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

Abstract

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 5ng/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±17.7ml/min/kg) and a relatively prolonged terminal elimination half-life (t1/2 λz) of 351±180min. Aqueous solubility played a crucial role in the oral absorption of DFS. When DFS was given as a suspension (6mg/kg), the absolute oral bioavailability (F) was almost negligible. However, when DFS was given in a solution prepared with hydroxypropyl-β-cyclodextrin (6mg/kg), the F was 12.4±10.7%. Dose-escalation to 15mg/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. © 2012 Elsevier B.V.