betadex and 3-4--5-trimethoxystilbene

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.

Topics: Administration, Intravenous; Administration, Oral; Animals; Area Under Curve; beta-Cyclodextrins; Biological Availability; Chemistry, Pharmaceutical; Drug Administration Schedule; Excipients; Gastrointestinal Absorption; Half-Life; Male; Metabolic Clearance Rate; Models, Biological; Rats, Sprague-Dawley; Solubility; Stilbenes; Technology, Pharmaceutical

E-3,5,4'-trimethoxystilbene (TMS) is a naturally occurring analog of resveratrol. The anti-neoplastic, antiallergic and anti-angiogenic activities of TMS have been recently reported. From the viewpoint of metabolism, TMS may be more favourable than resveratrol because all of its hydroxyl groups, which are subjected to extensive glucuronide or sulphate conjugation in the metabolic pathways of resveratrol, are protected by methylation. Moreover, methylation increases lipophilicity and may enhance cell membrane permeability, but it decreases its solubility in aqueous media. A way to increase TMS solubility can be represented by complexation with beta-cyclodextrins. In the present paper, the differential scanning calorimetry technique has been used to study the interaction of TMS with a biomembrane model constituted by dimyristoylphosphatidylcholine multilamellar vesicles. Furthermore, kinetic experiments have been carried out to follow the uptake of TMS by biomembranes in the presence of beta-cyclodextrins to gain information on the effect of beta-cyclodextrins on the uptake process. Our results indicate that opportune concentrations of beta-cyclodextrins greatly improve the uptake of TMS by biomembrane models.

Topics: Antineoplastic Agents; beta-Cyclodextrins; Calorimetry, Differential Scanning; Cell Membrane; Dimyristoylphosphatidylcholine; Permeability; Solubility; Stilbenes