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Resveratrol Delivery

By Liji Thomas, MD

With all the hype surrounding resveratrol’s anti-aging effects,  a central problem remains, namely, its poor bioavailability. Different approaches have been taken to solve this problem, but not all have been tested in human beings. This is another reason why resveratrol supplements are of doubtful value in the present scenario.

Resveratrol bioavailability depends on the dose administered. Resveratrol is quickly cleared from the plasma via biological enzyme activity, in the form of sulfates and glucuronides. The extent of activity of these metabolites is not well-known, though currently it is thought that they are less active than the drug itself, in most settings.

Resveratrol is a small, non-polar molecule and is freely absorbed across the small intestine, mostly in combination with an ATP-dependent binding cassette protein transporter.

Resveratrol administered in combination with food

Some evidence shows that resveratrol taken in combination with a standard breakfast increases the concentration in blood. However, a high-fat diet actually reduces the absorption.

Resveratrol in micronized form has a much increased absorption. One study showed a four-fold increase in plasma concentration, a doubling of the time to maximum plasma concentration, indicating a prolonged exposure, and a nearly five-fold increase in the area under the curve (AUC) which corresponds to greater bioavailability, with the use of the 5 g dose in micronized form.

Resveratrol administration in combination with other plant polyphenols or other compounds found in red wine itself was thought to increase the absorption. While grape juice increases the time to clearance most of all, it has not been shown to improve the absorption over red wine or other juices.

Resveratrol in combination with other compounds which share the same enzymes would have the theoretical advantage of escaping first-pass metabolism in the liver following intestinal absorption, because the metabolizing enzymes would be saturated with the other polyphenols. Piperine, the active compound found in pepper, increased the levels of resveratrol in blood by a thousand times in rats and delayed the formation of one of its major metabolites. However, this has not been proved experimentally in humans, though the brain blood level of resveratrol was shown to increase.

The use of prodrugs has been attempted in rodents, though not in humans, using the resveratrol prodrug  taRES, which showed an increase in bioavailability over the drug itself at comparable concentrations.

Nano-technology has brought promising results in rat trials, with the use of resveratrol nano-particles in various formulations. Such formulations show increased stability and bioavailability. It also prevents metabolism and so increases tissue availability. Especially in the liver, brain and kidney, it improves tissue concentrations. This includes lipid-mounted, solid or albumin-mounted nanoparticles. However, human study evidence is still lacking.

Sublingual or buccal capsules also have a higher absorption rate compared to oral administration. Encapsulation is also a viable way to achieve stability, and higher bioavailability. Grape skin extract and grape seed oil can be encapsulated to form a stable and spontaneous nanoemulsion, which has also been used as a delivery system.

Intravenous bolus doses not only achieved a higher plasma concentration than oral, but produced acute changes in renal blood flow and other metabolic parameters, indicating their promise in various clinical fields.

Resveratrol implants which release the drug over a long period of time were also found to achieve a longer time of exposure to the drug. Hydrogels have also been studied as the vehicles for resveratrol absorption through the skin, and their viscosity determines the rate of permeation of the drug.

Resveratrol stents have been studied, and shows some indications of usefulness in promoting healing of the injured arterial wall, as well as inhibiting stent closure after angioplasty and stenting. In contrast to other drug-eluting stents like Taxol or rapamycin-releasing devices, resveratrol does not inhibit healing and thus presents an advantage in preventing late thrombosis due to the persistence of unhealed intimal tissue in the coronary circulation.

Overall, it needs to be remembered that the bioavailability of resveratrol in blood is not limited by the plasma concentration. The amount of resveratrol delivered to various tissues is also important in measuring its absorption and tissue exposure.

References

Further Reading

Last Updated: May 25, 2015

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