Quantification of Resveratrol Analogs trans-2,3-dimethoxystilbene and trans-3,4-dimethoxystilbene in Rat Plasma: Application to Pre-clinical Pharmacokinetic Study

trans-2,3-Dimethoxystilbene (2,3-DMS) and trans-3,4-dimethoxystilbene(3,4-DMS) are two synthetic resveratrol (trans-3,5,4'-trihydroxystilbene) analogs. In thisstudy, a simple HPLC method was developed and validated to determine 2,3-DMS and3,4-DMS in rat plasma. Chromatographic separation was obtained with a reversed-phaseHPLC column through a 12.5-min gradient delivery of a mixture of acetonitrile and waterat the flow rate of 1.5 mL/min at 50 °C. The lower limit of quantification was 10 ng/mL.After successful validation, the pharmacokinetic profiles of 2,3-DMS and 3,4-DMS weresubsequently studied in Sprague-Dawley rats. Upon single intravenous administration(4 mg/kg), 2,3-DMS had a medium volume of distribution of the central compartment(Vc = 2.71 ± 0.51 L/kg), quite rapid clearance (Cl = 52.0 ± 7.0 mL/min/kg), moderate meantransit time (MTT0→last = 131.0 ± 4.5 min) but a fairly long terminal elimination half-life(t1/2 λZ = 288.9 ± 92.9 min). Interestingly, 3,4-DMS displayed a pharmacokinetic profileapparently distinct from 2,3-DMS and it had more extensive distribution (Vc = 5.58 ±1.73 L/kg), faster clearance (Cl = 143.4 ± 40.5 mL/min/kg) and shorter residence(MTT0→last = 61.4 ± 27.1 min). Following single oral administration (10 mg/kg), 2,3-DMShad low and erratic plasma exposure (Cmax = 37.5 ± 23.7 ng/mL) and poor oral bioavailability(2.22% ± 2.13%) while the oral bioavailability of 3,4-DMS was even poorer than 2,3-DMS.Clearly, the location of the methoxy groups had a significant impact on the pharmacokineticsof resveratrol analogs. This study provided useful information for the design of resveratrolderivatives in future study