 1 ng/ml). RESULTS: Grapefruit juice changed the area under the sildenafil plasma concentration-time curve from time zero to infinity [AUC(0-infinity) from 620 [1.53] ng/ml x h to 761 [1.58] ng/ml x h (geometric mean with geometric standard deviation), corresponding to a 23% increase (90% confidence interval, 13%-33%). N-Desmethyl sildenafil AUC(0-infinity) increased by 24% (90% confidence interval, 17%-32%). Maximum plasma concentrations (C(max)) of sildenafil and N -desmethylsildenafil were essentially unchanged. There was a trend toward a prolonged time to reach C(max) during the grapefruit juice period (from a median of 0.75 hour to a median of 1.13 hours), corresponding to an increase by 0.25 hour (90% confidence interval, 0-0.63 hour). Interindividual variability was pronounced in both periods. CONCLUSIONS: Grapefruit juice increases sildenafil bioavailability and tends to delay sildenafil absorption. Sildenafil pharmacokinetics may become less predictable with grapefruit juice. Although patients usually will not be endangered by concomitant use of grapefruit juice, it seems advisable to avoid this combination.


    Table 1. CYP3A4 Substrates and Interactions With Grapefruit Juice*
    Drug Interaction

    Calcium channel blockers
      Amlodipine X
      Felodipine X
      Nifedipine X
      Nimodipine X
      Nisoldipine X
      Nitrendipine X
      Pranidipine X
      Diltiazem X
      Verapamil X
    Antiarrhythmics
      Quinidine X
    Immunosuppressants
      Cyclosporine X
      Tacrolimus
    HMG-CoA reductase inhibitors
      Atorvastatin X
      Cerivastatin
      Fluvastatin X
      Lovastatin X
      Pravastatin X
      Simvastatin X
    Macrolides
      Clarithromycin X
    HIV protease inhibitors
      Indinavir X
      Nelfinavir X
      Ritonavir X
      Saquinavir X
    Antihistamines
      Ebastine X
      Terfenadine X
    Benzodiazepines
      Alprazolam X
      Clonazepam X
      Diazepam X
      Flurazepam X
      Midazolam X
      Triazolam X
    Other psychiatric medications
      Buspirone X
      Carbamazepine X
      Clomipramine X
      Haloperidol X
      Sertraline X
      Trazodone X
      Zaleplon X
      Zolpidem X
    Corticosteroids
      Ethinyl estradiol X
      Progesterone X
      Prednisone X
    Antiparasitic agents
      Dapsone X
      Quinine X
      Artemether X
    Prokinetics
      Cisapride X
    Others
      Carvedilol X
      Cilostazol X
      Losartan X
      Methadone X
      Montelukast X
      Ondansetron X
      Sildenafil X
    *“Yes” and “No” indicate published evidence of the presence or absence of an interaction with grapefruit juice. “?Yes” and “?No” indicate expected findings based on available data. CYP3A4=cytochrome P-450 3A4; HIV=human immunodeficiency virus; HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A.
    Dirk Tanis, BA, MSci
    Chief Operating Officer, Applied Nutriceuticals
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    Review
    Drug–Grapefruit Juice Interactions
    GARVAN C. KANE, MD; JAMES J. LIPSKY, MD

    From the Department of Internal Medicine (G.K.), Department of Molecular Pharmacology and Experimental Therapeutics, Clinical Pharmacology Unit (J.J.L.), and Division of General Internal Medicine (J.J.L.), Mayo Clinic, Rochester, Minn.

    Address reprint requests and correspondence to James J. Lipsky, MD, Department of Molecular Pharmacology and Experimental Therapeutics, Clinical Pharmacology Unit, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

    Abstract

    Grapefruit juice, a beverage consumed in large quantities by the general population, is an inhibitor of the intestinal cytochrome P-450 3A4 system, which is responsible for the first-pass metabolism of many medications. Through the inhibition of this enzyme system, grapefruit juice interacts with a variety of medications, leading to elevation of their serum concentrations. Most notable are its effects on cyclosporine, some 1,4-dihydropyridine calcium antagonists, and some 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. In the case of some drugs, these increased drug concentrations have been associated with an increased frequency of dose-dependent adverse effects. The P-glycoprotein pump, located in the brush border of the intestinal wall, also transports many cytochrome P-450 3A4 substrates, and this transporter also may be affected by grapefruit juice. This review discusses the proposed mechanisms of action and the medications involved in drug–grapefruit juice interactions and addresses the clinical implications of these interactions.

    Mayo Clin Proc. 2000;75:933-942

    AUC=area under the plasma concentration–time curve; CYP=cytochrome P-450; HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A; Pgp=P-glycoprotein

    Purchased by 21% of all households in the United States,1 grapefruit juice carries the American Heart Association’s healthy “heart-check” food mark and contains compounds that may both reduce atherosclerotic plaque formation2 and inhibit cancer cell proliferation.3,4 However, unlike other citrus fruit juice, grapefruit juice interacts with a variety of prescription medications, raising the potential for concern. This is particularly worrying in that juice and medications are commonly consumed together at breakfast. This drug-food interaction seems to occur through inhibition by grapefruit juice of one of the intestinal cytochrome P-450 (CYP) enzyme systems, cytochrome P-450 3A4 (CYP3A4). This enzyme system in the liver is well known for its involvement with drug-drug interactions. Most notably, terfenadine, mibefradil, and cisapride have been withdrawn from the US market in recent years, in part because of deaths due to drug-drug interactions involving the hepatic CYP3A4 system. This review discusses the mechanisms proposed for, the medications involved in, and the clinical implications of known drug–grapefruit juice interactions.

    CHANCE DISCOVERY

    Almost 10 years have passed since investigators, by chance, observed an interaction between felodipine and grapefruit juice in a study of felodipine and ethanol that used grapefruit juice to mask the taste of ethanol.5 Subsequent studies confirmed that grapefruit juice significantly increased the oral bioavailability of felodipine.6,7 Thus, a decade of grapefruit juice research was launched. Investigation has focused on the specific components of grapefruit juice, the medications with which it interacts, and, perhaps most fascinating, the mechanism of action.

    MECHANISM OF ACTION

    Cytochrome P-450 is a large multigene family of heme-containing proteins found in the endoplasmic reticulum of cells throughout the body. The largest concentrations of these enzymes are located in the liver and the intestinal wall, where they play a role in the oxidative biotransformation of numerous endogenous substances and xenobiotics. Several isoforms have been distinguished on the basis of their structure, substrate specificity, or responses to various types of inducers. The CYP3A subfamily represents the predominant and most abundant enzyme group. In the liver, CYP3A comprises on average 30% of all CYP content and as much as 70% in small intestine epithelial cells (enterocytes).8 Located in the apical brush border of the enterocytes is the P-glycoprotein (Pgp) membrane transporter, a member of the ABC (adenosine triphosphate–binding cassette) superfamily of proteins. The role of the Pgp transporter is to carry lipophilic molecules from the enterocyte back into the intestinal lumen. After uptake by the enterocyte, many lipophilic drugs are either metabolized by CYP3A4 or pumped back into the lumen by the Pgp transporter. Therefore, CYP3A4 and Pgp may act in tandem as a barrier to oral delivery of many drugs.

    Medications such as itraconazole, ketoconazole, cyclosporine, diltiazem, and erythromycin inhibit both intestinal CYP3A4 and hepatic CYP3A4. Thus, the reduced presystemic drug metabolism increases the quantity of drug absorbed (oral bioavailability).9-12 Grapefruit juice has now also been recognized as an inhibitor of this intestinal enzyme system.13

    Several points indicate that grapefruit juice acts on the CYP system at the intestinal level, not at the hepatic level. First, the medications that interact with grapefruit juice undergo metabolism by the CYP3A4 enzyme system in the small bowel. Second, grapefruit juice increases the area under the plasma concentration–time curve (AUC), probably the best measure of the body’s exposure to a drug, with minimal if any change in clearance or half-life. Third, in standard doses, grapefruit juice has no effect on the pharmacokinetics of these medications when they are given intravenously.13-16

    Grapefruit Juice Action on Intestinal CYP Enzymes

    The effects of some CYP3A4 inhibitors wane with repeated administration, as they cause induction of CYP3A4 through up-regulation of CYP3A messenger RNA and protein over time.17 However, this is not the case with grapefruit juice. Recurrent ingestion of grapefruit juice leads to a selective decrease of both CYP3A4 and CYP3A5 protein expression in enterocytes, resulting in increased drug bioavailability.18 Messenger RNA expression is not reduced, which suggests that this decrease in activity is not transcriptionally mediated. The mechanism of the decrease in CYP3A4 protein most likely reflects either accelerated protein degradation or reduced messenger RNA translation. It would be reasonable to suppose that 1 or more components of grapefruit juice cause a rapid intracellular degradation of the intestinal CYP3A4 enzyme through irreversible “suicide” inhibition. This would explain the rapid and sustained onset of inhibition by grapefruit juice. A 47% reduction in intestinal CYP3A4 concentration occurs within 4 hours of the ingestion of grapefruit juice, and grapefruit juice maintains a bioavailability-enhancing effect for up to 24 hours.19,20

    Grapefruit juice also inhibits the CYP1A2 enzyme system in vitro but not in vivo.21-25 This is consistent with the understanding that the effect of grapefruit juice occurs at the level of the intestinal wall where levels of CYP2A expression are low. These CYP2A substrates studied with grapefruit juice have included caffeine,21,22 theophylline,23 and coumarin.24,25

    The Interpatient Variability of the Grapefruit Juice Effect

    Wide variations exist among individuals in the expression of the CYP3A4 enzyme in the liver and intestine (8-fold intestinal variation).26 Higher concentrations of CYP3A4 in the intestine correlated with greater first-pass metabolism and lower drug levels, eg, felodipine.18 Ingestion of grapefruit juice has been shown to reduce enteric CYP3A4 levels to virtually the same degree in all subjects studied.18 Thus, patients with the highest intestinal CYP3A4 concentrations display the greatest effects from grapefruit juice. This concept has been demonstrated clinically with felodipine.18

    Grapefruit Juice Action on Pgp

    Given the overlap in substrate specificity between Pgp and CYP3A4, grapefruit juice might be expected to interact with this protein transporter also. In vitro data show that grapefruit juice activates Pgp in intestinal cell monolayers27; however, further studies are required. If grapefruit juice had this activating effect on Pgp in vivo, reducing drug bioavailability might partially counteract the increased bioavailability seen with inhibition of CYP3A. This notion is supported by the recognition that some drugs exhibiting a smaller grapefruit juice effect are also known to be substrates for Pgp.27,28

    Given that intestinal Pgp seems to be a more important determinant than intestinal CYP3A429 of the oral bioavailability of cyclosporine, grapefruit juice could be expected to decrease the oral bioavailability of cyclosporine. However, all clinical studies to date have shown, to the contrary, an increase in cyclosporine bioavailability.27,30-36 Edwards et al37 showed that the effects of grapefruit juice on cyclosporine seemed independent of a reduction of intestinal CYP3A4 and suggested that there was in vivo inhibition of Pgp, findings opposite those discussed above. Thus, the current data on the in vivo effect of grapefruit juice on CYP3A4 and Pgp, particularly in relation to a drug like cyclosporine, conflict and require further investigation. The in vivo impact of grapefruit juice on medications that are solely substrates for Pgp such as digoxin and fexofenadine is yet to be determined.

    Does the Quantity of Juice Matter?

    The majority of pharmacokinetic studies evaluating interactions between drugs and grapefruit juice have been performed using a single glass of juice (usually 200 mL). Many early studies, however, used frozen juice reconstituted with half the recommended water (“double-strength” juice) as well as multiple glasses of juice. The majority of the presystemic CYP3A4 inhibition is obtained following ingestion of 1 glass of grapefruit juice. One glass of regular-strength juice has a similar effect on the concentrations of felodipine and terfenadine as 2 or 3 glasses of double-strength juice.6,38-40 Daily ingestion of grapefruit juice over a few weeks may reduce slightly the juice’s effect,18,41 because 24 hours after ingestion of a glass of grapefruit juice, 30% of its effect is still present.19,20 However, consumption of very large quantities of grapefruit juice (6-8 glasses per day) may lead to inhibition of hepatic CYP3A4.42,43 Rogers et al42 showed that the effects seen on lovastatin are much less with a single glass of juice taken approximately 12 hours before the drug than with 3 glasses of double-strength juice per study day. Rogers et al42 report personal communication of unpublished data stating that very high quantities of grapefruit juice influence the pharmacokinetics of intravenous erythromycin, implying sufficient absorption of grapefruit juice constituents, and that hepatic enzyme activity is affected. A recent abstract also suggested that 1 glass of double-strength juice 3 times a day for 3 days may inhibit hepatic CYP3A4.43 Certainly amounts of grapefruit juice in the range normally consumed (up to 3 glasses per day) seem to have intestinal activity only.

    The Active Constituents of Grapefruit Juice

    Many compounds have been proposed to be the active ingredients in grapefruit juice. These include both flavonoids (eg, naringenin, naringin, quercetin, and kaempferol)44,45 and nonflavonoids (eg, 6′,7′-dihydroxybergamottin).46 All inhibit CYP3A4 in vitro; however, in vivo studies have shown modest if any effects.22,38,44,47-55

    Grapefruit contains several flavonoids, mainly as glycosides, which are hydrolyzed by intestinal microflora, to the corresponding aglycons and sugar.49 These molecules are polyphenolic and electron-rich, implying a potential to act as substrate inhibitors for the CYP enzymes. Naringin, the glycoside of naringenin, is the most abundant flavonoid in grapefruit juice, constituting up to 10% of its dry weight with a concentration in juice of 450 μg/mL. Naringin is what gives grapefruit juice its distinctive smell and bitter taste and is not found in other citrus or fruit juices. Naringin has no effect on the activity of the human CYP system in vitro, but its metabolite naringenin is a potent inhibitor of both the CYP3A44,47 and CYP1A222 isoforms in vitro. However, in vivo oral naringenin only weakly inhibits CYP3A4 and CYP1A2.38,48 For the CYP1A2 system, this is not surprising as most CYP1A2 is in the liver and not in the intestine, and only low levels of naringenin reach the plasma.49 However, the inability of oral naringin to markedly inhibit intestinal CYP3A4 likely implies that it is not the main active agent in grapefruit juice. Studies of other flavonoids have yielded similar results, ie, inhibition in the Petri dish47 but not in the intestine.50,51

    Others have suggested the furanocoumarin 6′,7′-dihydroxybergamottin or its parent compound bergamottin to be a major CYP3A4 inhibitor.52 Bergamottin is the furanocoumarin found in the highest concentration in fresh grapefruit. It is present in similar quantities in grapefruit juice and grapefruit segments and to a lesser degree in peel extract.53,54 Some data from Bailey et al55 suggest that 6′,7′-dihydroxybergamottin is not the major active ingredient causing drug–grapefruit juice interaction.

    Many of these constituents of grapefruit juice are present as a mixture of chiral isomers that vary markedly in proportion and concentration, depending on the maturity of the fruit and the method of juice extraction and purification.19,53,56 It is possible that the inhibition of first-phase intestinal metabolism by grapefruit juice is mediated by a combination of flavonoid and furanocoumarin compounds and does not occur in isolation.

    The majority of studies to date have used either fresh grapefruit juice or reconstituted frozen juice. However, it is believed that the active factors in grapefruit juice are present not just in the juice but also in the pulp, peel, and core of the fruit. Bailey and colleagues recently reported that blended grapefruit segments and extract from grapefruit peel cause a similar interaction with felodipine as does juice.54

    DRUG–GRAPEFRUIT JUICE INTERACTIONS (Tables 1 and 2)

    Calcium Antagonists

    1,4-Dihydropyridine calcium antagonists are lipid-soluble drugs used in the treatment of essential hypertension and angina pectoris and metabolized in vivo by CYP3A4. Since the effects of grapefruit juice were first noticed with felodipine, this class of drugs has been intensively studied with grapefruit juice. The degree to which the intestinal CYP system metabolizes this class of drugs and hence their oral bioavailability varies markedly. Grapefruit juice has the most marked effect on those calcium antagonists with the lowest oral bioavailabilities. One glass of grapefruit juice more than doubles the bioavailability of both standard7,20,38 and extended-release felodipine.57 The magnitude of this interaction varied widely among individuals. However, in the short term, this interaction is reproducible within individuals. Many studies have shown enhanced blood pressure reduction, an increase in heart rate, and an increase in vasodilatory adverse effects when felodipine is taken with grapefruit juice.7,13,20 This effect of grapefruit juice is in similar magnitude to that seen with erythromycin. Pranidipine, nisoldipine, and nimodipine have shown 1.5-fold increased bioavailabilities when given with single glasses of grapefruit juice.48,58,59 Amlodipine and nifedipine have better inherent oral bioavailabilities and hence are less affected by grapefruit juice. However, studies have still shown increased blood drug levels (20%-30% increases) but much less in the way of altered hemodynamic responses or adverse effects.6,14,60 Surprisingly, although metabolized in vivo by CYP3A4, the non–dihydropyridine calcium antagonists diltiazem and verapamil were not altered by grapefruit juice in small clinical studies.61


    Given the unpredictability of the effect of grapefruit juice on the bioavailability of the 1,4-dihydropyridine calcium antagonists in each patient, we should advise our patients to avoid this combination, thus preventing concern of potential adverse effects. This advice is particularly so for those with the greatest interaction with grapefruit juice such as nisoldipine and felodipine.

    Cyclosporine

    Cyclosporine is a potent T-cell immunosuppressant widely used as first-line therapy in the care of patients after solid organ and bone marrow transplantation. Its absorption is highly variable, ranging from less than 5% to 90%.62 Besides extensive metabolism by the CYP enzyme system in the liver, as discussed above, oral cyclosporine is affected in the intestine by the CYP3A4 and Pgp systems.

    Grapefruit juice, but not orange juice, increases the bioavailability of conventional oral cyclosporine by 62% as well as the microemulsion formulation.63,64 These effects have been shown in both healthy adults30 and renal transplant recipients31 taking cyclosporine for immunosuppression, leading to the elevation of trough concentrations by 77%.

    Coadministration of cyclosporine with a CYP3A4 inhibitor such as ketoconazole leads to increased cyclosporine levels and substantial cost savings to patients.65 Grapefruit juice has been proposed as a “natural” and safe means of cost reduction for patients taking cyclosporine.32,33 Brunner et al34 studied the benefits of coadministration of grapefruit juice with cyclosporine in stable renal transplant patients. However, they found that this interaction was limited and variable, leading the authors to recommend that grapefruit juice not be used to increase cyclosporine levels.34 Other editorials and commentaries have agreed, describing the cyclosporine–grapefruit juice interaction as unpredictable and hazardous.35,36 Much of this unpredictability is due to the inconsistency of the juice concentrations and the inability to standardize the active metabolites in grapefruit juice.

    In practice, given the fluctuating effects of grapefruit juice on the bioavailability of cyclosporine, the benefits in dose reduction are likely offset by the increased need for monitoring. We may in the future be able to harness the benefits of increases in drug bioavailability by grapefruit juice through either standardizing the constituents or isolating the active ingredients. This would then lead to a safe, effective, and cost-saving means to enhance the absorption of many therapeutic agents, including cyclosporine.

    Tacrolimus

    Tacrolimus, also metabolized by CYP3A4, is being used now extensively for immunosuppression in transplant patients. Its bioavailability is doubled when it is coadministered with the CYP3A4 inhibitor ketoconazole.11 Although there are no published data, tacrolimus is suspected to interact with grapefruit juice also, and the combination should be avoided.
    Dirk Tanis, BA, MSci
    Chief Operating Officer, Applied Nutriceuticals
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    Statins

    The statins are a family of drugs that act by inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase leading to reduction in plasma cholesterol. Lovastatin, simvastatin, cerivastatin, and atorvastatin undergo considerable intestinal metabolism by the CYP3A4 system and, to varying degrees, are affected by coadministered grapefruit juice. CYP3A4 plays only a minor role in the biotransformation of fluvastatin or pravastatin.67 Kantola et al68 caused much alarm when they showed grapefruit juice increasing the bioavailability of lovastatin 15-fold. The authors had used double-strength grapefruit juice 3 times a day (doses possibly high enough to inhibit hepatic metabolism). More recently 1 glass of regular-strength juice taken at breakfast, with the dose of lovastatin taken at night, increased mean lovastatin AUC by 2-fold, lovastatin acid by 1.6-fold, and mean AUC of active HMG-CoA reductase inhibitor by 36%.42 Indeed, it is likely the levels of HMG-CoA reductase inhibitors, and not the parent compounds, correspond most with both efficacy and the risk of adverse effects. “High-dose grapefruit juice” (6 glasses per day) increases the mean AUCs of simvastatin and simvastatin acid 16-fold and 7-fold, respectively, with the mean AUC of active HMG-CoA reductase inhibitor increasing 2.4- to 3.6-fold.69 Atorvastatin has also been studied with “high-dose juice” with the AUC of active and total HMG-CoA reductase inhibitors increased 1.3- and 1.5-fold.70 These increases approximate those seen when atorvastatin is taken with itraconazole.71 Studies evaluating single glasses of grapefruit juice ingested with oral simvastatin, atorvastatin, or cerivastatin need to be done. Although the mechanism by which statins cause myopathy or rhabdomyolysis is unknown, it does seem to be related to high plasma levels of HMG-CoA reductase inhibitors. Rhabdomyolysis has been reported when simvastatin or lovastatin is coadministered with CYP3A4 inhibitors—cyclosporine, diltiazem, erythromycin, itraconazole, or mibefradil.72-76 We conclude that grapefruit juice may predispose some patients taking statins, other than pravastatin, to these adverse effects. Unfortunately, at present, identification of patients who are at risk is not possible. This unpredictability may be due to a variety of factors such as genetic polymorphisms of CYP enzymes, the variable constituents of grapefruit juice, or the patient’s susceptibility to adverse effects. Until these issues are defined, it seems prudent to dissuade patients from combining grapefruit juice with these statins, particularly when they are taking these drugs for the first time or in high doses.

    Antimalarial Drugs

    Quinine, a drug long used in the treatment of malaria, is metabolized in vivo by the CYP3A4 system. However, its metabolism is predominantly hepatic rather than intestinal, which explains why no effect is seen when grapefruit juice is coadministered.77 These findings are similar to those seen with its isomer quinidine.78 Artemether, one of the artemisin family of drugs, is being increasingly used for the treatment of malaria in endemic areas, particularly falciparum. The oral bioavailability of artemether is doubled when taken with a glass of grapefruit juice.79 The impact of this with regard to efficacy and cost needs to be evaluated.

    Cisapride

    Elevated plasma concentrations of cisapride are associated with QTc prolongation and torsades de pointes, which has led to at least 80 reported deaths.80 For this reason, cisapride has recently been withdrawn from the US market and will only be prescribed on a limited-access basis. Since 1 glass of grapefruit juice increases the mean AUC of cisapride by 1.5-fold (range, 0.9- to 2.65-fold)81 and 3 glasses of double-strength juice a day by 2.4-fold (range, 1.7- to 3.4-fold),82 patients taking cisapride should not drink grapefruit juice to avoid potential risk.

    Cilostazol

    Cilostazol, used in the treatment of intermittent claudication, is extensively metabolized in vivo by CYP3A4. No studies evaluating an effect of grapefruit juice on cilostazol pharmacokinetics have been published; however, other CYP3A4 inhibitors such as erythromycin and diltiazem have been shown to increase cilostazol plasma concentrations.83,84 Therefore, the manufacturers of cilostazol suggest that patients receiving the drug avoid grapefruit juice consumption until the magnitude and timing of this interaction is evaluated further.83

    Protease Inhibitors

    Almost all protease inhibitors prescribed to treat human immunodeficiency virus infection are substrates for both CYP3A4 and Pgp. However, most have high oral bioavailabilities and hence are unlikely to be much affected by grapefruit juice. An exception to this is saquinavir, a potent protease inhibitor whose effectiveness is limited by low bioavailability (about 4%) because of extensive first-phase metabolism in the intestine. Grapefruit juice doubles the oral bioavailability of saquinavir.15 A newer formulation of saquinavir mesylate with a softer gel coating provides increased drug exposure. It has improved bioavailability, with levels 3 to 4 times higher than conventional capsules. Although not yet formally studied with grapefruit juice, these soft gel capsules are expected to interact also but perhaps to a lesser degree.

    Clarithromycin

    Clarithromycin, a CYP3A4 substrate, was evaluated with fresh grapefruit juice, and no increase in drug levels was noted.85 This is probably related to the fact that the oral bioavailability of clarithromycin is quite high (≥55%).

    Itraconazole

    Itraconazole is a broad-spectrum triazole antifungal that has erratic absorption and reduced oral bioavailability. Grapefruit juice, however, has not been shown to increase bioavailability86 and may even decrease it.87 A potential mechanism of this effect could be stimulation of the Pgp transporter. The effect of grapefruit juice on the other members of the conazole family has not been evaluated to date.

    Neuropsychiatric Medications

    Benzodiazepines.—There have been mixed reports on the degree to which grapefruit juice interacts with a variety of benzodiazepines. One glass of grapefruit juice more than triples the bioavailability of diazepam.88 One study16 has shown grapefruit juice increasing the bioavailability of oral midazolam by 50%, another42 by a factor of 2.4. Hukkinen et al89 showed an increase in the bioavailability of triazolam with more drowsiness, and Kupferschmidt et al16 showed at least an increase with respect to bioavailability. These studies, however, are contradicted by Vanakoski et al56 who found no effect on bioavailability of midazolam or triazolam by grapefruit juice. For these 3 benzodiazepines, patients should avoid drinking grapefruit juice with them to avoid the potential for interaction. No data exist for other commonly prescribed benzodiazepines: alprazolam, chlordiazepoxide, clonazepam, flurazepam, and lorazepam. However, they are all likely safe to take with grapefruit juice as their high oral bioavailability leaves little room for elevation by grapefruit juice.

    Buspirone.—Buspirone is an azapirone anxiolytic agent that produces less sedation and impairment of psychomotor performance than do benzodiazepines. It has poor bioavailability due to extensive first-pass metabolism. “High-dose grapefruit juice” has been shown to raise the AUC of buspirone between 3- and 20-fold (mean, 9-fold) and the maximum concentration between 2- and 16-fold (mean, about 4-fold).90 One can only speculate on the extent to which 1 glass of grapefruit juice would interact. It would be wise to counsel patients to avoid the coadministration of buspirone with grapefruit juice, particularly large amounts (more than 3 glasses per day).

    Sertraline.—Sertraline, a selective serotonin reuptake inhibitor used in the treatment of depression, panic disorder, and obsessive-compulsive disorder, undergoes first-pass metabolism by CYP3A4. A recent small study has shown both in vitro and in vivo evidence of grapefruit juice inhibiting this metabolism.91 Four of the study’s 5 patients had sertraline levels increased by approximately 1.5-fold when 1 glass of regular-strength grapefruit juice was drunk daily. The clinical implications of these findings are unclear.

    Carbamazepine.—Carbamazepine, an anticonvulsant widely used in the treatment of epilepsy, when coadministered with a large glass (300 mL) of fresh grapefruit juice results in increased oral bioavailability on average by 40%.92 Given carbamazepine’s narrow therapeutic index, it is wise to avoid the potential toxic effects induced by the coadministration of grapefruit juice.

    Clomipramine.—Clomipramine is a tertiary amine tricyclic antidepressant also used in the treatment of obsessive-compulsive disorder. Oesterheld and Kallepalli93 reported their experience of using grapefruit juice to elevate the drug levels of clomipramine and improve efficacy in 2 children with obsessive-compulsive disorder. The authors postulated that in some patients demethylation of clomipramine may be largely mediated by the intestinal CYP3A4 system. These data support a considerable interaction between grapefruit juice and clomipramine, and coadministration should probably be done only in a controlled setting.

    Other medications used in the fields of neurology and psychiatry, such as haloperidol, trazodone, and zolidem, all metabolized in vivo by CYP3A4, may interact with grapefruit juice. However, such an interaction is unlikely. All these medications have high oral bioavailabilities ranging between 60% and 70%, and any intestinal metabolism and possible inhibition by grapefruit juice are probably insignificant. Zaleplon, recently approved by the US Food and Drug Administration for use in the management of insomnia, is at least partially metabolized by CYP3A4, and given its low oral bioavailability, it may interact with grapefruit juice. Methadone, a long-acting oral narcotic used for its analgesic properties and in the management of narcotic withdrawal, is metabolized by CYP3A4 in the intestine and also likely interacts with grapefruit juice.

    Hormones

    The oral bioavailability of ethinyl estradiol, an estrogen in oral contraceptive pills, is low due to considerable first-pass metabolism and does seem to be increased when taken with grapefruit juice, by a factor of about 30%94 (albeit with up to 4 glasses of grapefruit juice per day in that study). Progesterone is also metabolized by CYP3A4 and undergoes considerable first-pass metabolism resulting in low oral bioavailability. Grapefruit juice has not been evaluated with oral progesterone, but one could expect it to increase serum levels markedly. The clinical implications, particularly with respect to dose-dependent adverse effects, of such changes are unclear. Cortisol is oxidized to inactive cortisone by the enzyme 11β-hydroxysteroid dehydrogenase. Lee et al95 suggested inhibition of this enzyme by grapefruit juice in vivo by lowering the urinary cortisone/cortisol ratios. They postulated that at high doses (more than 1 L per day) grapefruit juice might display mineralocorticoid activity. Grapefruit juice has been shown to have no effect on the metabolism of prednisone or prednisolone96 and would not be expected to affect oral thyroid hormone supplementation.

    Sildenafil

    Sildenafil oral therapy for erectile dysfunction has rapid absorption after oral administration with an absolute bioavailability of 40% and is known to be extensively metabolized by the CYP3A4 system. Erythromycin and itraconazole, potent inhibitors of this system, increase sildenafil plasma levels. Most recently the interaction of sildenafil with a number of protease inhibitors (also CYP3A4 substrates) has been reported.97,98 Although there are no published data, one can assume that grapefruit juice would also increase sildenafil levels if it were concurrently administered. Theoretically this would improve efficacy as well as increase the incidence of adverse effects, eg, headache, flushing, dyspepsia, and vision changes, albeit in a variable manner.

    CONCLUSION

    What does all this discussion mean for the practicing physician? The American public is consuming grapefruit juice in greater quantities,1 with 14% of men drinking the juice at least weekly.99 One can expect that, with the recent fortification of citrus juices with calcium, the intake of both orange juice and grapefruit juice will increase, particularly in middle-aged and elderly populations, groups in which the intake of medications is highest. There is an increased awareness of this potential for drug-food interaction in the clinical pharmacology and drug regulatory communities, although drug–grapefruit juice interactions may be underappreciated by general physicians.

    We have summarized the clinical findings on drug–grapefruit juice interactions. The majority of these studies are pharmacodynamic evaluations on small numbers of healthy adult volunteers, some of which provide secondary data on adverse effects. No specific studies have addressed the adverse effects of drug–grapefruit juice interactions. From the existing studies we have attempted to extract the extent of the risk to our patients. Although there are no published case reports of adverse effects due to such interactions, we must assume they do occur.

    Cisapride, cyclosporine, carbamazepine, tacrolimus, methadone, and many of the HMG-CoA reductase inhibitors and dihydropyridine calcium antagonists have severe dose-dependent adverse effects. Grapefruit juice is known or presumed to cause a marked increase in the serum levels of these medications. The effect of grapefruit juice varies from patient to patient, at least in part because of wide variations in intestinal concentrations of CYP3A4. The effect is similar in magnitude to that with itraconazole and erythromycin, and so if a drug should not be taken with these medications, then it should not be taken with grapefruit juice either.

    An argument could be made that, if a patient has been taking medication with grapefruit juice for some time without ill effect, it is probably safe to continue to do so. However, with the wide variability in the level of interaction with different types of juice and the sporadic manner in which grapefruit juice is commonly consumed, this approach may not be entirely safe. Each patient’s situation should be considered, and advice should be based on consumption history and the specific medications involved.

    There are exciting implications for research in this field for the future. Perhaps through modulation of the process of intestinal CYP3A4 metabolism, it may be possible to standardize absorption of many medications in the future, with possible identification and isolation of the active ingredients of grapefruit juice and coadministration of them in a controlled fashion.

    Refs- too long to list
    Dirk Tanis, BA, MSci
    Chief Operating Officer, Applied Nutriceuticals
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    thanks rms80. let this thread live. share what we know. what we dont know. we strive to improve!
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    where's POWER POINT when you need it?

    good info
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    God I am glad I have my RPM!
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    Quote Originally Posted by TheMyth View Post
    God I am glad I have my RPM!
    God I am glad that AN released RPM.
    M.Ed. Ex Phys
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    Very informative thread. I was looking for Pregnenolone in that list as I'm currently running Reset-A.D. with RPM and actually am kind of worried about how much the Naringin in RPM could possibly "juice up" the Pregnenolone in Reset-A.D?

    I have gone up to 4 Reset-A.D. a day with RPM, so I have been thinking that perhaps that is already too much Pregnenolone by itself (each cap has 25mg of Pregnenolone, so the 4 cap dose equals 100mg of Pregnenolone).

    Any idea anyone?
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    BUMPING MY THREAD CUZ ITS SWEET AND YUMMY
  

  
 

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