title: Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases--safety, pharmacokinetics, and pharmacodynamics.
abstract: The phytochemical resveratrol has undergone extensive preclinical investigation for its putative cancer chemopreventive properties. Low systemic availability of the parent compound due to rapid and extensive metabolism may confound its usefulness as a potential agent to prevent malignancies in organs remote from the site of absorption. Micronization allows increased drug absorption, thus increasing availability. Here we describe a pilot study of SRT501, micronized resveratrol, given as 5.0 g daily for 14 days, to patients with colorectal cancer and hepatic metastases scheduled to undergo hepatectomy. The purpose of the study was to assess the safety, pharmacokinetics, and pharmacodynamics of the formulation. SRT501 was found to be well tolerated. Mean plasma resveratrol levels following a single dose of SRT501 administration were 1,942 ± 1,422 ng/mL, exceeding those published for equivalent doses of nonmicronized resveratrol by 3.6-fold. Resveratrol was detectable in hepatic tissue following SRT501 administration (up to 2,287 ng/g). Cleaved caspase-3, a marker of apoptosis, significantly increased by 39% in malignant hepatic tissue following SRT501 treatment compared with tissue from the placebo-treated patients. SRT501 warrants further clinical exploration to assess its potential clinical utility.
authors.affiliation: Cancer Biomarkers and Prevention Group, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK. lh28@le.ac.uk
authors.forename: Lynne M
authors.initials: LM
authors.lastname: Howells
authors.forename: D P
authors.initials: DP
authors.lastname: Berry
authors.forename: P J
authors.initials: PJ
authors.lastname: Elliott
authors.forename: E W
authors.initials: EW
authors.lastname: Jacobson
authors.forename: E
authors.initials: E
authors.lastname: Hoffmann
authors.forename: B
authors.initials: B
authors.lastname: Hegarty
authors.forename: K
authors.initials: K
authors.lastname: Brown
authors.forename: W P
authors.initials: WP
authors.lastname: Steward
authors.forename: A J
authors.initials: AJ
authors.lastname: Gescher
mesh_terms: D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D003131:Combined Modality Therapy / Q000379:methods; D004311:Double-Blind Method; D005260:Female; D006498:Hepatectomy / Q000379:methods; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010865:Pilot Projects; D010919:Placebos; D011183:Postoperative Complications; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014025:Titanium / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D010919:Placebos; D013267:Stilbenes; C009495:titanium dioxide; D014025:Titanium; D053148:Caspase 3; D000077185:Resveratrol