Quantification of trans-2,6-difluoro-4'-N,N-dimethylaminostilbene in rat plasma: application to a pharmacokinetic...

trans-2,6-Difluoro-4'-N,N-dimethylaminostilbene (DFS), a synthetic stilbene, displayed potent pre-clinical anti-cancer activities exceeding that observed for naturally occurring resveratrol. In this study, a simple and sensitive HPLC method was developed and validated to quantify DFS in rat plasma. The lower limit of quantification (LLOQ) was 5 ng/ml. The intra- and inter-day variation in terms of relative standard deviation (RSD) was all less than 10%. The bias rate ranged from -11.5% to 6.2% while the absolute recovery ranged from 94.1 ± 2.3 to 97.3 ± 4.4%. The pharmacokinetic profiles of DFS were examined in Sprague-Dawley rats after intravenous administration (2 mg/kg). DFS displayed moderate clearance (Cl=61.5 ± 17.7 ml/min/kg) and a relatively prolonged terminal elimination half-life (t(1/2 λz)) of 351 ± 180 min. Aqueous solubility played a crucial role in the oral absorption of DFS. When DFS was given as a suspension (6 mg/kg), the absolute oral bioavailability (F) was almost negligible. However, when DFS was given in a solution prepared with hydroxypropyl-β-cyclodextrin (6 mg/kg), the F was 12.4 ± 10.7%. Dose-escalation to 15 mg/kg resulted in much higher systemic exposure (F=40.2 ± 10.0%). As DFS is orally available after formulation with hydroxypropyl-β-cyclodextrin and pharmacologically active systemic concentrations could be achieved after a single oral dose, the use of DFS as a cancer chemopreventive/chemotherapeutic agent is possible.