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 β-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_AGLand RES_GLU also displayed sudden increases in plasma concentrations 4 to 8 h after oral administration, withT_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 μmol·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.