Assessment of Oral Bioavailability and Biotransformation of Emulsified Nobiletin Using In Vitro and In Vivo Models

Abstract

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.

Pharmacokinetics and Metabolites of 12 Bioactive Polymethoxyflavones in Rat Plasma

“…However, when tangeretin was suspended in corn oil, its C max and AUClast were significantly improved but significantly lower than those of nobiletin . Similar results were reported in a recent study by Zhang et al Nobiletin also contains only one more 3′-position methoxy group than tangeretin, indicating that the group at the 3′ position improved C max and AUClast. In addition to the number of methoxy groups, human studies by Vallejo et al have shown that differences in solubility significantly alter C max and AUClast of citrus flavanones, , suggesting that water solubility is also a key factor affecting the pharmacokinetics of PMFs.…”

Novel Urinary Biomarkers of Orange Juice Consumption, Interindividual Variability, and Differences with Processing Methods

“…In contrast, the glucuronides were present at much lower concentrations than the sulfates. Only conjugates of desmethyl nobiletin (most probably 4′-desmethyl nobiletin and 3′-desmethyl nobiletin, consistent with recent publications in rats) were detected . Several isomers were observed for some metabolites (Table ).…”

“…Thus, three isomers of hydroxy-tetramethoxyflavone sulfate and two isomers of hydroxy-pentamethoxyflavone sulfate were found, as well as only one isomer of hydroxy-trimethoxyflavone sulfate and two isomers of hydroxy-pentamethoxyflavone glucuronide. The two last isomers’ occurrence is consistent with the two metabolites identified in rats after the nobiletin intake (4′-desmethyl nobiletin and 3′-desmethyl nobiletin), assuming a similar metabolism in humans …”

“…The two last isomers' occurrence is consistent with the two metabolites identified in rats after the nobiletin intake (4′-desmethyl nobiletin and 3′-desmethyl nobiletin), assuming a similar metabolism in humans. 34 Interestingly, in demethylated-polymethoxyflavones, sulfates were the main phase II metabolites, while glucuronides were only minor ones (Figure 5). This is a clear difference with citrus flavanones that were mainly present in the urine samples as glucuronide conjugates (Table 1), and this deserves further study.…”

“…Only conjugates of desmethyl nobiletin (most probably 4′-desmethyl nobiletin and 3′-desmethyl nobiletin, consistent with recent publications in rats) were detected. 34 Several isomers were observed for some metabolites (Table 2). Thus, three isomers of hydroxy-tetramethoxyflavone sulfate and two isomers of hydroxy-pentamethoxyflavone sulfate were found, as well as only one isomer of hydroxy-trimethoxyflavone sulfate and two isomers of hydroxy-pentamethoxyflavone glucuronide.…”