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'-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.

Trial registration: ClinicalTrials.gov NCT00098969.

Figure 1

Mean plasma concentrations of resveratrol (A),resveratrol-4′-O-glucuronide (B), resveratrol-3-O-glucuronide (C) and resveratrol-3-O-sulfate (D) versus time in healthy volunteers after the last of between 21 and 28 daily doses of resveratrol at either 0.5g (black, closed circles), 1g (green, open circles), 2.5g (blue, squares) or 5g (red, triangles). Values are the mean±SD of 10 volunteers per dose level. The range of coefficients of variation (as % of the mean) for the individual data points is shown in brackets.

Figure 2

Relationship between dose of resveratrol and maximal plasma concentration (C_max) (A) or area under the plasma concentration versus time curve (AUC_last) (B) for resveratrol (black, rhombi), resveratrol-4′-O-glucuronide (red, squares), resveratrol-3-O-glucuronide (green, triangles) and resveratrol-3-O-sulfate (blue, crosses) in healthy volunteers, after a dose of resveratrol at either 0.5, 1, 2.5 or 5g ingested on between day 21 and 28 of daily dosing. Values are the mean of 10 volunteers for each dose level. The range of coefficients of variation (as % of the mean) for individual data points is shown in brackets.

Figure 3

Circulating levels of IGF-1 (A) and IGFBP-3 (B) in individual healthy volunteers before and after consumption of resveratrol at 0.5, 1.0, 2.5 or 5.0g daily for 28 days. Results of the statistical analysis by paired t-test, i.e. mean differences between pre- and post-intervention levels (pre minus post values in ng/mL), 95% confidence intervals (in brackets) and P values, are shown for each group of 10 individuals below the graphs. Negative values signify an increase rather than decrease in levels. Blood samples were taken just prior to the first dose of resveratrol and on day 29.

Figure 4

Maximal plasma concentrations (C_max) of resveratrol (A), resveratrol-4′-O-glucuronide (B), resveratrol-3-O-glucuronide (C) and resveratrol-3-O-sulfate (D) in healthy volunteers who received either a single dose (open bars) or between 21 and 28 daily doses (closed bars) of resveratrol at either 0.5, 1, 2.5 or 5 g. Single dose results have been published previously (9). Values are the mean+SD of 10 volunteers at each dose level. Asterisks indicate *P<0.05,**P=0.01, ***P=0.001 and ****P<0.0005.