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.
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.
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