Abstract：
Flavonoids are considered as health-protecting food constituents. The testing of their biological effects is however hampered by their low oral absorption and complex metabolism. In order to investigate the direct effect(s) of unmetabolized flavonoid, a preparation in a biologically friendly solvent for intravenous administration is needed. Isorhamnetin, a natural flavonoid and a human metabolite of the most frequently tested flavonoid quercetin, has very low water solubility (<3.5 μg/mL). The aim of this study was to improve its solubility to enable intravenous administration and to test its pharmacokinetics in an animal model. By using polyvinylpyrrolidone (PVP10) and benzalkonium chloride, we were able to improve the solubility approximately 600 times to 2.1 mg/mL. This solution was then administered intravenously at a dose of 0.5 mg/kg of isorhamnetin to rats and its pharmacokinetics was analyzed. The pharmacokinetics of isorhamnetin corresponded to two compartmental model with a rapid initial distribution phase (t1/2α: 5.7 ± 4.3 min) and a slower elimination phase (t1/2β: 61 ± 47.5 min). Two sulfate metabolites were also identified. PVP10 and benzalkonium did not modify the properties of isorhamnetin (iron chelation and reduction, and cell penetration) substantially. In conclusion, the novel preparation reported in this study is suitable for future testing of isorhamnetin effects under in vivo conditions.
摘要：
黄酮类化合物被认为是保护健康的食品成分。然而,它们的生物效应的测试受到它们的低吸收和复杂代谢的阻碍。为了研究未代谢类黄酮的直接作用，需要用于静脉内给药的生物友好溶剂中的制剂。Isorhamnetin,一种天然的类黄酮和人类代谢产物的最经常测试的类黄酮槲皮素，具有非常低的水溶性(<3.5μg/mL)。这项研究的目的是改善其溶解度以实现静脉内给药并在动物模型中测试其药代动力学。通过使用聚乙烯吡咯烷酮（PVP10）和苯扎氯铵，我们能够将溶解度提高约600倍至2.1mg/mL。然后将该溶液以0.5mg/kg的剂量静脉内给予大鼠异鼠李素,并分析其药代动力学。异鼠李素的药代动力学对应于两个隔室模型，具有快速的初始分布阶段（t1/2α：5.7±4.3分钟）和较慢的消除阶段（t1/2β：61±47.5分钟）。还鉴定了两种硫酸盐代谢物。PVP10和苯扎氯铵没有改变异鼠李素的性质(铁螯合和还原，和细胞渗透)。总之,本研究中报道的新制剂适用于将来在体内条件下测试异鼠李素的作用。
