x
The chemical structure of resveratrol leads to low water solubility (<0.05 mg/mL), which affects its absorption. In order to increase its solubility, ethanol (50 mg/mL) or organic solvents may be used. It is important to highlight the ability of resveratrol to form a wide range of organic molecular complexes. Sterification of hydroxyl groups with aliphatic molecules can also be employed as a tool to increase its intestinal absorption and cellular permeability. For example, resveratrol acetylation can increase its absorption and its cellular capture without loss of activity.
At the intestinal level, resveratrol is absorbed by passive diffusion or forming complexes with membrane transporters, such as integrins. Once in the bloodstream, resveratrol can be found essentially in three different forms: glucuronide, sulfate, or free. The free form can be bound to albumin and lipoproteins such as LDL (low-density lipoprotein). These complexes, in turn, can be dissociated at cellular membranes that have receptors for albumin and LDL, leaving the resveratrol free and allowing it to enter cells. Resveratrol's affinity for albumin suggests that it could be a natural polyphenolic reservoir, playing an important role in its distribution and bioavailability.
Due to its chemical characteristics, resveratrol can interact with fatty acids. Recent studies in vitro show that more than 90% of free trans-resveratrol binds to human plasma lipoproteins. This binding is also found in vivo, as shown by the presence of dietary polyphenolic compounds detected in isolated LDL in blood samples of healthy human volunteers. Fatty acids facilitate a lipophilic environment, which favors resveratrol binding. Normally they are employed as vectors because of their high affinity for the liver and their efficient cellular uptake, resulting from specific interactions with transmembrane transporters.
Phase II metabolism of resveratrol or its metabolites occurs in liver. There is enterohepatic transport in bile, which may result in some returning cycles to the small intestine. Furthermore, resveratrol is able to induce its own metabolism, increasing the activity of phase II hepatic detoxifying enzymes.
Resveratrol has a high metabolism, leading to the production of conjugated sulfates, glucuronides, which retain some biological activity, and up to five different metabolites present in the urine: resveratrol monosulfate, two isomeric forms of resveratrol monoglucuronide, monosulfate dihydroresveratrol, and monoglucuronide dihydroresveratrol. However, the nature and quantity of these metabolites can differ between subjects due to interindividual variability.
Resveratrol metabolites.
Cis-metabolites have been identified in human urine samples, mainly as cis-resveratrol-4′-sulfate, cis-resveratrol-3-O-glucuronide, and cis-resveratrol-4′-O-glucuronide. Most research has been performed with trans-isomer due to the instability of cis-isomer. However, data indicate that both of them can have different biological effects. Other dietary flavonoids, such as quercetin, may inhibit resveratrol sulphation and glucuronidation in the liver and duodenal tissue, increasing its bioavailability.
Resveratrol exhibits lipophilic characteristics, which lead to a high absorption. However, it should be noted that resveratrol absorption can vary depending on the way it is consumed and the kind of food ingested. Low bioavailability of resveratrol is a factor that may reduce the efficacy of resveratrol. Although in vitro studies show a high efficacy in biologically beneficial effects of resveratrol in cells, it is known that its distribution in tissues is very low. Consequently, in vitro studies must be interpreted with caution when trying to extrapolate its effect in in vivo studies.
Despite its low bioavailability, resveratrol shows efficacy in vivo. This may be explained by the conversion of both sulfates and glucuronides again to resveratrol in target organs such as the liver Another possible explanation could be the enterohepatic recirculation of resveratrol metabolites, followed by its deconjugation in the small intestine and its reabsorption Finally, in vivo effects could be explained by the activity of its metabolites. Glucuronidation of the cis-form is faster (5–10 times) than that of the trans-form, thus leading to a lower bioavailability of the cis-form. The presence of hydroxyl groups allows polyphenols to associate with proteins and other nutrients. The solubility of these compounds determines its physiological effects. Thus, complexes including these macronutrients and polyphenols, which maintain solubility, can be absorbed in the small intestine, while insoluble complexes are eliminated in feces, reducing their availability.
Two of the first human studies on the absorption and bioavailability of resveratrol used a single oral dose treatment of 25 mg. Despite the use of high sensitivity methods and a specific molecular analysis, it was difficult to detect the nonmetabolized resveratrol in circulating plasma. Approximate calculations showed maximal concentrations of <10 ng/mL (≈40 nM), 0.5–2 hours after the oral dose. Estimates of the plasmatic concentrations of resveratrol plus total metabolites were considerably higher, around 400–500 ng/mL (≈2 μM), indicating a very low oral bioavailability of free resveratrol, but a significant one of its metabolites. Urinary excretion of total metabolites after a radio-labeled dose was administered showed that about 75% of orally or intravenously administered resveratrol was absorbed. This is an unusually high absorption for a dietary polyphenol, particularly in view of the poor aqueous solubility of this compound.
Several approaches have been used to increase the bioavailability of resveratrol in humans. The dose concentration curve seems to be a logical method, and it has been examined in two studies, with a dose range from 25 to 1000 mg. covering the wide range used in chemoprevention studies. The absorption in these cases reached a maximum of between 0.3 and 2.4 μM, which does not reach the anticancer properties found at concentrations higher than 5 μM. Furthermore, in these studies an increase in the bioavailability of resveratrol during the treatment was found and a lack of metabolism saturation with the highest concentrations (500 mg/mL). Nevertheless, other studies in rats, which were administered resveratrol for 15–20 weeks, showed that a saturation of metabolites exists, and it leads to an increase of resveratrol in plasma and thus in tissues. A pharmacokinetic study of repeated doses over two days concludes that tolerance is good, concentrations in plasma do not increase over time and even decrease, and the bioavailability is higher when administered in the morning.
Vitaglione et al. carried out an interesting study on the bioavailability of free trans-resveratrol present in red wine in humans. Subjects were randomly divided into three experimental groups, consuming different types of food and red wine. The first group consumed 300 mL of red wine with a free trans-resveratrol content of 0.82 mg/L with a meal consisting of beef, egg, bread, corn oil, and French fries. The second group consumed 600 mL of red wine containing 3.2 mg/L free trans-resveratrol while fasting (before breakfast). Lastly, the third group consumed two different meals with different lipid content and 600 mL of red wine, which assured a free trans-resveratrol total ingestion of 0.48 mg. The authors concluded that the kind of food does not affect resveratrol bioavailability and found much variability between individuals. However, these results are inconsistent with those of other studies, in which a high-fat meal decreased its absorption. Thus, we conclude that the different sample processing methods and the kind of analysis are the key to detect both free or conjugated resveratrol.
Read next article at: https://markethive.com/group/ama/blog/properties-of-resveratrol-in-vitro-and-in-vivo-studies-about-metabolism-bioavailability-and-biological-effects-in-animal-models-and-humans-p3
Read previous article at: https://markethive.com/group/ama/blog/properties-of-resveratrol-in-vitro-and-in-vivo-studies-about-metabolism-bioavailability-and-biological-effects-in-animal-models-and-humans--p1
Posted by
Chuck Reynolds
The reasoning for this article is in part to bring awareness of the Amazing qualities of what Amazingrape can do for you. It is a very helpful supplemental product. It can help you and others as well. You can make alot of money with this business or just be a customer for a very satisfying experience.
There is a video (4 of them, very short (total less then 5 min)) that explains how simple this business works. Check them out then if so inclined, click on my name above and sign up either as a Customer or Distributor.
Thank You
Chuck
