Preclinical Pharmacokinetic Evaluation of Resveratrol Trimethyl Ether in Sprague-Dawley Rats: The Impacts of Aqueous Solubility, Dose Escalation, Food and Repeated Dosing on Oral Bioavailability

J Pharm Sci. 2011 Oct;100(10):4491-500. doi: 10.1002/jps.22588. Epub 2011 Apr 24.

Abstract

Resveratrol trimethyl ether (trans-3,5,4'-trimethoxystilbene, RTE) is a naturally occurring and pharmacologically active resveratrol derivative. To evaluate its suitability as a drug candidate, a pharmacokinetic study was carried out in Sprague-Dawley rats with the emphasis to identify the impact of aqueous solubility, dose escalation, food, and repeated dosing on its oral bioavailability. Upon single intravenous administration (5 mg/kg), RTE displayed moderate clearance (35.5 ± 5.3 mL/min/kg) and a fairly long terminal elimination half-life (511 ± 136 min); dose escalation (5-20 mg/kg) did not cause nonlinear pharmacokinetics. When given orally in suspension (60 mg/kg), RTE was poorly absorbed with negligible bioavailability (< 1.5%), fasting further decreased its bioavailability (<1%). However, when administered in a solution formulated with randomly methylated-β-cyclodextrin (15 mg/kg), RTE was rapidly absorbed with good bioavailability (46.5 ± 4.8%). Dose escalation resulted in increased bioavailability (64.6 ± 8.0%) at the dose of 60 mg/kg. Repeated RTE dosing (7 daily oral doses) did not alter the clearance, terminal elimination half-life and bioavailability. In summary, the aqueous solubility of RTE was a barrier to oral absorption; repeated RTE administrations did not alter its pharmacokinetic profiles; as RTE possessed appropriate pharmacokinetic profiles, further investigation on RTE as a drug candidate is warranted.

Keywords: Bioavailability; Cyclodextrins; Dose proportionality; Oral absorption; Pharmacokinetics; Repeated dosing; Resveratrol; Resveratrol trimethyl ether; Solubility.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Administration, Oral
  • Animals
  • Area Under Curve
  • Biological Availability
  • Chemistry, Pharmaceutical
  • Drug Administration Schedule
  • Excipients / chemistry
  • Gastrointestinal Absorption
  • Half-Life
  • Male
  • Metabolic Clearance Rate
  • Models, Biological
  • Rats, Sprague-Dawley
  • Solubility
  • Stilbenes / administration & dosage*
  • Stilbenes / chemistry
  • Stilbenes / pharmacokinetics*
  • Technology, Pharmaceutical / methods
  • beta-Cyclodextrins / chemistry

Substances

  • 3,4',5-trimethoxystilbene
  • Excipients
  • Stilbenes
  • beta-Cyclodextrins
  • methyl-beta-cyclodextrin