Development of a Population Pharmacokinetic Model Characterizing the Tissue Distribution of Resveratrol After Administration by Different Routes and Doses in Rats

Background: Studies have demonstrated that resveratrol exerts several pharmacological effects. However, the pharmacokinetic parameters are not completely established. Objectives: This study describes the plasma pharmacokinetics and tissue distribution of resveratrol after administration by different routes and doses in rats. Methods: A reliable, simple, and sensitive HPLC method using UV detection for the quantification of resveratrol in rat plasma and tissues was developed and validated. In addition, a pharmacokinetic analysis using non-compartmental and population modeling was performed. Results: The pharmacokinetic parameters of resveratrol after the administration of 5 mg/kg via i.v. bolus calculated by non-compartmental analysis were a constant of elimination (ke) of 0.09 h^-1 ± 0.04, a half-life (t1/2) of 9.5 h ± 3.7, an apparent volume of distribution (Vd) of 5.8 L/kg ± 4.7, a clearance (Cl) of 0.39 L/h/Kg ± 0.26, and an area under the curve (AUC) of 6076 ng/h/mL ± 2959. The results obtained after the administration of 100 mg/kg p.o. were an elimination constant (ke) of 0.12 ± 0.07 h^-1, a half-life (t1/2) of 7.9 ± 4.2 h, the apparent volume distribution (Vd) of 13.3 ± 3.3 L/kg, a clearance (Cl) of 1.76 ± 0.49 L/h/Kg ± 0.26, and an area under the curve (AUC) of 6519 ± 1592 ng/h/mL. For the tissue distribution analysis, 10 mg/kg of resveratrol was intravenously administered to rats and the molecule was quantified in the liver, lung, kidney, heart, stomach, spleen, adipose tissue, and brain of the animals. Conclusions: The population pharmacokinetic modeling showed that resveratrol has a two-compartment model in both routes of administration and has a higher volume of distribution when it is given orally. In addition, resveratrol showed a high brain concentration after iv administration, which indicates that this molecule is capable of crossing the blood-brain barrier of animals, a crucial capacity for its neuroprotective activity.