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

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...

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Published in:	Cancer research (Chicago, Ill.) Vol. 70; no. 22; pp. 9003 - 9011
Main Authors:	BROWN, Victoria A, PATEL, Ketan R, BROWN, Karen, STEWARD, William P, GESCHER, Andreas J, BRENNER, Dean E, VISKADURAKI, Maria, CROWELL, James A, PERLOFF, Marjorie, BOOTH, Tristan D, VASILININ, Grygoriy, SEN, Ananda, SCHINAS, Anna Maria, PICCIRILLI, Gianfranca
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 15-11-2010
Subjects:	Abdominal Pain - chemically induced Adult Antineoplastic agents Antineoplastic Agents, Phytogenic - adverse effects Antineoplastic Agents, Phytogenic - metabolism Antineoplastic Agents, Phytogenic - pharmacokinetics Area Under Curve Biological and medical sciences Chromatography, High Pressure Liquid Diarrhea - chemically induced Dose-Response Relationship, Drug Enzyme-Linked Immunosorbent Assay Glucuronides - blood Glucuronides - metabolism Humans Insulin-Like Growth Factor Binding Protein 3 - blood Insulin-Like Growth Factor I - metabolism Medical sciences Metabolic Clearance Rate Middle Aged Nausea - chemically induced Pharmacology. Drug treatments Resveratrol Stilbenes - adverse effects Stilbenes - blood Stilbenes - metabolism Stilbenes - pharmacokinetics Tumors Young Adult Human Healthy subject Toxicity Anticarcinogen Stilbene derivatives Multiple dose Insulin like growth factor Polyphenol Phytoalexin Resveratrol Phenols Safety Pharmacokinetics
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Summary:	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.
ISSN:	0008-5472 1538-7445
DOI:	10.1158/0008-5472.can-10-2364