Population Pharmacokinetic Modeling of trans-Resveratrol and Its Glucuronide and Sulfate Conjugates After Oral and Intravenous Administration in Rats
To develop a population pharmacokinetic (PK) model which allowed the simultaneous modeling of trans-resveratrol and its glucuronide and sulfate conjugates.
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.
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.
A robust population PK model has been built for trans-resveratrol and its glucuronide and sulfate conjugates that adequately predict plasmatic concentrations.
KEY WORDSglucuronide and sulfate conjugates NONMEM polyphenols population pharmacokinetics trans-resveratrol
Akaike information criterion
area under the curve
breast cancer resistance protein
individual model predicted concentrations
multidrug resistance protein
objective function value
prediction corrected visual predictive check
population model predicted concentrations
relative standard error
This study was supported by the Ministerio de Ciencia y Tecnología grants AGL2005-05728 and AGL2009-12866 and the Generalitat de Catalunya grants 2005-SGR-00632 and 2009-SGR-00471.
- 7.Sale S, Verschoyle RD, Boocock D, Jones DJ, Wilsher N, Ruparelia KC, et al. Pharmacokinetics in mice and growth-inhibitory properties of the putative cancer chemopreventive agent resveratrol and the synthetic analogue trans 3, 4, 5, 4′-tetramethoxystilbene. Br J Cancer. 2004;90(3):736–44.PubMedCrossRefGoogle Scholar
- 17.Beal SL, Sheiner LB. NONMEM User’s guide. Icon Development Solutions: Ellicot City, MD 1989–2006.Google Scholar
- 21.Karlsson MO, Holford NH. A Tutorial on Visual Predictive Checks. 2008, pp 17 (Abstract 1434). Available at: http://www.page-meeting.org/?abstract=1434.
- 22.Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-Corrected Visual Predictive Checks for Diagnosing Nonlinear Mixed-Effects Models. AAPS J. 2011. doi: 10.1208/s12248-011-9255-z.