Departament de Farmàcia i Tecnologia Farmacèutica Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028, Barcelona, Spain.
Pharm Res. 2011 Jul;28(7):1606-21. doi: 10.1007/s11095-011-0395-8. Epub 2011 Mar 23.
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.
建立一个群体药代动力学（PK）模型，以同时对反式白藜芦醇及其葡萄糖醛酸和硫酸盐缀合物进行建模。
雄性 Sprague-Dawley 大鼠分别静脉注射和口服给予 2、10 和 20 mg·kg(-1) 的反式白藜芦醇。在 24 小时内的不同时间采集血液。使用顺序分析，结合非线性混合效应建模（NONMEM），建立综合 PK 模型。使用预测校正的可视化预测检查（pcVPC）评估模型性能。还通过静脉注射 15 mg·kg(-1) 后进行模拟来评估模型预测能力，并与外部数据集进行比较。
反式白藜芦醇及其代谢物的处置 PK 最好用三连接两室模型来描述。反式白藜芦醇通过转化为其缀合物的清除是通过一级过程发生的，而两种代谢物则通过平行一级和米氏动力学消除。pcVPC 证实了模型的稳定性和精度。最终模型成功应用于外部数据集，显示其稳健性。
已经建立了一个用于反式白藜芦醇及其葡萄糖醛酸和硫酸盐缀合物的稳健群体 PK 模型，可以充分预测血浆浓度。
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