Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats

Abstract

Purpose-Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a naturally occurring polyphenol with a broad range of possible health benefits, including anti-cancer activity. However, the biological activity of resveratrol may be limited by poor absorption and first-pass metabolism: only low plasma concentrations of resveratrol are seen following oral administration, and metabolism to glucuronide and sulfate conjugates is rapid. Methylated polyphenol analogs (such as pterostilbene [3,5-dimethoxy-4′-hydroxy-trans-stilbene], the dimethylether analog of resveratrol) may overcome these limitations to pharmacologic efficacy. The present study was designed to compare the bioavailability, pharmacokinetics, and metabolism of resveratrol and pterostilbene following equimolar oral dosing in rats.Methods-The agents were administered orally via gavage for 14 consecutive days at 50 or 150 mg/kg/day for resveratrol and 56 or 168 mg/kg/day for pterostilbene. Two additional groups were dosed once intravenously with 10 and 11.2 mg/kg for resveratrol and pterostilbene, respectively. Plasma concentrations of agents and metabolites were measured using a high-pressure liquid chromatograph-tandem mass spectrometer system. Noncompartmental analysis was used to derive pharmacokinetic parameters.Results-Resveratrol and pterostilbene were approximately 20 and 80% bioavailable, respectively. Following oral dosing, plasma levels of pterostilbene and pterostilbene sulfate were markedly greater than were plasma levels of resveratrol and resveratrol sulfate. Although plasma levels of resveratrol glucuronide exceeded those of pterostilbene glucuronide, those differences were smaller than those of the parent drugs and sulfate metabolites.Conclusions-When administered orally, pterostilbene demonstrates greater bioavailability and total plasma levels of both the parent compound and metabolites than does resveratrol. These differences in agent pharmacokinetics suggest that the in vivo biological activity of equimolar doses of pterostilbene may be greater than that of resveratrol.

The R2R3-MYB Transcription Factors MYB14 and MYB15 Regulate Stilbene Biosynthesis in Vitis vinifera

“…Therefore, a comparative transcriptome analysis of transgenic MYB15 and GFP:GUS grapevine hairy roots could lead to the identification of genes involved in stilbene modification and transport. The analysis of these unknown enzymes would expand our knowledge of the stilbene biosynthetic pathway in plants and would be valuable tools for the pharmacological industry exploring modified resveratrol derivatives and their beneficial effect on human health (Mikulski and Molski, 2010;Agarwal and Baur, 2011;Kapetanovic et al, 2011). Quantitative variation of polyphenol levels, including anthocyanins and stilbenes, has been detected for different grapevine cultivars and susceptibility to fungal diseases has been correlated to the content and composition of the stilbene derivatives (Pezet et al, 2004).…”

Pterostilbene attenuates acute kidney injury in septic mice

“…And it has been suggested that the in vivo biological activity of equimolar doses of Pte may be greater than that of resveratrol (6), and the antioxidant activity of Pte are superior to resveratrol due to its higher lipophilicity, which increases its ability to be absorbed compared to resveratrol (6). Studies have demonstrated that resveratrol has salutary effect on sepsis-induced multiple organ dysfunction, such as myocardial depression (7), AKI (8)(9)(10).…”

Involvement of the Nrf2 Pathway in the Regulation of Pterostilbene-Induced Apoptosis in HeLa Cells via ER Stress

“…Since sub stitution of a hydroxy group by a methoxy group increases the transport into cells and increases the metabolic stability of Pte (Fig. 1a), it show higher biological activity based on relatively higher bioavailability compared to resveratrol (42). Different published data in vitro show that Pte has a potent activity with lower toxicity in various cancer types at concentration ranges from 0 to 100 mM (A375, A549, HT29, MCF7, NCI-H460, SK-MES-1) (22,43,44).…”