title: Quantification of the resveratrol analogs trans-2,3-dimethoxy-stilbene and trans-3,4-dimethoxystilbene in rat plasma: application to pre-clinical pharmacokinetic studies.
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.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore. ng.yali.shermain@nus.edu.sg.
authors.forename: Shermain Yali
authors.initials: SY
authors.lastname: Ng
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Catania, Viale A. Doria 6, I-95125 Catania, Italy. nunzio.cardullo@hotmail.it.
authors.forename: Nunzio
authors.initials: N
authors.lastname: Cardullo
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore. yeo.cms@nus.edu.sg.
authors.forename: Samuel Chao Ming
authors.initials: SC
authors.lastname: Yeo
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Catania, Viale A. Doria 6, I-95125 Catania, Italy. cspatafo@unict.it.
authors.forename: Carmela
authors.initials: C
authors.lastname: Spatafora
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Catania, Viale A. Doria 6, I-95125 Catania, Italy. ctringali@unict.it.
authors.forename: Corrado
authors.initials: C
authors.lastname: Tringali
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore. phaops@nus.edu.sg.
authors.forename: Pei-Shi
authors.initials: PS
authors.lastname: Ong
authors.affiliation: Department of Pharmacy, Faculty of Science, 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
mesh_terms: D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D015203:Reproducibility of Results; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: C582097:3,4-dimethoxystilbene; D013267:Stilbenes; D000077185:Resveratrol