纳米乳液传递体系对柑橘川陈皮素生物利用度和生物转化的影响

Effects of a Nano-Emulsion Delivery System on the Bioavailability and Biotransformation of Nobiletin in Citrus Peel

摘要:

【目的】川陈皮素（nobiletin，NOB）是柑橘属果皮中重要的多甲氧基黄酮类化合物之一，具有多种生物活性与健康功能，但水溶性差、易结晶。纳米乳液传递体系是提高脂溶性成分生物利用度的常用方式，作者旨在探究纳米乳液传递体系对NOB生物利用度和体内生物转化的影响，为提升NOB等柑橘黄酮的生物利用度和健康功效提供科学指导，同时为其在功能食品中的应用提供借鉴。【方法】构建NOB纳米乳液传递体系，以小鼠为动物模型，提取粪便进行代谢产物分析，并进行药代动力学分析与组织器官分布研究。【结果】小鼠粪便中共鉴定出6种代谢产物，其中NOB、4’-去甲基川陈皮素、3’-去甲基川陈皮素、3’，4’-二去甲基川陈皮素为主要代谢产物；纳米乳液可以显著提高NOB的生物利用度，提高血药质量浓度、延长作用时间，曲线下面积（AUC_t）和最大血药质量浓度（C_max）分别是未包埋NOB的5.8~14.4倍和1.9~3.6倍，半衰期延长2.5~4.9倍；组织器官分布研究表明，肝脏中的代谢产物浓度很低。【结论】纳米乳液提高NOB生物利用度的机理为：纳米乳液传递体系包埋的NOB通过淋巴循环进入血液可以避免肝脏首过效应；在小肠中，代谢产物主要以结合态的形式存在，而在盲肠和结肠中，肠道菌群将结合态代谢产物水解为游离态代谢产物。

Abstract:

[Objective] Nobiletin (NOB), an important polymethoxy-flavonoid in citrus peel, has a variety of biological activities and health-promoting effects. However, it has poor water solubility and it is prone to crystallization. Nano-emulsion delivery systems have been widely used to improve the bioavailability of lipophilic components. The effects of these systems on the bioavailability and biotransformation of NOB are studied, with the aim of providing guidance for improving the bioavailability and health-promoting effects of citrus flavonoids including NOB and promoting the application of NOB in functional food. [Method] A NOB-encapsulated nano-emulsion delivery system was established. Feces of mice were collected for the identification of metabolites, and then the pharmacokinetics and in vivo distribution of NOB were analyzed. [Result] Six metabolites were identified from mouse feces, among which NOB, 4’-demethylnobiletin, 3’-demethylnobiletin, and 3’,4’-didemethylnobiletin were the main metabolites. Pharmacokinetic analysis showed that the nano-emulsion significantly improved the bioavailability of NOB, increasing the blood mass concentration and prolonging the action time. The area under the curve (AUC_t) and the maximum blood mass concentration (C_max) of NOB in the nano-emulsion were 5.8~14.4 and 1.9~3.6 times that of unencapsulated NOB. Moreover, the nano-emulsion system prolonged the half-life of NOB by 2.5~4.9 times. The in vivo distribution analysis of metabolites showed that the concentrations of metabolites in the liver were very low. [Conclusion] The NOB encapsulated in the nano-emulsion delivery system can enter the serum through lymphatic circulation, which avoids the liver first pass effect and may explain the improving effects of the nano-emulsion delivery system on the bioavailability of NOB. Metabolites mainly exist in the form of conjugation in the small intestine, while they are hydrolyzed into the free form by the gut microbiota in the cecum and colon.