18 replies to this topic

[stephen_b]

I'd like to explore the absorption issue around delivery to the blood or to the lymph system and hopefully learn something in the process.

Lots of effort has gone into achieving high blood plasma levels of resveratrol, often involving making it more water soluble by the addition of things like lecithin and micronization. Levels of resveratrol in blood plasma have been used as a measure of bioavailability. I wonder if this is a fair test for lipophilic resveratrol.

In a Grouppe Kurosawa press release, Dr. Steve brings up a point that I find very interesting:

“Most of the natural medicine supplements sold in the US are total garbage. Many of these so-called natural remedies are not standardized. You have no idea what you are taking. The other problem is bioavailability. Many of the active ingredients are not soluble in water. They form clumps in the GI tract and pass right through the body. We are constantly working to enhance the bioavailability of these natural medicine compounds by dissolving them in fat compounds such as coconut milk, a great carrier of natural medicines and drugs into the lymphatic system. The lymphatic system is exactly where you want to target these medicines because lymph fluid bathes all the cells in the body.

According to the wikipedia article:

MCTs passively diffuse from the GI tract to the portal system (longer fatty acids are absorbed into the lymphatic system) without requirement for modification like long chain fatty acids or very long chain fatty acids do. In addition MCTs do not require bile salts for digestion. ... Coconut oil is composed of approximately 66% Medium chain triglycerides...

So, what is the fate of lipophilic molecules like resveratrol and curcumin that are dissolved in coconut milk? Presumably, some of it goes into the lymphatic system and some to the hepatic portal system. The hepatic portal system sends it right to the liver where it is processed before going to the heart. The liver would see a bunch of resveratrol in a short amount of time this way.

Another portion would presumably go into the lymphatic system:

While most other nutrients absorbed by the small intestine are passed on to the portal venous system to drain, via the portal vein, into the liver for processing, fats (lipids) are passed on to the lymphatic system, to be transported to the blood circulation via the thoracic duct. The enriched lymph originating in the lymphatics of the small intestine is called chyle. As the blood circulates, fluid leaks out into the body tissues. This fluid is important because it carries food to the cells and waste back to the bloodstream. The nutrients that are released to the circulatory system are processed by the liver, having passed through the systemic circulation. The lymph system is a one-way system, transporting interstitial fluid back to blood.

From this description it seems to me that the liver only sees the lymph (and substances dissolved in it) after it has passed through the body tissues.

If so, then blood plasma measurements of resveratrol delivered via a water soluble route measure all of the resveratrol available to the tissues. Blood plasma levels of resveratrol that has passed through the lymphatic system measure the leftover resveratrol in the blood after resveratrol has bathed the tissues via the lymphatic system.

StephenB

[Anthony_Loera]

If Medium Chain Triglycerides are key...

The Licaps based capsules all use and have this as part of the formula, just check the label.

Cheers
A

Edited by Anthony_Loera, 20 July 2009 - 04:33 PM.

[stephen_b]

MCT oils would seem to fast-track resveratrol to the liver via the portal system.

I know that you have tests showing very high peak levels of resveratrol in plasma for your licaps product. Perhaps this level is actually attained after first pass through the liver.

If the hypothesis (that the best bioavailability is attained through lymphatic transport) is correct, then a long chain oil such as olive oil might be better. I think that this could be tested by looking at how tissues react to each delivery system rather than just resveratrol blood levels.

By the way Anthony, you should look into a licaps based micronized curcumin product too.

Edited by stephen_b, 24 July 2009 - 04:07 PM.

[Anthony_Loera]

By the way Anthony, you should look into a licaps based micronized curcumin product too.

Hi Stephen,

Sounds good, but let me get the Quercetin licaps product out first...

Cheers!
A

[Joey]

I'd like to explore the absorption issue around delivery to the blood or to the lymph system and hopefully learn something in the process.

Lots of effort has gone into achieving high blood plasma levels of resveratrol, often involving making it more water soluble by the addition of things like lecithin and micronization. Levels of resveratrol in blood plasma have been used as a measure of bioavailability. I wonder if this is a fair test for lipophilic resveratrol.

In a Grouppe Kurosawa press release, Dr. Steve brings up a point that I find very interesting:

According to the wikipedia article:
So, what is the fate of lipophilic molecules like resveratrol and curcumin that are dissolved in coconut milk? Presumably, some of it goes into the lymphatic system and some to the hepatic portal system. The hepatic portal system sends it right to the liver where it is processed before going to the heart. The liver would see a bunch of resveratrol in a short amount of time this way.

Another portion would presumably go into the lymphatic system:

From this description it seems to me that the liver only sees the lymph (and substances dissolved in it) after it has passed through the body tissues.

If so, then blood plasma measurements of resveratrol delivered via a water soluble route measure all of the resveratrol available to the tissues. Blood plasma levels of resveratrol that has passed through the lymphatic system measure the leftover resveratrol in the blood after resveratrol has bathed the tissues via the lymphatic system.

StephenB

According to some MD's all forms of Omega-3 fatty acids(triglycerides, phospholipids, ethyl esters) are equally absorbed & bioavailable. However based on the fact that only the long chain triglycerides are absorbed through the lymphatic system, these triglycerides, in my layman's view, have three advantages whose importance I am not able to judge:
- they avoid the initial first pass in the liver & may increase the half life(not by much for buccal resveratrol which also tries to circumvent the liver)
- they are likely to have a wider body distribution
- they are bathing the lymph nodes which may be significant in fighting diseases progressing through nodes (Omega-3 fatty acids have been shown to cause reduction of node size in mice with the equivalent of metastatic breast cancer).

The ethyl esters can be produced to about 85% purity while the highest purity for heat distilled triglycerides is about 60% (40% EPA, 20% DHA)

Regarding coconut milk I do not believe it helps very much the absorption of such things as curcumin. First because not much curcumin disolves in the milk & second because the milk does not have much long chain omega-3's. A few modified versions of curcumin with higher gut absorption have recently been developed & are mentioned in an other forum.

[stephen_b]

Joey, my thoughts on absorption of lipophilic drugs have been trending along the same lines.

I found this study interesting (PMID 10906731):

The contribution of lymphatic transport and absorption directly into the portal blood to the overall oral bioavailability of a model lipophilic drug, halofantrine (Hf), was determined in lymph-cannulated, conscious, unrestrained rats after administration in lipidic vehicles with different fatty acid chain lengths. Both lymphatic transport (C(18)-based vehicle, 15.8% of dose > C(8-10), 5. 5% > C(4), 2.22% > C(0), 0.34%) and total systemic exposure (C(18), 22.7% of dose > C(8-10), 19.2% > C(4), 15.2% > C(0), 6.4%) of Hf were enhanced by the presence of lipids in the formulation and specifically by an increase in the fatty acid chain length of the coadministered lipid. Increases in lymphatic drug transport appeared to correlate with increases in lymphatic lipid transport. Surprisingly, where lymphatic transport was the primary mechanism of drug transport to the systemic circulation (i.e., after administration in a C(18)-based lipid vehicle), Hf bioavailability assessed in nonlymph-cannulated animals was lower than the extent of total availability measured in lymph-cannulated animals (estimated as percent appearing in the intestinal lymph plus percent transported directly into the blood), suggesting either presystemic drug clearance within the lymphatics or an altered systemic clearance pattern for lymphatically transported drug.

The long chain fatty acid resulted in the highest bioavailability of the drug, and the drug seems to have been chosen because it is a good model for lipophilic drugs in general.

From this google book snippet from "Models for assessing drug absorption and metabolism" (xxxx):

Drugs which reach the systemic circulation via the lymphatic system avoid the first pass metabolic processes associated with absorption via the portal blood. This can lead to changes in the proportion of metabolite relative to parent if the extent of drug absorption via the portal blood and intestinal lymphatic transport changes in response to the administered formulation. A candidate drug must be extremely lipophilic for lymphatic transport to be a major contributor to oral bioavailability, and consequently the use of lipophilic prodrugs can be a useful strategy to facilitate the passage of some compounds into the lyphatics. This strategy becomes particularly attractive for compounds whose site of action is located within the lymphatic system.

StephenB

[JLL]

Regarding coconut milk I do not believe it helps very much the absorption of such things as curcumin. First because not much curcumin disolves in the milk & second because the milk does not have much long chain omega-3's.

Haven't tried it with pure curcumin, but turmeric dissolves nicely in coconut milk if it's warm/hot. Plus heating curcumin further improves its bioavailability. But yeah, that may not matter if long chain omega-3's are needed.

[niner]

A candidate drug must be extremely lipophilic for lymphatic transport to be a major contributor to oral bioavailability

This is a problem for resveratrol, as it is not extremely lipophilic. It has a logP of ~3, which is modestly lipophilic. I would expect on this basis that lymphatic transport would be only a minor contributor to oral bioavailability.

[stephen_b]

A candidate drug must be extremely lipophilic for lymphatic transport to be a major contributor to oral bioavailability

This is a problem for resveratrol, as it is not extremely lipophilic. It has a logP of ~3, which is modestly lipophilic. I would expect on this basis that lymphatic transport would be only a minor contributor to oral bioavailability.

Interesting. Unfortunately the paper didn't quantify what it meant by 'extremely lipophilic'. Can you explain the scale? I'd be interested in seeing where other supplements (like curcumin) fall on it.

Edited by stephen_b, 04 August 2009 - 04:35 PM.

[niner]

A candidate drug must be extremely lipophilic for lymphatic transport to be a major contributor to oral bioavailability

This is a problem for resveratrol, as it is not extremely lipophilic. It has a logP of ~3, which is modestly lipophilic. I would expect on this basis that lymphatic transport would be only a minor contributor to oral bioavailability.

Interesting. Unfortunately the paper didn't quantify what it meant by 'extremely lipophilic'. Can you explain the scale? I'd be interested in seeing where other supplements (like curcumin) fall on it.

Sure,

LogP is the log (base 10) of the partition coefficient of the compound between water and n-octanol. (Well, that clears it up, eh?) More explanation: If you take a liter of water and a liter of n-octanol (an oil), add a small quantity of the compound you are testing, and shake them together for a long time until everything comes to equilibrium, the compound will be found upon analysis to be almost all in the water if it is very hydrophilic, or almost all in the oil if it is very hydrophobic. If it is intermediate, you'll find some of the compound in both phases. If you divide the concentration in the oil phase by the conc. in the water phase, you will get a partition coefficient P, and the log of it is logP. A logP of 3 means that for every 1 unit of the compound found in the water, there will be 10**3 = 1000 units in the oil. That probably sounds extremely hydrophobic, but as drug-sized molecules go, it's moderate. An extreme value would be (IMHO) above 5-ish, but ultimately, it's not clear what their definitions might have been. For that matter, there probably is some lymphatic transport with resveratrol; it's just not clear that it would be a huge effect. An ideal log P for an orally bioavailable drug would be around 1.5 to 2, but there's more to bioavailability than log P, and there's lots of drugs that are outside that range. Curcumin would be around 2.5 on this scale. Acetone is -0.23, hexane is 3.9, Cimetidine is 0.4. Log P becomes somewhat meaningless if the molecule is ionizable. If you have a full charge on a molecule, that can pull it into water very effectively.

[stephen_b]

A logP of 3 means that for every 1 unit of the compound found in the water, there will be 10**3 = 1000 units in the oil. That probably sounds extremely hydrophobic, but as drug-sized molecules go, it's moderate.

You're right, it does sound fairly hydrophobic. If a resveratrol molecule ends up in oil 1000 more often than water, won't 99.9% of it go with the oil? I could live with the 0.1% loss.

I tried an experiment: I mixed up a coupe of tablespoons of olive oil and 500 mg of 99% t-res. I added the mixture to lecithin and water. I was surprised to see how much the oil was dispersed in the lecithin water. I see that Twinlab's Emulsified Norwegian Cod Liver Oil product "is emulsified with natural soy lecithin and apple pectin making the EPA and DHA more readily available to the digestive system for better absorption, assimilation and utilization".

It seems that the mechanical spreading out of the oil is what makes it more bioavailable. Apple or citrus pectin is another interesting option. Carlson Labs uses apple pectin to disperse their 25,000 IU vitamin A product.

StephenB

Edited by stephen_b, 04 August 2009 - 09:52 PM.

[niner]

A logP of 3 means that for every 1 unit of the compound found in the water, there will be 10**3 = 1000 units in the oil. That probably sounds extremely hydrophobic, but as drug-sized molecules go, it's moderate.

You're right, it does sound fairly hydrophobic. If a resveratrol molecule ends up in oil 1000 more often than water, won't 99.9% of it go with the oil? I could live with the 0.1% loss.

I tried an experiment: I mixed up a coupe of tablespoons of olive oil and 500 mg of 99% t-res. I added the mixture to lecithin and water. I was surprised to see how much the oil was dispersed in the lecithin water. I see that Twinlab's Emulsified Norwegian Cod Liver Oil product "is emulsified with natural soy lecithin and apple pectin making the EPA and DHA more readily available to the digestive system for better absorption, assimilation and utilization".

It seems that the mechanical spreading out of the oil is what makes it more bioavailable. Apple or citrus pectin is another interesting option. Carlson Labs uses apple pectin to disperse their 25,000 IU vitamin A product.

Did the resveratrol dissolve in the olive oil? I tried that once, and was surprised at how insoluble in the olive oil it was. I'm still not sure what was going on there. Maybe I should have heated it. Lecithin is an emulsifier, so it should be good at getting oil and water to mix.

[niner]

I did a little poking around on the topic of lymphatic transport to try to get a sense of the log P requirements. Generally speaking, they look pretty high. CoQ10 has a log P of 9.9, and 70% of its oral bioavailability is lymphatic. Cyclosporine, on the other hand, has a log P of ~3, and only ~2% of the absorbed dose is transported lymphatically. This was from Lymphatic Transport of Drugs, by Charman and Stella. They say:

A common characteristic of lymphatically transported drugs and xenobiotics is their lipophilicity, generally typified by a large partition coefficient between and organic solvent, such as n-octanol and an aqueous phase (e.g., logarithm of partition coefficients at least 5 or 6 at physiological pH). A high partition coefficient of a drug is required, but not necessarily sufficient, for ensuring significant intestinal lymphatic drug transport.

So their call is a log P of 5 or 6.

[stephen_b]

After thinking a bit more on this, I have to wonder if they are considering the medium the lipophilic drugs are mixed in; perhaps the claim in regards to needing extreme lipophilicity to enter into the lymphatic system is for the drug taken orally by itself.

We already have a study showing that longer chain fatty acids get into the lymph system and that lymphatic drug transport correlates with increases in lipids. If those lipids (like olive oil) are making it into the lymphatic system, then for the drugs dissolved in them not to make it in, there would have to be some sort of mechanism to separate the drugs from the fats.

[niner]

After thinking a bit more on this, I have to wonder if they are considering the medium the lipophilic drugs are mixed in; perhaps the claim in regards to needing extreme lipophilicity to enter into the lymphatic system is for the drug taken orally by itself.

We already have a study showing that longer chain fatty acids get into the lymph system and that lymphatic drug transport correlates with increases in lipids. If those lipids (like olive oil) are making it into the lymphatic system, then for the drugs dissolved in them not to make it in, there would have to be some sort of mechanism to separate the drugs from the fats.

They do consider the medium, and even in a case like cyclosporin where the amount that is transported lymphatically is pretty small, there is still a significant effect of the medium on bioavailability, varying by a factor of two from best to worst lipid. Triglycerides like olive or coconut oils actually don't solvate very well. The log P is a little deceptive in that octanol, chloroform, or other organic solvents that are used for log P measurements solvate hydrophobes better than the triglycerides do, even though you might think they would be equivalent. While the oils do get into the lymphatic system, particularly if you consume a lot of them, there is also the potential for the drug to partition out of the triglyceride before that happens.

The news isn't all bad though; considering the example of cyclosporine, with a log P about the same as resveratrol, suggests that we could get a couple percent of the absorbed resveratrol into the lymphatic system, and thereby dodge first-pass metabolism. Given how efficient the liver is at gobbling up resveratrol, this might end up significantly improving the level of free resveratrol in plasma, at least for the few minutes it would take to get back to the liver on the second pass. I don't know which oil would be best at this. The Pfizer guys seem to be in favor of MCTs, which would argue for coconut oil. I think I'll give this a try, since I love the taste of coconut oil, and I haven't tried it yet as a resveratrol solvent.

[Joey]

A logP of 3 means that for every 1 unit of the compound found in the water, there will be 10**3 = 1000 units in the oil. That probably sounds extremely hydrophobic, but as drug-sized molecules go, it's moderate.

You're right, it does sound fairly hydrophobic. If a resveratrol molecule ends up in oil 1000 more often than water, won't 99.9% of it go with the oil? I could live with the 0.1% loss.

I tried an experiment: I mixed up a coupe of tablespoons of olive oil and 500 mg of 99% t-res. I added the mixture to lecithin and water. I was surprised to see how much the oil was dispersed in the lecithin water. I see that Twinlab's Emulsified Norwegian Cod Liver Oil product "is emulsified with natural soy lecithin and apple pectin making the EPA and DHA more readily available to the digestive system for better absorption, assimilation and utilization".

It seems that the mechanical spreading out of the oil is what makes it more bioavailable. Apple or citrus pectin is another interesting option. Carlson Labs uses apple pectin to disperse their 25,000 IU vitamin A product.

StephenB

Speaking of dispersion, I wonder what contribution to absorption of any fat (& drug in oil) in the gut, would result of supplementing with digestive enzymes such as lipase. Those individuals whose gallbladder has been surgically removed because of gallstone related problems often suffer from digestion discomfort when consumming fatty meals. The insufficient bile flow continually released by the liver does not fully compensate for the missing spurts of gallbladder bile. For these people taking digestive enzymes shortly before meals improves their well being & perhaps prevents deficiencies in fat soluble vitamins such as E,A,D,K.
Could these supplements be also beneficial in people with normal functioning gallbladder trying to improve absorption of some drugs or supplements including omega-3's? Or would this be overkill?

[Anthony_Loera]

By the way Anthony, you should look into a licaps based micronized curcumin product too.

Hi Stephen,

Sounds good, but let me get the Quercetin licaps product out first...

Cheers!
A

StephenB,

Just a quick update to your suggestion, we are finished with the MCT Quercetin (it's scheduled to be bottled soon) and I am now checking into the best curcumin raw material supplier to provide with MCT.

Cheers
A

Edited by Anthony_Loera, 18 September 2009 - 12:34 PM.

[stephen_b]

Nice Anthony, I look forward to it coming out.

[Anthony_Loera]

Quick update.

MCT Quercetin is available, and MCT Super Curcumin is being bottled....

Cheers
A