Sunday, May 5, 2013

Pharmacology of Hederagenin


Introduction 
Hederagenin is a highly water insoluble triterpenoid compound that can be found in various plants including Hedera helix and Chenopodium quinoa. It has been used as a component of the Fructus akebiae extract (FAE) in Traditional Chinese Medicine for the treatment of depression. In rodent studies, hederagenin was identified as the active compound in FAE and was determined to have potent anti-depressant qualities.

Hederagenin as a Psychotropic Drug 
In a 2010 study, Chinese researchers extracted and purified hederagenin from FAE and tested the compound on rats exposed to stress-inducing experiments [1]. As compared with the proven antidepressant escitalopram, hederagenin performed equally in reducing overt signs of stress. Additionally, hederagenin was shown to decrease biochemical markers of distress including serum ACTH and cortisol. In 2012, the same group of researchers further elucidated the mechanisms behind the antidepressant nature of hederagenin [2]. In an en vitro experiment, they found that hederagenin markedly inhibited the serotonin, norepinephrine, and dopamine, monoamine transporters with a Ki of 3.89±0.18 nm, 0.22±0.04 nm, and 2.87±0.54 nm, respectively. (As a comparison, cocaine is known to inhibit these transporters with a Ki of between 0.2 and 0.7 micromoles, which is several orders of magntitude less potent than hederagenin). To support their results, the researchers then used microdialysis to directly measure the CNS monoamine levels of living rats exposed to varying armounts of FAE. They found that FAE at doses of 12.6, 25, and 50 mg/kg significantly increased the extracellular concentrations of serotonin, norepinephrine, and dopamine, which would be expected with reuptake inhibition. Converting this to a Human Equivalent Dosage (HED) for a 70 kg adult equates to about 142 to 565 mg's.

Pharmacokinetics
In 2011, a benchmark study was conducted to examine the pharmacokinetics of orally administered hederagenin in rats [3]. They found that not only was hederagenin orally bioavailable, but that it successfully crossed the blood brain barrier (BBB). The former is surprising since similar compounds are known to have exceptionally poor bioavailability, even in rats.

Physicochemical Characteristics and Kinetic Predictions
Hederagenin is an acidic and hydrophobic compound with a pKa of 4.9 and a Log Sw of -6.92. It has an estimated volume of distribution (Vd) of 0.41 L/kg, an estimated GI transluminal diffusional capacity of 30-70%, and a blood brain barrier permeability coefficient (LogPS) of -3.5 [4].

My Interpretation
Most of the positive studies done on hederagenin were performed by the same institution (Southern Medical University, Guangzhou, China), and mostly by the same group of researchers [1, 2, 3]. And although I do not propose any research fabrication or bias, results this impressive should be replicated and verified. Similarly, although the rat pharmacokinetic study referenced above showed adequate bioavailability and BBB penetration, I suspect this will not be the case with humans.

For example:

  • With an estimated Vd of 0.41 L/kg, it is expected that this compound would be restricted to the total body water (TBW)
  • Acidic compounds without basic groups (pKa >6) are known to have limited distributive properties due to high-affinity binding to complexes I & II on serum albumin.
  • Based on albumin-dissociation calculations, only 0.0072% would be expected to be unbound in plasma [5], which would further restrict its Vd from the TBW to the vascular compartment.
  • Despite being highly hydrophobic (Log P: 7.08), which lends itself to BBB penetration, hederagenin would be heavily ionized in the plasma and therefore much less likely to cross the blood brain barrier.

Summary
Hederagenin is a very interesting compound which has demonstrated potent monoamine reuptake inhibitory properties in at least one study. These results are not exceptionally surprising since hederagenin is a component of an extract that is commonly used to treat depression in China. Unfortunately, there are no human safety or pharmacokinetic studies, and the existing en vitro and animal studies have not been independently replicated. Furthermore, the compounds chemical structure itself inspires doubt as to its true bioavailability and BBB accessibility, which I predict to be much worse. Ultimately, the studies performed on this compound to date are a great starting point but much more research is necessary to reconcile its physicochemical disparity with the remarkable effects it seems to be capable of. 


References
[1] http://www.ncbi.nlm.nih.gov/pubmed/19931301 
[2] http://www.sciencedirect.com/science/article/pii/S0091305711003236 
[3] http://www.ncbi.nlm.nih.gov/pubmed/21680262
[4] http://www.ncbi.nlm.nih.gov/pubmed/9466345
[5] http://www.pnas.org/content/82/5/1563.full.pdf

9 comments:

  1. someone in the bodybuilding forum said it is a stimulant, do you agree with that? Curious about it.

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  2. If it had significant access to the CNS (Vd > 100 L), then it could act as a stimulant. Unfortunately, we know very little about its pharmacodynamic profile. For example, some reuptake inhibitors (i.e. vanoxerine) also block other catecholamine receptors, and so the end effect could be anything but stimulation. Based on the numbers above (0.22±0.04 nm), hederagenin appears to be *significantly* more potent at inhibiting norepinephrine reuptake, which may actually make it sedating (i.e. atomoxetine). Ultimately, I do not see this compound being able to penetrate the blood brain barrier (at all) and so its probably just an exercise in mental gymnastics.

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  3. There is indeed little data out there where Hederagenin is concerned. So let's look at very similar molecules instead of pure conjecture: 11-keto-beta-boswellic acid has a Vd of approximately 141 L in human volunteers, following oral administration. (PMID: 15070181) It is extremely close to Hederagenin in terms of chemical structure and molecular properties. What's more, there's evidence that it, too, crosses the BBB.

    (When assessing a compound's a ability to cross the blood brain barrier, Vd is certainly not the only thing I would look at, but that's another matter entirely...)

    From where do you draw the assumption that the rat BBB is so much less permeable than ours? I don't think that the data is on your side here. There are several studies to look at, but this is perhaps the most direct: http://dmd.aspetjournals.org/content/37/3/635.long
    "Distribution to the brain of the three studied radioligands [11C]verapamil, [11C]GR205171, and [18F]altanserin were clearly higher in humans, monkeys, and minipigs than in rats and guinea pigs, as described with brain concentrations; SUV; and the brain-to-plasma concentration ratios, Kp."

    In this study, morphine seemed to have a significantly harder time crossing the rat BBB as opposed to the human or porcine BBB: http://europepmc.org/abstract/ETH/8586

    The pharmacokinetic studies of Hederagenin in rats are compelling, and to discount them utterly without a clear reason for doing so is nonsensical.

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  4. 11-keto-beta-boswellic acid is an amphipathic compound which allows for greater distributive properties in addition to BBB penetration (thus explaining the Vd and the BBB permeability you report). Hederagenin is not. They are not physicochemically similar except for possessing the steroidal backbone.

    They first study you posted above is in reference to a specific active transport mechanism (P-glycoprotein), and hederagenin is not even a substrate.

    The second study is contextually irrelevant. Please do not cherry pick the literature.

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  5. I'll ask again. From where do you get the assumption that the rat blood brain barrier is somehow more porous than the human blood brain barrier? The scant evidence out there seems to suggest the opposite, if anything.
    Cherry-picking is one thing, but I haven't been able to find a shred of evidence which supports your position. I've 'cherry-picked' the only decent studies on the subject, as far as I'm aware. I'd honestly be happy if you were to provide evidence to the contrary.


    As for boswellic acid: I don't believe that the pharmacokinetic differences would be nearly so great as you suggest, but let's leave it aside for now. Where there is data to look at, most triterpenes seem to have large volumes of distribution. β-glycyhrritinic acid, decidedly not any more amphipathic than hederagenin, is said to have a large volume of distribution: http://webda.mums.ac.ir/pdf/Glycyrrhiza%2520sp.pdf
    ...And, like the boswellic acids and presumably like hederagenin, it also crosses the BBB quite easily. (PMID: 22488528)

    Celastrol -- an extremely interesting compound, by the way -- crosses the BBB and is strongly neuroprotective in animal models. (PMID: 16092942, 20211007 )

    Ursolic acid is also presumed to cross the BBB. (PMID: 21835916) It's part of an FDA compound screening library, "selected for their [high] likelihood to cross the blood-brain barrier."

    I believe that the consensus opinion is that betulinic acid also crosses the BBB. It was, at least, shown to cross the BBB in mice to some extent.

    We'll both agree that the bioavailability of hederagenin is very poor. That said, I think that it's misguided to assume that hederagenin has absolutely null bioavailability and zero ability to cross the blood brain barrier, when there seems to be plenty of evidence to the contrary.
    As an aside, I quite enjoy reading your blog.

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  6. You are perseverating about the idea of a "porous" BBB. It is a well known axiom that the human BBB is more selective and with much more effective efflux mechanisms. If you want to argue with this idea, then perhaps this blog is not for you.

    Please tell me the Vd of glycyhrritinic acid. Tyler et al. 1988 is not a suitable citation. The article you referenced was a review article which simply noted a "large" Vd, which is quite subjective depending on the context.

    Ultimately, if you want to argue that hederagenin would have the potential for BBB penetration, you need to demonstrate an adequate volume of distribution (or an active influx mechanism, which doesn't exit).

    The second thing you need to explain is how hederagenin would remain unionized in the blood (since hydrophobicity) would establish BBB penetration). A lot of people think the "Log P" of a compound is an adequate reflection of its lipophilicity, however they aren't taking into consideration the solvent for which it will be coadministered.

    In order to calculate its ionization in the blood, start with the base formula:

    pH = pKa + log([A-]/[HA])

    Which can be qualitatively tweaked for a weak acid:

    log (nonizonized/anionic) = pKa - pH

    and further:

    pKa - pH = (4.9 - 7.4) = -2.5

    The difference of >2 = 99 to 99.9% ionzied (when inverted for the negative)

    There are ways to decrease ionization (glucuronidation), but they only diminish the BBB permeability coefficient even further (from negligable to zero).

    I just don't see hederagenin reaching the CNS without covalent modifications.

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  7. any info on 3-(4-aminophenyl)-3-cyclohexyl-2, 6-piperidinedione

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  8. Never heard of it, off hand. Does it have a common name? Any research?

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