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.

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Abbreviations

EDTA:

Ethylenediaminetetraacetic acid

QC:

Quality control

MP:

Mobile phase

LLOQ:

Lowest limit of quantitation

Tmax :

Time to maximum plasma concentration

Cmax :

Peak plasma concentration

AUC:

Area under the curve

t½ :

Elimination half-life

CL:

Clearance

Vss :

Apparent volume of distribution

F%:

Percent bioavailability

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Acknowledgments

These studies were supported by contract number N01-CN-43304 from the National Cancer Institute, Department of Health and Human Services. The authors thank Leigh Ann Senoussi for assistance in preparing the manuscript.

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Correspondence to Miguel Muzzio.

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Kapetanovic, I.M., Muzzio, M., Huang, Z. et al. Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemother Pharmacol 68, 593–601 (2011). https://doi.org/10.1007/s00280-010-1525-4

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Keywords

  • Resveratrol
  • Pterostilbene
  • Pharmacokinetics
  • Bioavailability
  • Metabolites
  • Rat