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Determination of naturally occurring resveratrol analog trans-4,4′-dihydroxystilbene in rat plasma by liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study

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Abstract

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.

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Acknowledgments

This research work was carried out under the financial support from a startup grant awarded from the National University of Singapore (R-148-000-174-133). SCMY is an awardee of the President’s Graduate Fellowship of the National University of Singapore. MGAAE is a recipient of the Singapore International Graduate Award.

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    Authors and Affiliations

    1. Department of Pharmacy, National University of Singapore, 10 Kent Ridge Crescent, Singapore, 119260, Singapore

      Wan Chen, Samuel Chao Ming Yeo, Mai Gamal Ahmed Ahmed Elhennawy & Hai-Shu Lin

    2. Department of Clinical Pharmacy, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China

      Xiaoqiang Xiang

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    1. Wan Chen
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    Correspondence to Hai-Shu Lin.

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    Wan Chen and Samuel Chao Ming Yeo contributed equally to this work.

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    Chen, W., Yeo, S.C.M., Elhennawy, M.G.A.A. et al. Determination of naturally occurring resveratrol analog trans-4,4′-dihydroxystilbene in rat plasma by liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study. Anal Bioanal Chem 407, 5793–5801 (2015). https://doi.org/10.1007/s00216-015-8762-7

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