trans-4,4'-Dihydroxystilbene (DHS) is a naturally occurring resveratrol analog that displayed promising anti-cancer activities in pre-clinical studies. To further probe its therapeutic potential, a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the measurement of DHS in rat plasma using electrospray ionization and multiple reaction monitoring in its negative ion mode. This analytical method demonstrated excellent linearity (R(2) > 0.99), selectivity, sensitivity (with a lower limit of quantification of 2.0 ng/mL), accuracy (both intra- and inter-day analytical recovery within 100 ± 15%) and precision (both intra- and inter-day relative standard deviation within 10%). The pharmacokinetic profiles of DHS were subsequently assessed in Sprague-Dawley rats. Following intravenous injection (4 mg/kg), DHS had a moderate apparent volume of distribution of the central compartment (V(c) = 887 ± 297 mL/kg), clearance (Cl = 44.7 ± 5.1 mL/min/kg) and a relatively short mean transit time (MTT = 24.1 ± 8.8 min). When it was given as an oral suspension (10 mg/kg), DHS was absorbed slowly (t max 180 or 300 min) with very limited plasma exposure and absolute oral bioavailability (F = 2.22 ± 0.72%). On the other hand, when DHS was fully solubilized by hydroxypropyl-β-cyclodextrin, it was absorbed rapidly (t(max) 30 or 45 min) with more than 15-fold increase in maximal plasma concentration (C(max)), plasma exposure (AUC(0→last)) and bioavailability (F = 36.3 ± 4.8%). Statistical comparison provided clear evidence that DHS was better than resveratrol from the perspective of pharmacokinetics. In conclusion, further explorations of DHS as an anti-cancer agent are warranted.
Tangeretin (TAN) is a dietary polymethoxylated flavone that possesses a broad scope of pharmacological activities. A simple high-performance liquid chromatography (HPLC) method was developed and validated in this study to quantify TAN in plasma of Sprague-Dawley rats. The lower limit of quantification (LLOQ) was 15 ng/mL; the intra- and inter-day assay variations expressed in the form of relative standard deviation (RSD) were all less than 10%; and the assay accuracy was within 100 ± 15%. Subsequently, pharmacokinetic profiles of TAN were explored and established. Upon single intravenous administration (10 mg/kg), TAN had rapid clearance (Cl = 94.1 ± 20.2 mL/min/kg) and moderate terminal elimination half-life (t1/2 λz = 166 ± 42 min). When TAN was given as a suspension (50 mg/kg), poor but erratic absolute oral bioavailability (mean value < 3.05%) was observed; however, when TAN was given in a solution prepared with randomly methylated-β-cyclodextrin (50 mg/kg), its plasma exposure was at least doubled (mean bioavailability: 6.02%). It was obvious that aqueous solubility hindered the oral absorption of TAN and acted as a barrier to its oral bioavailability. This study will facilitate further investigations on the medicinal potentials of TAN.
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