caa a22 4500 445312246 CHVBK 20180317142634.0 cr unu---uuuuu 170323e20110701xx s 000 0 eng 10.1007/s11095-011-0395-8 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0395-8 Population Pharmacokinetic Modeling of trans- Resveratrol and Its Glucuronide and Sulfate Conjugates After Oral and Intravenous Administration in Rats [Elektronische Daten] [Helena Colom, Irene Alfaras, Mònica Maijó, M. Juan, Joana Planas] 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 20mg·kg−1 of trans-resveratrol. Blood was collected at different times during 24h. 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 15mg·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. Springer Science+Business Media, LLC, 2011 glucuronide and sulfate conjugates nationallicence NONMEM nationallicence polyphenols nationallicence population pharmacokinetics nationallicence trans- resveratrol nationallicence ABC : ATP-binding cassette nationallicence AIC : Akaike information criterion nationallicence AUC : area under the curve nationallicence BCRP : breast cancer resistance protein nationallicence DV : observed concentrations nationallicence IAV : inter-animal variability nationallicence IPRED : individual model predicted concentrations nationallicence MRP : multidrug resistance protein nationallicence OFV : objective function value nationallicence pcVPC : prediction corrected visual predictive check nationallicence PD : pharmacodynamic nationallicence PK : pharmacokinetic nationallicence PRED : population model predicted concentrations nationallicence RSE : relative standard error nationallicence UGT : UDP-glucuronosyltransferase nationallicence Colom Helena Departament de Farmàcia i Tecnologia Farmacèutica Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028, Barcelona, Spain aut Alfaras Irene Departament de Fisiologia, Facultat de Farmàcia Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB), Universitat de Barcelona, Barcelona, Spain aut Maijó Mònica Departament de Fisiologia, Facultat de Farmàcia Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB), Universitat de Barcelona, Barcelona, Spain aut Juan M. Departament de Fisiologia, Facultat de Farmàcia Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB), Universitat de Barcelona, Barcelona, Spain aut Planas Joana Departament de Fisiologia, Facultat de Farmàcia Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB), Universitat de Barcelona, Barcelona, Spain aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/7(2011-07-01), 1606-1621 0724-8741 28:7<1606 2011 28 11095 https://doi.org/10.1007/s11095-011-0395-8 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0395-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Colom Helena Departament de Farmàcia i Tecnologia Farmacèutica Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028, Barcelona, Spain aut NATIONALLICENCE 700 1- Alfaras Irene Departament de Fisiologia, Facultat de Farmàcia Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB), Universitat de Barcelona, Barcelona, Spain aut NATIONALLICENCE 700 1- Maijó Mònica Departament de Fisiologia, Facultat de Farmàcia Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB), Universitat de Barcelona, Barcelona, Spain aut NATIONALLICENCE 700 1- Juan M. Departament de Fisiologia, Facultat de Farmàcia Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB), Universitat de Barcelona, Barcelona, Spain aut NATIONALLICENCE 700 1- Planas Joana Departament de Fisiologia, Facultat de Farmàcia Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB), Universitat de Barcelona, Barcelona, Spain aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/7(2011-07-01), 1606-1621 0724-8741 28:7<1606 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer