title: Analytical method development for synthesized conjugated metabolites of trans-resveratrol, and application to pharmacokinetic studies.
abstract: Trans-3,5,4'-trihydroxystilbene (trans-resveratrol, RES) exhibits very low bioavailability due to extensive conjugative metabolism. Whether RES metabolites exhibit pharmacologic activity is of great interest. The present study aimed at synthesis of monoconjugates of RES - the 3- and 4' monosulfates (R3S and R4'S), and the 3- and 4' monoglucuronides (R3G and R4'G). Synthesis, purification, and yield are described. Synthesized metabolites were utilized to develop a sensitive LC-MS(n) assay for direct quantitation of all analytes. The assay was validated for intra- and inter-day precision and accuracy. Synthesis of RES conjugates and development and validation of a sensitive bioanalytical assay were applied to pharmacokinetic evaluation of RES and its circulating monoconjugates in C57BL mice. The study is a first report of direct quantitation of RES monosulfates and monoglucuronides. These results will aid in characterizing the disposition of RES and its major or active metabolites in vivo.
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
authors.forename: Otito F
authors.initials: OF
authors.lastname: Iwuchukwu
authors.forename: Satish
authors.initials: S
authors.lastname: Sharan
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Canney
authors.forename: Swati
authors.initials: S
authors.lastname: Nagar
mesh_terms: D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D002853:Chromatography, Liquid / Q000592:standards; D020719:Glucuronides / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D007269:Injections, Intra-Arterial; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D012015:Reference Standards; D015203:Reproducibility of Results; D000077185:Resveratrol; D021241:Spectrometry, Mass, Electrospray Ionization / Q000592:standards; D013267:Stilbenes / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D013431:Sulfates / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry / Q000592:standards
chemical_list: D020719:Glucuronides; D013267:Stilbenes; D013431:Sulfates; C499731:resveratrol-4'-O-glucuronide; D000077185:Resveratrol