title: 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 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.
authors.affiliation: Department of Pharmacy, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore. phalh@nus.edu.sg
authors.forename: Hai-Shu
authors.initials: HS
authors.lastname: Lin
authors.forename: Vitaliy M
authors.initials: VM
authors.lastname: Sviripa
authors.forename: David S
authors.initials: DS
authors.lastname: Watt
authors.forename: Chunming
authors.initials: C
authors.lastname: Liu
authors.forename: Tian-Xiang
authors.initials: TX
authors.lastname: Xiang
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Anderson
authors.forename: Pei Shi
authors.initials: PS
authors.lastname: Ong
authors.forename: Paul C
authors.initials: PC
authors.lastname: Ho
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D006207:Half-Life; D007262:Infusions, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013267:Stilbenes / Q000097:blood* / Q000493:pharmacokinetics*; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D013267:Stilbenes; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin