Division of Toxicology, Wageningen University & Research, Wageningen, The Netherlands.
Mol Nutr Food Res. 2017 Aug;61(8). doi: 10.1002/mnfr.201600894. Epub 2017 Mar 21.
To develop a physiologically based kinetic (PBK) model that describes the absorption, distribution, metabolism, and excretion of hesperidin in humans, enabling the translation of in vitro concentration-response curves to in vivo dose-response curves.
The PBK model for hesperidin in humans was developed based on in vitro metabolic parameters. Hesperidin was predicted to mainly occur in the systemic circulation as different monoglucuronides. The plasma concentrations of hesperidin aglycone (hesperetin) was predicted to be <0.02 mg/L at an oral dose of 50 mg/kg bw. The developed PBK model allowed conversion of in vitro concentration-response curves for different effects to in vivo dose-response curves. The BMD (benchmark dose for 5% response) values for protein kinase A inhibition ranged between 135 and 529 mg/kg bw hesperidin, and for inhibition of endothelial cell migration and prostaglandin E and nitric oxide production ranged between 2.19 and 44 mg/kg bw hesperidin. These values are in line with reported human data showing in vivo effects by hesperidin and show that these effects may occur at Western dietary and supplementary intake of hesperidin.
The developed PBK model adequately predicts absorption, distribution, metabolism, and excretion of hesperidin in humans and allows to evaluate the human in vivo situation without the need for human intervention studies.
开发一种描述橙皮苷在人体内吸收、分布、代谢和排泄的生理基础的动力学（PBK）模型，使体外浓度-反应曲线能够转化为体内剂量-反应曲线。
基于体外代谢参数，建立了橙皮苷在人体内的 PBK 模型。橙皮苷主要以不同的单葡萄糖醛酸苷形式存在于体循环中。口服 50mg/kgbw 剂量时，橙皮苷苷元（橙皮素）的血浆浓度预计<0.02mg/L。所开发的 PBK 模型允许将不同效应的体外浓度-反应曲线转化为体内剂量-反应曲线。蛋白激酶 A 抑制的 BMD（5%反应的基准剂量）值范围在 135 至 529mg/kgbw 橙皮苷之间，而对内皮细胞迁移和前列腺素 E 和一氧化氮产生的抑制作用范围在 2.19 至 44mg/kgbw 橙皮苷之间。这些值与报道的橙皮苷在体内的人体数据一致，表明这些作用可能发生在西方饮食和补充橙皮苷的情况下。
所开发的 PBK 模型充分预测了橙皮苷在人体内的吸收、分布、代谢和排泄，并允许在无需人体干预研究的情况下评估人体的体内情况。
