Comparison of the pharmacokinetic and pharmacodynamic profiles of resveratrol at dietary and pharmacological doses
thesisposted on 2012-03-28, 13:21 authored by Edwina Nga-Wing Scott
Epidemiological and preclinical studies suggest that dietary-derived cancer chemopreventive agents may be active at dietary and supra-dietary doses. This project therefore investigated the effect of dose on the pharmacokinetic and pharmacodynamic actions of resveratrol, a polyphenol found in grapes. An achievable dietary intake (5 mg/day in humans) and a supra-dietary dose, previously used in clinical trials, were compared in preclinical systems, in healthy volunteers and in patients. Accelerator mass spectrometry (AMS) was used in the clinical part of this project as its sensitivity allowed the safe administration of radiolabelled resveratrol to participants. In vitro microarray results from human colon HCA7 cancer cells showed that resveratrol exposure for 3 months at 0.01 μM, the estimated plasma level in man after an oral 5 mg dose, altered the apoptosis, glucose transport and cell adhesion pathways. Resveratrol exposure at 1.4 μM, the plasma Cmax value in man after a 1 g dose, did not significantly alter any pathways. The equivalent doses, determined by conversion by body weight and resulting in the same tissue levels as in man, were administered to ApcMin+/- mice. Resveratrol reduced the tumour burden at a dietary dose in the presence of a high fat diet, but this was not seen when administered with a standard fat diet, nor at supra-dietary doses. The mechanisms of actions of resveratrol in vivo were unclear. Clinically, oral administration of [14C]-resveratrol resulted in detectable levels in plasma, colon and prostate tissue even at the 5 mg dose. The metabolite profiles were similar between prostate tissue and plasma, with metabolites predominating. Overall, these results suggest that the dose-response relationship of resveratrol may be biphasic or U-shaped. The confirmation of detectable levels of resveratrol and its metabolite in prostate and colon tissue suggest that resveratrol could exert pharmacodynamic actions in these organs.