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 (AUCt) and the maximum blood mass concentration (Cmax) 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.
