Thomas Walle and colleagues at the University of South Carolina confirm that a minimum of 70 percent of oral resveratrol, as a small molecule, is absorbed in the human digestive tract, but thereafter most resveratrol in blood plasma is conjugated with (complexed with) sulfur and glucuronic acid as it passes through the liver.
[Drug Metabolism Disposition 32:1377–82, 2004]
Pharm Res. 2006 Sep;23(9):2107-15. Epub 2006 Aug 9. Links
Increased transport of resveratrol across monolayers of the human intestinal Caco-2 cells is mediated by inhibition and saturation of metabolites.
………….. PURPOSE: The study's aim was to investigate the dose-dependent effect of sulfation and glucuronidation on intestinal absorption of resveratrol, a dietary constituent found in grapes and various medical plants. MATERIALS AND METHODS: The intestinal epithelial membrane transport kinetics and metabolism of resveratrol (10-200 microM) was studied using Caco-2 monolayers cultured in Transwells.
RESULTS: Along with resveratrol it was possible to identify three metabolites, namely, resveratrol-4'-O-glucuronide (M1), resveratrol 3-O-gucuronide (M2), and resveratrol-3-O-sulfate (M3) by LC/MS and NMR.
Efflux of the glucuronides M1 and M2 followed Michaelis-Menten kinetics significantly favouring basolateral efflux. The predominant metabolite was the monosulfate M3, however, its formation was strongly inhibited at higher resveratrol concentrations. As biotransformation was either inhibited or saturated, total amount of resveratrol transported across the Caco-2 monolayers increased as much as 3.5-fold at 200 microM resveratrol. This value might be even higher when taking into account the high intracellular concentration of resveratrol, which accounted for up to 61% of the applied dose. CONCLUSIONS: Our data demonstrate a concentration-dependent biotransformation of resveratrol in Caco-2 cells, which may also apply to human enterocytes affecting oral bioavailability.
Researchers at the Institute of Human Virology, University of Maryland Biotechnology Institute, have written an extensive report describing the biological aspects of liver metabolism and resveratrol. Here is an excerpt paraphrased from their paper:
What is the biological function of glucuronidation of resveratrol in humans? What is the real bioactive form of resveratrol in living organisms? …There are examples showing that liver metabolism (glucuronidation) has a role in drug disposition and drug targeting in humans. It is known that beta-glucuronidase, the enzyme that breaks down glucuronide, is widely expressed in organs, tissues, and body fluids in humans. Therefore, this enzyme may release a drug or bound molecule like resveratrol locally or systemically from a glucuronide conjugate (such as resveratrol glucuronide)
. In fact, many glucuronide prodrugs have been designed and are under development that bind a synthetic drug molecule to glucuronide which subsequently depends upon the beta-glucuronidase enzyme to release it into living tissues. Therefore, it is likely that at least a portion of resveratrol is unzipped from its protective carrier by the glucuronidase enzyme and could be converted back to free resveratrol. Since tissue or serum beta-glucuronidase enzyme activity is elevated in certain diseased tissues, such as cancer, liver diseases, and AIDS, resveratrol would be targeted and released more so in these tissues than in healthy ones. Researchers state that “these observations… raise the possibility that glucuronidation of resveratrol may have a role in detoxification, disposition, and prolongation of the effectiveness of resveratrol in humans.”
[Journal Pharm Science 93:2448–2457, 2004]