Repeat Dose Study of the Cancer Chemopreventive Agent Resveratrol in Healthy Volunteers: Safety, Pharmacokinetics, and Effect on the Insulin-like Growth Factor Axis

Abstract

Resveratrol, a naturally occurring polyphenol, has cancer chemopreventive properties in preclinical models. It has been shown to downregulate the levels of insulin-like growth factor-1 (IGF-I) in rodents. The purpose of the study was to assess its safety, pharmacokinetics, and effects on circulating levels of IGF-I and IGF-binding protein-3 (IGFBP-3) after repeated dosing. Forty healthy volunteers ingested resveratrol at 0.5, 1.0, 2.5, or 5.0 g daily for 29 days. Levels of resveratrol and its metabolites were measured by high performance liquid chromatography-UV in plasma obtained before and up to 24 hours after a dose between days 21 and 28. IGF-I and IGFBP-3 were measured by ELISA in plasma taken predosing and on day 29. Resveratrol was safe, but the 2.5 and 5 g doses caused mild to moderate gastrointestinal symptoms. Resveratrol-3-O-sulfate, resveratrol-4′-Oglucuronide, and resveratrol-3-O-glucuronide were major plasma metabolites. Maximal plasma levels and areas under the concentration versus time curve for the metabolites dramatically exceeded those for resveratrol, in the case of areas under the concentration versus time curve, by up to 20.3-fold. Compared with predosing values, the ingestion of resveratrol caused a decrease in circulating IGF-I and IGFBP-3 (P < 0.04 for both), respectively, in all volunteers. The decrease was most marked at the 2.5 g dose level. The results suggest that repeated administration of high doses of resveratrol generates micromolar concentrations of parent and much higher levels of glucuronide and sulfate conjugates in the plasma. The observed decrease in circulating IGF-I and IGFBP-3 might contribute to cancer chemopreventive activity. Cancer Res; 70(22); 9003-11. ©2010 AACR.

Endocytosis of Resveratrol via Lipid Rafts and Activation of Downstream Signaling Pathways in Cancer Cells

“…Mechanisms responsible for the resveratrol chemopreventive and chemosensitization properties are poorly known in tumor cells, but evidence indicates that resveratrol uptake and the cancer microenvironment plasma membrane play a key role in these processes. Here, we show that resveratrol activates MAPK pathways to induce apoptosis both in colon carcinoma cell lines and in leukemic lymphoma cells but not in normal cells such as human normal monocytes or rat nontransformed intestinal cells in accordance with recent phase I/ II trials showing the absence of resveratrol toxicity (28). The inhibition of resveratrol-induced apoptosis by monensin in tumor cells suggests a clathrin-independent endocytosis of the compound.…”

Piceatannol, Natural Polyphenolic Stilbene, Inhibits Adipogenesis via Modulation of Mitotic Clonal Expansion and Insulin Receptor-dependent Insulin Signaling in Early Phase of Differentiation

“…For example, oral administration of a single high dose of resveratrol (100 mg/kg) in mice with or without piperine (10 mg/kg) supplementation resulted in a dramatic increase in maximum plasma resveratrol concentration from 10 to 154 M (63). Furthermore, a repeated dose of resveratrol up to 5 g/day, which is equivalent to ϳ85 mg/kg for a 60-kg man, has been shown to be safe in humans (64). Because piceatannol is often compared with resveratrol due to their similar chemical structures, these studies underscore the importance of the development of a novel piceatannol formulation that would allow us to overcome its poor solubility and bioavailability in vivo, thereby achieving elevated plasma concentration of piceatannol for exerting its maximum health benefit.…”

Resveratrol and health – A comprehensive review of human clinical trials

“…The greatest plasma trans-resveratrol concentrations have been reported by Boocock et al [29] and Brown et al [30], both of whom supplemented humans with up to 5 g trans-resveratrol. 5 g trans-resveratrol as a single dose resulted in a 24 h mean plasma concentration of 51.9 mg/L 24 h after administration, with a C max of 538.8 mg/ L attained 1.5 h after administration.…”

“…The CV for C max was large, similar to that reported by Boocock et al, ranging from 40 to 113%. Although C max was not reported following initial dose, data from Brown et al [30] demonstrate that this occurs at higher dosages as well. Following 29 days of 5 g trans-resveratrol administration, Brown et al [30] found plasma C max to be 958.6 mg/L.…”