Pharmacokinetics and brain permeability of 3,5,4'-trimethoxy-trans-stilbene (TMS)

Purpose: 3,5,4’-trimethoxy-trans-stilbene (TMS) is a naturally occurring analog of resveratrol. Its anti-neoplastic, anti-allergic and anti-angiogenic activities have been reported recently. TMS has been reported to be more potent than resveratrol in various in vitro studies. The objective of this study was to understand the TMS pharmacokinetics and permeability in brain in an in vivo mouse model.

Methods: Based on in silico predictions with Chemdraw software we hypothesized that TMS had favorable physicochemical properties to cross the blood-brain barrier.  We further evaluated our hypothesis by conducting a pharmacokinetic study in which TMS (5 mg/kg, IA) was administered to C57BL/6J male mice (n=2). Carotid artery was cannulated and blood samples were serially collected at 2.5, 5, 10, 15, 45, 90, 180, 300, 420 and 600 min. Samples were analyzed with a validated LC-ESI/MS/MS method. Noncompartmental pharmacokinetic parameters of TMS were estimated with WinNonlin. Based on the pharmacokinetic parameters and simulations, an infusion study to achieve steady state was designed to measure TMS permeability in brain at steady state. Thus, a single IV bolus loading dose of 20 mg/kg of TMS and a constant-rate infusion of 10 mg/kg was administered to 3 healthy C57BL/6 male mice. Brain and plasma samples were collected by euthanizing the animals at 30 min and the TMS concentrations in brain and plasma were measured using a validated LC-ESI/MS/MS method.

Results: The table below lists the physicochemical properties of TMS with Chemdraw:

	Mol Wt.	tPSA	logP	ClogP
TMS	270.32	27.69	3.85	4.761

Average TMS plasma exposure (AUC_0-10hrs) was found to be 162.96 min*ug/ml. The predicted steady state plasma concentration of TMS at 30 min was 889 ng/ml and the experimental plasma concentration at 30 min was found to be 774.67 ± 176.6 ng/ml.  This was well within the range of the predicted plasma concentration. The brain to plasma ratio of TMS at steady state was found to be 10.4 ± 1.15.

Conclusion: TMS concentration in mouse brain was found to be 10 fold higher than plasma at steady state plasma concentrations. Due to significantly higher brain concentrations of TMS than those reported for resveratrol, and its previously reported anti-cancer and anti-angiogenic activities, TMS can be considered a promising candidate for further evaluation for treatment of brain tumors. (Supported by NIH grant 1RO3CA133943-01 to SN)