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 -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 RE-S AGL and RES GLU were determined using an electrospray ionization-liquid chromatography/tandem mass spectrometry method. After i.v. administration, plasma concentrations of RE-S 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 mol⅐ h/l). Enterohepatic recirculation was confirmed in the linked-rat model since significant plasma concentrations of RES AGL and RES GLU were observed in bilerecipient 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.Interest in the study of phenolic compounds present in red wine has grown since epidemiological studies have shown an inverse correlation between red wine consumption and the incidence of cardiovascular diseases (Nanji and French, 1986;Hegsted and Ausman, 1988). Resveratrol (3,5,4Ј-trihydroxystilbene), a molecule from the viniferin family of polymers, was identified as a biologically active compound in red wine in 1992 (Siemann and Creasy, 1992). Since then, numerous in vivo and in vitro studies have assessed the ability of resveratrol in preventing multiple pathophysiological processes. Resveratrol has the ability to inhibit the peroxidation of lipid membranes (Fauconneau et al., 1997), to decrease the concentration of low-and very-low-density lipoproteins (Frankel et al., 1993), and to inhibit platelet aggregation (Kimura et al., 1985), three conditions that help prevent cardiovascular diseases. Although significant estrogenic-like activity of resveratrol has been demonstrated in vitro (Gehm et al., 1997;Bhat et al., 2001), this was not proven in vivo in rats (Turner et al., 1999). Finally, trans-resveratrol was shown to have cancer chemoprotective properties and to induce apoptosis in leukemia and human breast carcinom...
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