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  1. #1
    Bruce Lee^2 Chimpinzo's Avatar
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    6, 7-Dihydroxybergamottin (aka. DHB) Effectiveness

    I was looking into 6, 7-Dihydroxybergamottin recently, and have seen it often claimed to extend the half life of supplements in the body by considerable amounts.

    After a bit of reading, I stumbled across this website.
    http://www.pharmainfo.net/reviews/dr...apefruit-juice


    The effect seems to be mediated mainly by suppression of the cytochrome P450 enzyme CYP3A4 in the small intestine wall. This results in a diminished first pass metabolism with higher bioavailability and increased maximal plasma concentrations of substrates of this enzyme. The effect was most pronounced in drugs with high first pass degradation.

    The components of grapefruit juice which are the most probable causes of the interaction are furanocoumarins derivatives, but the flavonoid naringenin may also contribute. Concomitant grapefruit juice intake does not generally decrease the variability of drug pharmacokinetic parameters. Therefore, it is recommended that patients abstain from drinking grapefruit juice when they are taking a drug that is extensively metabolised, unless a lack of interaction has already been demonstrated for that drug. It is also recommended that drugs possibly interacting with grapefruit juice should be appropriately labelled.

    The discovery that grapefruit juice can increase the oral availability of some medications was an accidental discovery made when grapefruit juice was used to mask the taste of ethanol in a study involving the calcium channel blocker felodipine. Since then, more different drugs have shown to enhance oral availability when consumed with grapefruit juice. Most of the drugs affected by grapefruit juice have poor and highly variable oral bioavailability. In addition, most of these drugs are chiefly metabolized in the body by CYP3A4, an enzyme present in the liver and intestine.

    The major effect of grapefruit juice appears to reduce ?first-pass? metabolism by reducing CYP3A4 activity. Because grapefruit juice does not generally affect the systemic clearance of affected drugs, it appears that grapefruit juice selectively reduces intestinal CYP3A4 activity while having little effect on liver CYP3A4. Grapefruit juice has no effect on drug disposition after intravenous administration and does not alter liver CYP3A4 activity. 1
    Clinical significance of grapefruit drug interaction

    Firstly, the drugs affected by grapefruit juice characteristically have highly variable apparent oral clearance, presumably because of well-established inter-patient variability in activity of intestinal CYP3A4. For this reason, affected drugs must generally have a very wide therapeutic index (an exception is cyclosporine, for which blood level monitoring is generally used to guide individualization of dosing).

    An additional situation might be when a patient has severe liver disease such that the intestine is the major site for metabolism of the drug. Such a patient would be expected to have high systemic exposure to the drug at usual doses; loss of intestinal CYP3A4 activity would further increase the exposure. Finally, patients who have a peculiar susceptibility to toxic effects of a susceptible drug will be more likely to have toxicity when they consume the medicine with grapefruit juice, simply because systemic exposure to the drug would increase. In the future it should be possible to use grapefruit-derived furanocoumarins as additives to certain drugs to improve the oral delivery of some drugs by reducing variability. Such formulations would obviously be no longer susceptible to grapefruit juice interactions. It should also be possible to remove furanocoumarins from grapefruit juice to reduce drug interaction potential.

    Finally to thoroughly assess the clinical significance of grapefruit-drug interactions, the type and amount of grapefruit juice must also be considered. Consumption of a single glass of regular-strength grapefruit juice is sufficient to inhibit CYP3A4. The magnitude of interaction may vary depending on the extent of intestinal CYP3A4 expression in an individual patient. This variation between individuals may be significant and is difficult to predict. The grapefruit-drug interaction appears to affect patients with high quantities of small bowel CYP3A4 isoenzymes. 1
    Active components of grapefruit juice

    The assumption is that the active components in grapefruit juice do not reach the liver in sufficient concentrations to affect CYP3A4 activity; although a variety of juice components have been implicated to inhibit these enzymes. 4, 5

    In addition to flavonoids, researchers have also focused on furanocoumarins found in grapefruit juice as CYP3A4 inhibitors. The furanocoumarins such as bergamottin was mainly thought to be responsible for the inhibition of intestinal CYP enzymes. 6, 7 Bergamottin is present in grapefruit juice in concentrations ranging from 2 to 30 μmol/L. Relative exposure to bergamottin is not known, and doses administered were typically larger than those encountered by humans after normal consumption of grapefruit juice. Thus the relevance of bergamottin in the clinical interaction of grapefruit juice in humans is currently uncertain. 8 But, the most abundant and probably the most important single furanocoumarin is 6,7- dihydroxybergamottin (DHB). 1,9,10

    When bergamottin administered as a pure substance enhanced the oral bioavailability of some drugs. However, the effect was substantially less than that produced by grapefruit juice even at markedly higher doses of bergamottin than normally present in the juice. It appears probable that the interaction also involves other furanocoumarins present in whole grapefruit juice, possibly acting in combination by additive or synergistic mechanisms. Bergamottin has systemic availability and is metabolized to 6?, 7?- dihydroxybergamottin in humans. 10

    The more hydrophilic metabolite, 6?, 7?-dihydroxybergamottin, is often present in grapefruit juice in similar concentrations (0.8 to 58 ?mol/L), but initial investigations indicated that it is a less potent with respect to in vitro mechanism-based inactivator of CYP3A4 than bergamottin. 8 However, recent reports by different groups indicate that 6?,7?-dihydroxybergamottin is a more potent mechanism-based inactivator or inhibitor of CYP3A4.

    The interaction between grapefruit juice serum and felodipine can be attributed largely to DHB. This establishes DHB as an important contributor to the grapefruit juice effect. These novel findings indicate that DHB could account almost entirely for the effect of the aqueous extract of grapefruit juice on the systemic exposure of felodipine, supporting a major role for DHB in the grapefruit juice effect. 10

    Orange juice has no CYP3A4-inhibiting effects. When orange juice was spiked with a synthetic DHB, however, no significant difference between the degrees of inhibition produced by either of the 2 citrus fruits was observed. Therefore, the DHB component in grapefruit appears to be another potent inhibitor of CYP3A4 and is most likely primarily responsible for the interaction.

    The furanocoumarins are divided into 6 components: 6',7'-dihydroxybergamottin (DHB), GF-I-1, bergamottin (GF-I-2), GF-I-4, GF-I-5 (bergamottin-6',7'-epoxide), and GFI- 6.12 Significant inhibition of CYP3A4 isoenzyme activity is exhibited by DHB, GF-I-1, and GF-I-4 with minimal activity exhibited by bergamottin (a presumed precursor of GF-I-1 and GF-I-4 and a known ingredient of grapefruit essential oil). 11

    The CYP3A4 isoenzyme, which is found in the intestine and liver, accounts for about 40% to 60% of all CYP450 isoenzymes (although it is important to note that grapefruit inhibits CYP450 in the gastrointestinal tract, not the liver) and is involved in the majority of significant CYP450-mediated drug interactions. Inhibition of the CYP3A4 isoenzyme, either reversible or irreversible, will result in a reduced metabolism and metabolic clearance of CYP3A4 substrates. 5

    Some of the components of grapefruit such as Paradisin C have also shown CYP3A4 isoenzyme inhibitory activity. Paradicin C was isolated from the grapefruit and the activity was reported as against Paradicin A and B. 12 Other reported components are β-citraurin, D-limonene, myrcene, sabinene 13 and limonoids. Grapefruit contains many flavonoid glycosides, naringenin, quercetin, kaempferol, hesperetin and apigenin being the most abundant among their aglycones. 14, 15, 16
    Mechanism of action of grapefruit juice components

    DHB and other furanocoumarins appear to reduce CYP3A4 activity by three related but distinct mechanisms, as follows:

    (1) Competitive or reversible inhibition,

    (2) Mechanism-based inactivation (also called irreversible inhibition), and

    (3) Actual loss of CYP3A4 enzyme. 1, 9, 17, 18

    The first and most common mechanism is known as competitive inhibition and results from the competition between the inhibitor and substrate for the same CYP isoenzyme required for substrate metabolism and elimination. The effects of competitive inhibition can be observed after administration of the first dose of the inhibitor.

    The second mechanism is known as mechanism-based inhibition and occurs with grapefruit juice. The most potent grapefruit components causing a mechanism-based inactivation of CYP3A4 are furanocoumarins, which bind irreversibly to CYP3A4 and permanently inactivate the isoenzyme. The duration of mechanism based inhibition may be longer than competitive inhibition because new CYP3A4 isoenzymes must be synthesized for activity to be restored. Complete recovery of the CYP3A4 may take 48 to 72 hours after the last exposure to grapefruit juice, which explains why the effects can last for at least 72 hours after drinking grapefruit juice. Most important, because of mechanism-based inhibition, separating the administration of grapefruit juice and substrate drug by a few hours does not minimize grapefruit drug interactions. Pharmacists should advise patients to entirely avoid grapefruit if they are taking medications known to significantly interact with grapefruit juice.

    Literature indicated that grapefruit juice at normal volume did not change the terminal half-life (t?) or intravenous pharmacokinetics of drugs. Therefore this pharmacokinetic interaction is thought to be primarily due to grapefruit juice? mediated inhibition of intestinal CYP3A4 activity without apparent inhibition of hepatic CYP3A4 activity. Grapefruit juice inhibition of CYP3A4 in vivo appears to involve irreversible inactivation of CYP3A4, as evidenced by down-regulation of intestinal CYP3A4 protein content without alteration of intestinal messenger ribonucleic acid levels.
    Quite a bit of reading here, lots I had to cut out b/c the texts were too long. But I'm trying to figure out what supplement's half lives would be effected by DHB


    Grapefruit - drug interactions appear to occur only under well-defined circumstances. First, the drug substrate must be predominantly metabolized by CYP3A4. Second, the drug substrate must undergo extensive first-pass metabolism (ie, drugs with low oral bioavailability). Knowledge of these two factors will allow pharmacists to predict whether a medication is likely to interact with grapefruit juice. For example, felodipine has a low oral bioavailability of 15% and is significantly affected by grapefruit juice; whereas amlodipine has a high oral bioavailability of 75% and does not interact with grapefruit juice. Other examples are verapamil and quinine. Grapefruit juice significantly increased plasma concentrations of verapamil (oral bioavailability of 20%) and had no significant effect on the pharmacokinetics of quinine (oral bioavailability of 80%).
    Anyone with some science background want to help me out with this bit? Which / what supplements would be effected by grapefruits / dhb?
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  2. #2
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    i've read about this before while working on some formulas for inducing growth spurts in full grown adults if i remember correctly, there are a variety of cyp enzymes each responsible for multiple and/or different interactions with specific molecules. some also serve as substrates or inducers or inhibitors. which supplements halflives would be affected is goverened soley by which cytochrome is responsible for its degredation
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    Big Bulkin' antihero's Avatar
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    Originally Posted by ToshiroMifune View Post
    i've read about this before while working on some formulas for inducing growth spurts in full grown adults if i remember correctly, there are a variety of cyp enzymes each responsible for multiple and/or different interactions with specific molecules. some also serve as substrates or inducers or inhibitors. which supplements halflives would be affected is goverened soley by which cytochrome is responsible for its degredation
    correct.

    and CYP3A4 has been noted to have an effect on hormones, there might also be other things to consider using to extend the half-life than just grapefruit juice, however I haven't checked availability or pricing of those things yet.
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  4. #4
    Mr. Nice guy thauncle's Avatar
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    this is an interesting compound i've been looking at for awhile.I'm going to give it a go in a few weeks and see how it goes.I'm still wondering why this isn't used on a wider scale in ph/ds and etc use i know i'm kinda narrow minded in my thinking of uses for this compound as i know it can be used for a number of things but i like the promise it could show in aiding other supplements.
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    Bruce Lee^2 Chimpinzo's Avatar
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    See, this is the interesting part. It's proven significant effectiveness. Now lets just find what supplements / compounds it effects so we know when to use it and when we're just wasting it!
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    steroid metabolism
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    Bruce Lee^2 Chimpinzo's Avatar
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    Bump

    So this only effects hormonal metabolism? Aka would be best used with test boosters / AI's / etc?
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    yep
    i do it for the tacos.
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