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Molecules 2014, 19(7), 9577-9590; https://doi.org/10.3390/molecules19079577

Quantification of the Resveratrol Analogs trans-2,3-Dimethoxy-stilbene and trans-3,4-Dimethoxystilbene in Rat Plasma: Application to Pre-Clinical Pharmacokinetic Studies

1
Department of Pharmacy, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore
2
Dipartimento di Scienze Chimiche, Università di Catania, Viale A. Doria 6, I-95125 Catania, Italy
*
Author to whom correspondence should be addressed.
Received: 4 May 2014 / Revised: 26 June 2014 / Accepted: 28 June 2014 / Published: 7 July 2014
(This article belongs to the Special Issue Resveratrol)
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Abstract

trans-2,3-Dimethoxystilbene (2,3-DMS) and trans-3,4-dimethoxystilbene (3,4-DMS) are two synthetic resveratrol (trans-3,5,4'-trihydroxystilbene) analogs. In this study, a simple HPLC method was developed and validated to determine 2,3-DMS and 3,4-DMS in rat plasma. Chromatographic separation was obtained with a reversed-phase HPLC column through a 12.5-min gradient delivery of a mixture of acetonitrile and water at the flow rate of 1.5 mL/min at 50 °C. The lower limit of quantification was 10 ng/mL. After successful validation, the pharmacokinetic profiles of 2,3-DMS and 3,4-DMS were subsequently studied in Sprague-Dawley rats. Upon single intravenous administration (4 mg/kg), 2,3-DMS had a medium volume of distribution of the central compartment (Vc = 2.71 ± 0.51 L/kg), quite rapid clearance (Cl = 52.0 ± 7.0 mL/min/kg), moderate mean transit time (MTT0→last = 131.0 ± 4.5 min) but a fairly long terminal elimination half-life (t1/2 λZ = 288.9 ± 92.9 min). Interestingly, 3,4-DMS displayed a pharmacokinetic profile apparently distinct from 2,3-DMS and it had more extensive distribution (Vc = 5.58 ± 1.73 L/kg), faster clearance (Cl = 143.4 ± 40.5 mL/min/kg) and shorter residence (MTT0→last = 61.4 ± 27.1 min). Following single oral administration (10 mg/kg), 2,3-DMS had low and erratic plasma exposure (Cmax = 37.5 ± 23.7 ng/mL) and poor oral bioavailability (2.22% ± 2.13%) while the oral bioavailability of 3,4-DMS was even poorer than 2,3-DMS. Clearly, the location of the methoxy groups had a significant impact on the pharmacokinetics of resveratrol analogs. This study provided useful information for the design of resveratrol derivatives in future study. View Full-Text
Keywords: resveratrol; trans-2,3-dimethoxystilbene; trans-3,4-dimethoxystilbene; HPLC; pharmacokinetics resveratrol; trans-2,3-dimethoxystilbene; trans-3,4-dimethoxystilbene; HPLC; pharmacokinetics
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Ng, S.Y.; Cardullo, N.; Yeo, S.C.M.; Spatafora, C.; Tringali, C.; Ong, P.-S.; Lin, H.-S. Quantification of the Resveratrol Analogs trans-2,3-Dimethoxy-stilbene and trans-3,4-Dimethoxystilbene in Rat Plasma: Application to Pre-Clinical Pharmacokinetic Studies. Molecules 2014, 19, 9577-9590.

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