Population pharmacokinetic modeling of trans-resveratrol and its glucuronide and sulfate conjugates after oral and intravenous administration in rats

Abstract

Purpose: To develop a population pharmacokinetic (PK) model which allowed the simultaneous modeling of trans-resveratrol and its glucuronide and sulfate conjugates.

Methods: Male Sprague-Dawley rats were administered i.v. and p.o. with 2, 10 and 20 mg·kg(-1) of trans-resveratrol. Blood was collected at different times during 24 h. An integrated PK model was developed using a sequential analysis, with non-linear mixed effect modeling (NONMEM). A prediction-corrected visual predictive check (pcVPC) was used to assess model performance. The model predictive capability was also evaluated with simulations after the i.v. administration of 15 mg·kg(-1) that were compared with an external data set.

Results: Disposition PK of trans-resveratrol and its metabolites was best described by a three-linked two-compartment model. Clearance of trans-resveratrol by conversion to its conjugates occurred by a first-order process, whereas both metabolites were eliminated by parallel first-order and Michaelis-Menten kinetics. The pcVPC confirmed the model stability and precision. The final model was successfully applied to the external data set showing its robustness.

Conclusions: A robust population PK model has been built for trans-resveratrol and its glucuronide and sulfate conjugates that adequately predict plasmatic concentrations.