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'-O-glucuronide, 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.