14 replies to this topic

[malbecman]

My 'bot somehow missed this one when it came out:


Pharm Res. 2008 Jul 16. [Epub ahead of print]
The Impact of Aqueous Solubility and Dose on the Pharmacokinetic Profiles of Resveratrol.
Das S, Lin HS, Ho PC, Ng KY.
Department of Pharmacy, Faculty of Science, National University of Singapore, Building S4, Rm 05-02, 18 Science Drive 4, Singapore, 117543, Singapore.

PURPOSE: This study aimed at the investigation of the impact of aqueous solubility and dose manipulation on the pharmacokinetics of resveratrol. METHODS: Water soluble intravenous and oral formulations of resveratrol were prepared with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and randomly methylated-beta-cyclodextrin (RM-beta-CD), respectively. Sodium salt and suspension of resveratrol in carboxymethyl cellulose (CMC) were used as the reference intravenous and oral formulations, respectively. The pharmacokinetics of resveratrol was assessed in Sprague-Dawley rats. Plasma resveratrol concentrations were measured by high performance liquid chromatography (HPLC). RESULTS: Both HP-beta-CD and RM-beta-CD enhanced the aqueous solubility of resveratrol. After intravenous administration, rapid elimination of resveratrol was observed at all tested doses (5, 10, and 25 mg kg(-1)) regardless of formulation types; with non-linear elimination occurring at the dose of 25 mg kg(-1). RM-beta-CD significantly increased the maximal plasma concentration of orally administered resveratrol, but, it did not increase the oral bioavailability in comparison with the CMC suspension. Furthermore, the oral bioavailability remained unchanged among all tested doses (15, 25, and 50 mg kg(-1)). CONCLUSIONS: Aqueous solubility barrier might affect the speed but not the extent of resveratrol absorption. Further, dose manipulation (up to 50 mg kg(-1)) did not have a significant impact on the oral bioavailability of resveratrol.

PMID: 18629618

[malbecman]

Not to be self-promoting and post to my own topic but I found this paper very interesting. On first read thru: They saw similar blood levels in rats via both IV dosing at 15 mg/kg and oral dosing of their formulation up to 50mg/kg. I would have expected the IV dose to be much higher given the generally low oral bioavailability of resveratrol. Also, escalating the oral dose did not results in higher blood levels, implying there is some saturation going on. Anyone else checked it out?

[maxwatt]

Not to be self-promoting and post to my own topic but I found this paper very interesting. On first read thru: They saw similar blood levels in rats via both IV dosing at 15 mg/kg and oral dosing of their formulation up to 50mg/kg. I would have expected the IV dose to be much higher given the generally low oral bioavailability of resveratrol. Also, escalating the oral dose did not results in higher blood levels, implying there is some saturation going on. Anyone else checked it out?

This is in accord with the Boocock paper Hedgehog analyzed, and with some measurements he made on himself and on some volunteers. In humans there is a peak blood-level/oral-intake ratio, somewhere over 1 gram and nder two grams; not that increasing the dose didn't increase the level, it did but not by as much. The studies did not exceed the asymptote, but iI think it would have been not much more than five grams (for people.) Another factor not yet measured, is that different genotypes in the population have different efficiencies of conjugation. Thus an Asian might achieve a higher level than a European at half the dose (just a possible example, don't take it as hard information.)

I have been comparing different methods of administration, with my arthritic joints as a measure. I have concluded that for me using milk protein as a carrier
(milk, yogurt, sour cream, whey protein drinks) is more effective than HPMC, alcohol, lecithin or various combinations of these. Not by a lot, maybe a factor of two. I suspect the resveratrol binds to the mikl protein, and is sequestered from conjugation, yet is released to the cell membranes and absorbed there, giving a higher effective level. This is surmise based on my observation of my own responses. It should be confirmed by controlled trials and measurements, but I think it i a place to start.

[Mixter]

I have concluded that for me using milk protein as a carrier (milk, yogurt, sour cream, whey protein drinks) is more effective than HPMC, alcohol, lecithin or various combinations of these. Not by a lot, maybe a factor of two. I suspect the resveratrol binds to the mikl protein, and is sequestered from conjugation, yet is released to the cell membranes and absorbed there, giving a higher effective level. This is surmise based on my observation of my own responses. It should be confirmed by controlled trials and measurements, but I think it i a place to start.

Hmm strange, and you have no other indications for that? Because the strong reason against that
idea would be that absorption of other, similar polyphenols (green tea ECGC, cocoa flavonoids)
are inhibited by adding any milk, reported by many studies.

Personally I'm thinking about using both PEG and HPMC, but I'm unsure whether using a less good
bioavailablility enhancer (PEG in this duo) could dilute the effects of the better one?

[maxwatt]

I have concluded that for me using milk protein as a carrier (milk, yogurt, sour cream, whey protein drinks) is more effective than HPMC, alcohol, lecithin or various combinations of these. Not by a lot, maybe a factor of two. I suspect the resveratrol binds to the mikl protein, and is sequestered from conjugation, yet is released to the cell membranes and absorbed there, giving a higher effective level. This is surmise based on my observation of my own responses. It should be confirmed by controlled trials and measurements, but I think it i a place to start.

Hmm strange, and you have no other indications for that? Because the strong reason against that
idea would be that absorption of other, similar polyphenols (green tea ECGC, cocoa flavonoids)
are inhibited by adding any milk, reported by many studies.

Personally I'm thinking about using both PEG and HPMC, but I'm unsure whether using a less good
bioavailablility enhancer (PEG in this duo) could dilute the effects of the better one?

Much less than initially thought, ECGC is affected more than other polyphenols by milk. Resveratrol is only weakly bound by milk proteins, they are digested and the resveratrol is released. Even ECGC is released, though milk slows its absorption. Not much in Pubmed, this seems the most thorough study:

PMID: 17688297

[krillin]

Hmm strange, and you have no other indications for that? Because the strong reason against that
idea would be that absorption of other, similar polyphenols (green tea ECGC, cocoa flavonoids)
are inhibited by adding any milk, reported by many studies.

No gallate group, no problemo.

J Agric Food Chem. 2002 Feb 27;50(5):1184-7.
Interactions between flavonoids and proteins: effect on the total antioxidant capacity.
Arts MJ, Haenen GR, Wilms LC, Beetstra SA, Heijnen CG, Voss HP, Bast A.
Department of Pharmacology and Toxicology, Faculty of Medicine, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Mariken.Arts@farmaco.unimaas.nl

Flavonoids are potent antioxidants. It is also known that flavonoids bind to proteins. The effect of the interaction between tea flavonoids and proteins on the antioxidant capacity was examined. Their separate and combined antioxidant capacities were measured with the Trolox equivalent antioxidant capacity (TEAC) assay. It was observed that the antioxidant capacity of several components of green and black tea with alpha-, beta-, and kappa-casein or albumin is not additive; that is, a part of the total antioxidant capacity is masked by the interaction. This masking depends on both the protein and the flavonoid used. Components in green and black tea, which show the highest masking in combination with beta-casein, are epigallocatechin gallate and gallic acid. The results demonstrate that the matrix influences the efficacy of an antioxidant.

PMID: 11853501

J Food Sci. 2007 Apr;72(3):S230-3.
The effect of milk protein on the bioavailability of cocoa polyphenols.
Keogh JB, McInerney J, Clifton PM.
CSIRO Human Nutrition, PO Box 10041 Adelaide BC, South Australia 5000, Australia. jennifer.keogh@csiro.au

In order to determine whether milk proteins interact with cocoa polyphenols to modulate the uptake and concentration of polyphenols in plasma, 24 middle-aged men and women consumed 2 g of chocolate polyphenols, plus sugar and cocoa butter in 200 mL water, on 2 occasions. On 1 occasion, the chocolate mix contained 2.45 g of milk proteins. Blood samples were taken fasting and at regular intervals for 8 h. Catechin and epicatechins levels were measured in these samples and no differences were seen in average concentrations between the 2 treatments. Milk protein caused a slight increase in concentration at the early time points and a decrease at the later time points. In conclusion, milk powder did not influence the average concentration of polyphenols. While it slightly accelerated absorption, this is of no physiological significance.

PMID: 17995820

J Agric Food Chem. 2007 Oct 31;55(22):9235-40. Epub 2007 Sep 12.
Interactions between flavan-3-ols and poly(L-proline) studied by isothermal titration calorimetry: effect of the tannin structure.
Poncet-Legrand C, Gautier C, Cheynier V, Imberty A.
UMR1083 Sciences pour l'Knologie, INRA, Université Montpellier 1, France. celine.poncet@supagro.inra.fr

Interactions of proline-rich proteins (PRPs) with flavan-3-ols was studied using poly(L-proline) as a model protein by means of isothermal titration calorimetry (ITC). Several parameters were varied: (i) the galloylation and B-ring trihydroxylation of the flavan-3-ols (catechin, epicatechin, epicatechin gallate, and epigallocatechin gallate) and (ii) the degree of polymerization (monomers were compared to a mixture of oligomers with average degree of polymerization of 3.85). Large differences were observed between the flavan-3-ol monomers: no enthalpy change was measured when catechin and epicatechin were titrated by poly(L-proline), whereas thermodynamic parameters were determined in the case of galloylated monomers and mixture of oligomers. Stoichiometry ranged from 1 oligomer bound for each 12 proline units to 1 galloylated monomer for each 8 or 10 proline units. Association constants were in the range of 10(4)-10(5) M(-1), indicating a relatively high affinity of galloylated flavanols toward poly(L-proline), and the coexistence of both enthalpy- and entropy-driven phenomena was suggested. Finally, the binding of grape seed tannins to proteins was shown to be a cooperative process.

PMID: 17850090

[bdelfin]

No gallate group, no problemo.

But see the topic Antioxidant activity of blueberry fruit, is impaired by association with milk, where we see that blueberry phenols, such as caffeic acid, are also highly impaired. So while a gallate group causes problems, the absence of a gallate group does not equate to no problem.

[FILY]

My 'bot somehow missed this one when it came out:


Pharm Res. 2008 Jul 16. [Epub ahead of print]
The Impact of Aqueous Solubility and Dose on the Pharmacokinetic Profiles of Resveratrol.
Das S, Lin HS, Ho PC, Ng KY.
Department of Pharmacy, Faculty of Science, National University of Singapore, Building S4, Rm 05-02, 18 Science Drive 4, Singapore, 117543, Singapore.

PURPOSE: This study aimed at the investigation of the impact of aqueous solubility and dose manipulation on the pharmacokinetics of resveratrol. METHODS: Water soluble intravenous and oral formulations of resveratrol were prepared with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and randomly methylated-beta-cyclodextrin (RM-beta-CD), respectively. Sodium salt and suspension of resveratrol in carboxymethyl cellulose (CMC) were used as the reference intravenous and oral formulations, respectively. The pharmacokinetics of resveratrol was assessed in Sprague-Dawley rats. Plasma resveratrol concentrations were measured by high performance liquid chromatography (HPLC). RESULTS: Both HP-beta-CD and RM-beta-CD enhanced the aqueous solubility of resveratrol. After intravenous administration, rapid elimination of resveratrol was observed at all tested doses (5, 10, and 25 mg kg(-1)) regardless of formulation types; with non-linear elimination occurring at the dose of 25 mg kg(-1). RM-beta-CD significantly increased the maximal plasma concentration of orally administered resveratrol, but, it did not increase the oral bioavailability in comparison with the CMC suspension. Furthermore, the oral bioavailability remained unchanged among all tested doses (15, 25, and 50 mg kg(-1)). CONCLUSIONS: Aqueous solubility barrier might affect the speed but not the extent of resveratrol absorption. Further, dose manipulation (up to 50 mg kg(-1)) did not have a significant impact on the oral bioavailability of resveratrol.

PMID: 18629618

Resverareol is a high potential active ingredient. However, its solubility in water is 2-5mg/100ml. Now, We have developed water-solubility resveratrol, its solubility can be 10mg-15mg/ml. I think it can be used in Non-lcohol drink pretty soon.

[Anthony_Loera]

You know beta-cyclodextrin is limited to about 2%?

I don't think you can sell it as a dietary supplement here in the USA without getting into trouble with the FDA.

A

[2tender]

There is, or was, a legal, patented cyclodextrin delivery system available. The man that had it in his product is still around. I dont know if he owns the patent, but if you PM me, we can discuss it. A Resveratrol lozenge combined with this would sell to all the buccal enthusiasts.

[Anthony_Loera]

I am specifically talking about beta-cylodextrin, we have already done a taste test on other cyclodextrins that are acceptable in foods... and these others do taste horrible.

It reminds me of what one of the folks at the Convention said last week, while walking out of that place...
"Yes, these guys can market that their products as healthy and organic, but if it tastes like shit, who's going to buy them?" -Unknown Buyer

I am not sure which product he was talking about at the time, but many 'organic' or 'natural' manufactured products at the convention didn't really taste 'natural', ' healthy' or good at all for that matter. I suspect if we use some of the cyclodextrins available with resveratrol, they would not be sold very well simply because of the nasty taste.

A

[niner]

I suspect if we use some of the cyclodextrins available with resveratrol, they would not be sold very well simply because of the nasty taste.

If the idea is to deliver it as a food or beverage, then yeah, but would it make any sense to cap up a CD-resveratrol complex? Any advantage in terms of bioavailability or cost over the nitro strategy?

[2tender]

I am specifically talking about beta-cylodextrin, we have already done a taste test on other cyclodextrins that are acceptable in foods... and these others do taste horrible.

It reminds me of what one of the folks at the Convention said last week, while walking out of that place...
"Yes, these guys can market that their products as healthy and organic, but if it tastes like shit, who's going to buy them?" -Unknown Buyer

I am not sure which product he was talking about at the time, but many 'organic' or 'natural' manufactured products at the convention didn't really taste 'natural', ' healthy' or good at all for that matter. I suspect if we use some of the cyclodextrins available with resveratrol, they would not be sold very well simply because of the nasty taste.

A

Understood, but, I think there are a large number of supplement users for whom palatability would not be an issue. The name of the dextrin was Hydroxypropyl and I could find no patent on it. Theoretically it would heighten, if not maximize absorbtion.

[2tender]

I suspect if we use some of the cyclodextrins available with resveratrol, they would not be sold very well simply because of the nasty taste.

If the idea is to deliver it as a food or beverage, then yeah, but would it make any sense to cap up a CD-resveratrol complex? Any advantage in terms of bioavailability or cost over the nitro strategy?

In my mind there would be a definate bioavailable advantage. It probably wouldnt be much cheaper to produce or purchase,

[Anthony_Loera]

I suspect if we use some of the cyclodextrins available with resveratrol, they would not be sold very well simply because of the nasty taste.

If the idea is to deliver it as a food or beverage, then yeah, but would it make any sense to cap up a CD-resveratrol complex? Any advantage in terms of bioavailability or cost over the nitro strategy?

From the numbers, it looks like the current Strategy has many advantages:

1- We can use more resveratrol in the capsule, as a cyclodextrin equivalent only produces a 10% - 14% complex. (A 100mg capsule would have to contain a large amount of the complex)
2- Absorption doesn't seem to stack up compared to the tween (I haven't seen a good comparison, but if you have one, let me know).
3- Price for cyclodextrin complex is higher than tween emulsion
4- No patent issues with GSK

I am interested in the Jello mixture that Maxwatt proposed, and will be doing a comparison this week. Sure Vegetarians will hate it, but to nail down a water soluble method that does not include nasty tasting cyclodextrin will help many, in my opinion.

Cheers
A