期刊
PHARMACEUTICAL RESEARCH
卷 28, 期 7, 页码 1606-1621出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-011-0395-8
关键词
glucuronide and sulfate conjugates; NONMEM; polyphenols; population pharmacokinetics; trans-resveratrol
资金
- Ministerio de Ciencia y Tecnologia [AGL2005-05728, AGL2009-12866]
- Generalitat de Catalunya [2005-SGR-00632, 2009-SGR-00471]
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 center dot 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 center dot 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.
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