title: Absorption and metabolism of resveratrol carboxyesters and methanesulfonate by explanted rat intestinal segments.
abstract: Model prodrugs of resveratrol carrying protecting substituents at the hydroxyls have been synthesised and tested. Resveratrol triacetate and resveratrol-tri-mPEG(1900) were formed by linking methyl groups or poly(ethylene glycol) chains, respectively, via carboxyester bonds. Resveratrol trimesylate, a molecule less susceptible to hydrolytic attack, was synthesised as well. This latter compound proved to be stable in vitro, while the carboxyester derivatives were slowly hydrolysed in solutions mimicking the gastric or intestinal environment, and rapidly converted to resveratrol in blood. In ex vivo permeation experiments with explanted intestinal segments, resveratrol and its triacetate derivative appeared in the basolateral compartment essentially as a mixture of Phase II metabolites. When the PEGylated derivative was provided on the apical side, unconjugated resveratrol accounted for about 50% of the compounds in the basolateral-side chamber. The same result was obtained by providing an equivalent physical mixture of resveratrol and PEG polymer, indicating that this behaviour is likely due to an adjuvating effect of PEG rather than to the covalent polymer conjugation. These observations suggest that the ester derivatives are rapidly hydrolysed at the intestinal surface or inside enterocytes, and are then processed as resveratrol. On the other hand, the mesylate was transported from the apical to the basolateral side without modification. It may thus be possible to enhance absorption and hinder metabolism of natural polyphenols by constructing pro-drugs incorporating bonds with appropriate resistance to enzymatic hydrolysis.
authors.affiliation: Department of Experimental Biomedical Sciences, University of Padova, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Biasutto
authors.forename: Ester
authors.initials: E
authors.lastname: Marotta
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattarei
authors.forename: Silvia
authors.initials: S
authors.lastname: Beltramello
authors.forename: Paolo
authors.initials: P
authors.lastname: Caliceti
authors.forename: Stefano
authors.initials: S
authors.lastname: Salmaso
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnurch
authors.forename: Spiridione
authors.initials: S
authors.lastname: Garbisa
authors.forename: Mario
authors.initials: M
authors.lastname: Zoratti
authors.forename: Cristina
authors.initials: C
authors.lastname: Paradisi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D000077185:Resveratrol; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011355:Prodrugs; D013267:Stilbenes; D011092:Polyethylene Glycols; D000077185:Resveratrol