Resveratrol - Pharmacokinetics

Pharmacokinetics

One way of administering resveratrol in humans may be buccal delivery, that is without swallowing, by direct absorption through tissues on the inside of the mouth. When one milligram of resveratrol in 50 ml 50% alcohol/ water solution was retained in the mouth for one minute before swallowing, 37 ng/ml of free resveratrol were measured in plasma two minutes later. This level of unchanged resveratrol in blood can only be achieved with 250 mg of resveratrol taken in a pill form. However, the viability of a buccal delivery method is called into question due to the low aqueous solubility of the molecule. For a drug to be absorbed transmucosally it must be in free-form or dissolved. Resveratrol fits the criteria for oral transmucosal dosing, except for this caveat. The low aqueous solubility greatly limits the amount that can be absorbed through the buccal mucosa, which is why the method has not been explored further. All resveratrol that is attempted to be taken buccaly will fail to pass through the mucous membrane of the mouth and be absorbed as an oral dose, however, a need to explore buccal delivery in future pharmaceutical formulations has been expressed.

While 70% of orally administered resveratrol absorbed its oral bioavailability is aproximately 1% due to extensive hepatic gluconuridation and sulfation. Only trace amounts (below 5 ng/ml) of unchanged resveratrol could be detected in the blood after 25 mg oral dose. Even when a very large dose (2.5 and 5 g) was given as an uncoated pill, the concentration of resveratrol in blood failed to reach the level claimed to be necessary for the systemic cancer prevention. A formulation of resveratrol in a chewing gum form is now in production, and this would be expected to achieve much higher blood levels than oral formulations. Resveratrol given in a proprietary formulation SRT-501 (3 or 5 g), developed by Sirtris Pharmaceuticals, reached five to eight times higher blood levels. These levels did approach the concentration necessary to exert the effects shown in animal models and in vitro experiments. On May 5, 2010, however, GlaxoSmithKline (GSK) said it had suspended a small clinical trial of SRT501, a proprietary form of resveratrol, due to safety concerns, and terminated the study on December 2, 2010. Sirtris Pharmaceuticals, which U.K.-based GlaxoSmithKline bought for $720 million in 2008, was developing the drug. GlaxoSmithKline is now focusing its efforts on more potent and selective SIRT1 activators—SRT2104 and SRT2379—both of which are involved in several exploratory clinical trials.

Full formal pharmacokinetics of oral resveratrol 2000 mg twice daily in humans, studying interaction with concurrent ethanol, quercetin, and fat meal has been published. Mean peak serum resveratrol concentration was 1274 ng/ml at steady-state, which was reduced 46% by a fat meal at dosing. There was no effect of concurrent oral quercetin or ethanol. Healthy volunteers had frequently reported minor diarrhea, and laboratory measures identified slight changes in liver function tests and in serum potassium. No adverse effect on renal function was identified, although only eight healthy adults were observed in the two-week study.

In humans and rats less than 5% of the oral dose was observed as free resveratrol in blood plasma. The most abundant resveratrol metabolites in humans, rats, and mice are trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate. Walle suggests sulfate conjugates are the primary source of activity, Wang et al. suggests the glucuronides, and Boocock et al. also emphasized the need for further study of the effects of the metabolites, including the possibility of deconjugation to free resveratrol inside cells. Goldberd, who studied the pharmacokinetics of resveratrol, catechin and quercetin in humans, concluded "it seems that the potential health benefits of these compounds based upon the in vitro activities of the unconjugated compounds are unrealistic and have been greatly exaggerated. Indeed, the profusion of papers describing such activities can legitimately be described as irrelevant and misleading. Henceforth, investigations of this nature should focus upon the potential health benefits of their glucuronide and sulfate conjugates."

The hypothesis that resveratrol from wine could have higher bioavailability than resveratrol from a pill has been refuted by experimental data. For example, after five men took 600 ml of red wine with the resveratrol content of 3.2 mg/l (total dose about 2 mg) before breakfast, unchanged resveratrol was detected in the blood of only two of them, and only in trace amounts (below 2.5 ng/ml). Resveratrol levels appeared to be slightly higher if red wine (600 ml of red wine containing 0.6 mg/ml resveratrol; total dose about 0.5 mg) was taken with a meal: trace amounts (1–6 ng/ml) were found in four out of ten subjects. In another study, the pharmacokinetics of resveratrol (25 mg) did not change whether it was taken with vegetable juice, white wine, or white grape juice. The highest level of unchanged resveratrol in the serum (7–9 ng/ml) was achieved after 30 minutes, and it completely disappeared from blood after four hours. The authors of both studies concluded the trace amounts of resveratrol reached in the blood are insufficient to explain the French paradox. The beneficial effects of wine apparently could be explained by the effects of alcohol or the whole complex of substances wine contains; for example, the cardiovascular benefits of wine appear to correlate with the content of procyanidins.