title: Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model.
abstract: Pharmacokinetics of trans-resveratrol in its aglycone (RES(AGL)) and glucuronide (RES(GLU)) forms were studied following intravenous (15 mg/kg i.v.) and oral (50 mg/kg p.o.) administration of trans-resveratrol in a solution of beta-cyclodextrin to intact rats. In addition, the enterohepatic recirculation of RES(AGL) and RES(GLU) was assessed in a linked-rat model. Multiple plasma and urine samples were collected and concentrations of RES(AGL) and RES(GLU) were determined using an electrospray ionization-liquid chromatography/tandem mass spectrometry method. After i.v. administration, plasma concentrations of RES(AGL) declined with a rapid elimination half-life (T(1/2), 0.13 h), followed by sudden increases in plasma concentrations 4 to 8 h after drug administration. These plasma concentrations resulted in a significant prolongation of the terminal elimination half-life of RES(AGL) (T(1/2TER), 1.31 h). RES(AGL) and RES(GLU) also displayed sudden increases in plasma concentrations 4 to 8 h after oral administration, with T(1/2TER) of 1.48 and 1.58 h, respectively. RES(AGL) bioavailability was 38% and its exposure was approximately 46-fold lower than that of RES(GLU) (AUC(inf), 7.1 versus 324.7 micromol.h/l). Enterohepatic recirculation was confirmed in the linked-rat model since significant plasma concentrations of RES(AGL) and RES(GLU) were observed in bile-recipient rats at 4 to 8 h. The percentages of the exposures of RES(AGL) and RES(GLU) that were due to enterohepatic recirculation were 24.7 and 24.0%, respectively. The fraction of drug excreted in the urine over a period of 12 h was negligible. These results confirm that RES(AGL) is bioavailable and undergoes extensive first-pass glucuronidation, and that enterohepatic recirculation contributes significantly to the exposure of RES(AGL) and RES(GLU) in rats.
authors.affiliation: Pharmacokinetics and Pharmacodynamics, MDS Pharma Services, 1350 Cohen Street, St-Laurent (Montreal), Quebec, Canada H4R 2N6.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Marier
authors.forename: Pascal
authors.initials: P
authors.lastname: Vachon
authors.forename: Ari
authors.initials: A
authors.lastname: Gritsas
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Moreau
authors.forename: Murray P
authors.initials: MP
authors.lastname: Ducharme
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D004764:Enterohepatic Circulation; D020719:Glucuronides / Q000378:metabolism; D007408:Intestinal Absorption; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013267:Stilbenes / Q000378:metabolism / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D020719:Glucuronides; D013267:Stilbenes; D000077185:Resveratrol