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 ␤-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...

Trans-resveratrol self-nano-emulsifying drug delivery system (SNEDDS) with enhanced bioavailability potential: optimization, pharmacokinetics andin situsingle pass intestinal perfusion (SPIP) studies

“…Much higher values of the absorptivity parameters from OPT formulation can be ascribed to the transport of drug via lymphatic pathways, in accordance with an earlier literature report (Sun et al, 2011). The existence of enterohepatic circulation and extensive first-pass metabolism by CYP3A4 in liver has been documented as the plausible cause for low oral bioavailability of t-RVT (Marier et al, 2002;Amri et al, 2012). Marked enhancement in the effective permeability, a direct measure of absorption across the intestine (Bandyopadhyay et al, 2012), of the SNEDDS clearly demonstrates that the OPT formulation was able to augment drug absorption in rat.…”

“…Second peak at 2 h indicates enterohepatic recirculation of the drug that has been well documented and enterohepatic recirculation is susceptible to circadian variation (Almeida et al, 2009) (as is evident from Figure 4 where two peaks of C max and T max were observed). A major portion of the bile acids secreted are reabsorbed from the intestines and returned via the portal circulation to the liver, thus completing the enterohepatic cycle (Marier et al, 2002). The parent compound and its conjugated metabolite undergo enterohepatic recirculation, resulting in multiple peaks in the plasma concentration-time profile.…”

“…trans-resveratrol (t-RVT), chosen in the present study is a BCS class II drug with poor water-solubility and high permeability (log P of 3.1) (Amri et al, 2012). Besides these, it undergoes rapid first-pass metabolism by CYP3A4 in the liver and suffers enterohepatic recirculation (Marier et al, 2002;, leading eventually to marked reduction in the drug oral bioavailable fraction (almost zero) in humans and animals like rats (Amri et al, 2012). Under the aforementioned circumstances, various formulation approaches of t-RVT have been reported, such as liposome (Hung et al, 2006), solid dispersions (Wegiel et al, 2013), b-cyclodextrins inclusion complex (TrochePesqueira et al, 2013), microspheres (Nam et al, 2005), suspensions, but all with limited fruition.…”

Pharmacokinetics in mice and growth-inhibitory properties of the putative cancer chemopreventive agent resveratrol and the synthetic analogue trans 3,4,5,4′-tetramethoxystilbene

“…The discrepancy between resveratrol and DMU 212 in concentration achieved in the small intestine and colon may be a corollary of their differential metabolic susceptibilities. The lower availability of resveratrol compared to DMU 212 may be the consequence of the high propensity of resveratrol to undergo conjugation reactions catalysed by enzymes (De Santi et al, 2000;Kuhnle et al, 2000;Marier et al, 2002), which are abundantly present in the gut (Eisenhofer et al, 1999). In contrast, on the basis of the fact that activities of oxidising enzymes in the gut are much lower than in the liver (Doherty and Charman, 2002), the ability of the gut mucosa to O-demethylate or hydroxylate DMU 212 is arguably much lower than its ability to biotransform resveratrol by conjugation.…”

“…As is the case with many polyphenols with putative cancer chemopreventive properties, the systemic bioavailability of resveratrol is probably poor. This notion is borne out by studies in mice, rats and dogs, which suggest consistently that resveratrol is well absorbed but avidly glucuronidated and sulphated both in the liver and in intestinal epithelial cells (Asensi et al, 2002;Juan et al, 2002;Marier et al, 2002). One study in humans also hints at a poor bioavailability of resveratrol (Goldberg et al, 2003).…”