Repeat Dose Study of the Cancer Chemopreventive Agent Resveratrol in Healthy Volunteers: Safety, Pharmacokinetics and Effect on the Insulin-like Growth Factor Axis
By V. Brown, K. Patel, M. Viskaduraki, J. Crowell, M. Perloff, T. Booth, G. Vasilinin, Ananda Sen, A. Schinas, G. Piccirilli and 4 more. Cancer Research, 2010
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Resveratrol, a naturally occurring polyphenol, has cancer chemopreventive properties in preclinical models. It has been shown to downregulate levels of insulin-like growth factor-1 (IGF-1) in rodents. The purpose of the study was to assess its safety, pharmacokinetics and effects on circulating levels of IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) after repeated dosing. Forty healthy volunteers ingested resveratrol at 0.5, 1.0, 2.5 or 5.0g daily for 29 days. Levels of resveratrol and its metabolites were measured by HPLC-UV in plasma obtained before and up to 24h after a dose between days 21 and 28. IGF-1 and IGFBP-3 were measured by enzyme-linked immunosorbent assay in plasma taken pre-dosing and on day 29. Resveratrol was safe, but the 2.5 and 5g 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 (AUC) for the metabolites dramatically exceeded those for resveratrol, in the case of the AUC by up to 20.3-fold. Ingestion of resveratrol caused a decrease in circulating IGF-1 and IGFBP-3 (P<0.04 for both), respectively, compared to pre-dosing values, in all volunteers. At the 2.5g dose level the decrease was most marked. 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-1 and IGFBP-3 may contribute to cancer chemopreventive activity.
Subfields: Endocrinology, Diabetes and Metabolism, Geriatrics and Gerontology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/f406fa639c849f13e694bdb0235d1a8f98779a65
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Citations in the corpus
- Resveratrol: A Double-Edged Sword in Health Benefits (2018, background): “5 g or more per day, side effects may occurs, like nausea, vomiting, diarrhea and liver dysfunction in patients with non-alcoholic fatty liver disease [140].”
- Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats (2010, background): “However, two very recent references reported data suggesting that biologically active concentrations of resveratrol and/or metabolites may be achievable in human subjects on chronic dosing [8, 22].”
- Resveratrol and health--a comprehensive review of human clinical trials. (2011, background): “[30], both of whom supplemented humans with up to 5 g trans-resveratrol.”
- The Role of Resveratrol in Cancer Therapy (2017, background): “5 g/day for 29 days resulted in a reduction of the circulating levels of IGF-1 and IGFBP-3 in healthy volunteers [335].”
- Potential Adverse Effects of Resveratrol: A Literature Review (2020, background): “This advances the notion that RE has chemopreventive activities [172].”