Pharmaceutical Research

, 28:1606 | Cite as

Population Pharmacokinetic Modeling of trans-Resveratrol and Its Glucuronide and Sulfate Conjugates After Oral and Intravenous Administration in Rats

  • Helena ColomEmail author
  • Irene Alfaras
  • Mònica Maijó
  • M. Emília Juan
  • Joana M. Planas
Research Paper



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.


glucuronide and sulfate conjugates NONMEM polyphenols population pharmacokinetics trans-resveratrol 



ATP-binding cassette


Akaike information criterion


area under the curve


breast cancer resistance protein


observed concentrations


inter-animal variability


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.


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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Helena Colom
    • 1
    Email author
  • Irene Alfaras
    • 2
  • Mònica Maijó
    • 2
  • M. Emília Juan
    • 2
  • Joana M. Planas
    • 2
  1. 1.Departament de Farmàcia i Tecnologia Farmacèutica Facultat de FarmàciaUniversitat de BarcelonaBarcelonaSpain
  2. 2.Departament de Fisiologia, Facultat de Farmàcia Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB)Universitat de BarcelonaBarcelonaSpain

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