title: 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.
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.
authors.affiliation: Department of Pharmacy, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260. phalh@nus.edu.sg.
authors.forename: Hai-Shu
authors.initials: HS
authors.lastname: Lin
authors.forename: Paul C
authors.initials: PC
authors.lastname: Ho
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D004334:Drug Administration Schedule; D005079:Excipients / Q000737:chemistry; D065569:Gastrointestinal Absorption; D006207:Half-Life; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013267:Stilbenes / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D013678:Technology, Pharmaceutical / Q000379:methods; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: C497286:3,4',5-trimethoxystilbene; D005079:Excipients; D013267:Stilbenes; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin