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5-Demethylnobiletin (5-DMN), identified in the aged citrus peels, has received increasing attentions due to its outstanding bioactivity among citrus polymethoxyflavones (PMFs). However, the poor water solubility and high crystallinity limit its oral bioavailability. Besides, the solubility of 5-DMN in the oil is very limited, which restricts its loading capacity in emulsions for bioavailability enhancement. In this study, an organogel formulation was developed to improve the solubility of 5-DMN in medium-chain triacylglycerols by 3.5 times higher without crystal formation during 5-day storage at room temperature. Increasing the gelator (i.e., sugar ester) concentration led to the increase of viscosity and a gel-like structure of the organogel. The ternary phase diagram of organogel-based emulsions was explored, and 40% organogel was selected as the oil phase for emulsion preparation. Increasing the concentration of Tween 80 from 0% to 6% decreased the droplet size and viscoelasticity of the emulsions. Two in vitro models, the pH-stat lipolysis model and TNO gastro-intestinal model (TIM-1), were applied to investigate the bioaccessibility of 5-DMN in different delivery systems. Compared with the conventional emulsion and oil suspension, the pH-stat lipolysis demonstrated that the organogel-based emulsion was the most efficient tool to enhance 5-DMN bioacccessibility. Moreover, TIM-1 digestive study indicated that 5-DMN bioaccessibility delivered by organogel-based emulsions was about 3.26-fold higher than that of oil suspension. Our results suggested that the organogel-based emulsion was an effective delivery route to enhance the loading and bioaccessibility of lipophilic compounds of high crystallinity., (Copyright © 2021. Published by Elsevier Ltd.)

Nobiletin has received much attention for its promising biological activities. Owing to its limited solubility, various encapsulation strategies have been developed to enhance nobiletin bioavailability. However, the understanding of the bioavailability and biotransformation of nobiletin in vivo and the correlation between in vitro and in vivo data remains limited. This study developed a high-loading nobiletin (1%) emulsion. The in vitro models, which combined pH-stat lipolysis with a Franz cell, showed very good correlation with in vivo data for the relative bioavailability. Rat studies showed that nobiletin had a high absolute bioavailability (≈20% for oil suspension). Besides, the emulsification improved the amount of bioavailable nobiletin and its major metabolite in the blood by about two times, as compared to an oil suspension. This work provides scientific insights into a rapid screening method for delivery systems and a better understanding of the biological fate of nobiletin in vivo .

Nobiletin, one of the prevalent polymethoxyflavones in citrus peels, was reported to possess various health benefits. We conducted the excretion study and pharmacokinetics study of nobiletin via oral administration and intravenous injection and 15 day consecutive dosing study using the high fat diet-induced obese rats and their lean counterparts. By comparing the demethylated metabolite profiles in the urine and feces, gut microbiota demonstrated greater biotransformation activity on nobiletin than the host. The absolute oral bioavailability of nobiletin in lean (22.37% ± 4.52%) and obese (18.67% ± 4.80%) rats has a negligible statistically significant difference ( P > 0.05). However, a higher extent of demethylated metabolites was found in the feces and plasma of obese rats than lean rats ( P < 0.05). Moreover, the consecutive dosing of nobiletin might lead to a higher extent of demethylated metabolites in the plasma and in feces. These results suggested that gut microbiota played important roles in nobiletin metabolism.