Improved bioavailability of hesperetin 7-O-glucoside inclusion complex with β-cyclodextrin in Sprague-Dawley rats and healthy humans

The flavonoid hesperidin and its aglycone are widely recognized for their functionality, wherein bioavailability is the key to ensuring their bio-efficacy for diverse health benefits. The aim of the present study was to evaluate the pharmacokinetics of a inclusion complex of hesperetin-7-O-glucoside with β-cyclodextrin (HEPT7G/βCD) in Sprague-Dawley (SD) rats, and in a randomized, double-blind, placebo-controlled, and crossover study in healthy human subjects. A significantly higher bioavailability (P < 0.01) of hesperetin metabolites derived from the HEPT7G/βCD inclusion complex compared with hesperetin-lecithin (Peretin-D) and α-monoglucosyl hesperidin formulations was observed in SD rats administered with identical doses by oral gavage feeding. Furthermore, in healthy human subjects, an acute single dose of the HEPT7G/βCD inclusion complex significantly enhanced the plasma hesperetin metabolites concentration (P < 0.001) and displayed an improved pharmacokinetic profile (P < 0.001) compared to an identical dose of hesperetin from hesperidin in maltodextrin (placebo: HES-Dex). The Tmax was nearly 10-fold faster (P = 0.016) after subjects consumed the HEPT7G/βCD inclusion complex compared with HES-Dex, and the MRT was significantly lowered (P = 0.011), respectively. Results also indicated the absence of any sequence (order effect) and period effect. No adverse effects were reported, and no clinically significant changes were noticed in blood biochemical markers. The oral intake of the HEPT7G/βCD inclusion complex in human subjects was well tolerated and safe. In summary, the bioavailability of hesperetin metabolites was regulated with HEPT7G/βCD inclusion complex consumption due to shifting the absorption site from the colonocyte to the enterocyte, and probably due to higher -2R enantiomer content. Such modulation of metabolites may be beneficial for regulating the biological functions of the dietary HEPT7G/βCD inclusion complex when used in foods, functional beverages, dietary supplements, and nutraceuticals.