Background and objective: Hesperetin and naringenin, the aglycones of the flavanone glycosides hesperidin and naringin, occur naturally in citrus fruits. They exert interesting pharmacological properties such as antioxidant, anti-inflammatory, blood lipid and cholesterol lowering and are considered to contribute to health benefits in humans. However, no information is available on the pharmacokinetics of the citrus flavanones hesperetin and naringenin after their oral administration to humans as pure aglycones. Therefore, the objective of the present investigation was the evaluation of the pharmacokinetic parameters of hesperetin and naringenin in plasma and urine, after their single oral administration in humans in the form of solid dispersion capsules, and also to improve the absorption rate of flavanones by using aglycones rather than the naturally occurring glycosides. Design: Six healthy volunteers received orally 135 mg of each compound, hesperetin and naringenin, under fasting conditions. Blood samples were collected at 14 different time points over a 12 h period. Urine was collected over 24 h, in five sequential timed intervals. Plasma and urine hesperetin and naringenin concentrations, after enzymatic hydrolysis of their conjugated forms, were measured using validated high-pressure liquid chromatography methods. Pharmacokinetic parameters for hesperetin and naringenin, such as C max , T max , AUC 0Àt , AUC 0ÀN , CL/F, V/F, t 1/2 , MRT, A e , A e ( 0-24 ), and R max were calculated from their plasma or urine concentrations. Results: Pharmacokinetic analysis showed that both hesperetin and naringenin were rapidly absorbed and their concentrations in plasma observed 20 min after dosing and reached a peak in 4.0 and 3.5 h, respectively. The mean peak plasma concentration (C max ) for hesperetin and naringenin were 825.787410.63 ng/ml (2731.871358.4 nmol/l) and 2009.517770.82 ng/ml (7386.672833.4 nmol/l), respectively and the mean AUC 0ÀN values were 4846.2071675.99 ng h/ml and 9424.527 2960.52 ng h/ml for hesperetin and naringenin, respectively. The elimination half-life for hesperetin was found to be 3.0570.91 h and for naringenin 2.3170.40 h, respectively. The mean values of the relative cumulative urinary excretion, as percentage of the administered dose, for hesperetin and naringenin, were found to be 3.2670.44 and 5.8170.81%, respectively. Conclusions: Oral administration of the flavanone aglycones, hesperetin and naringenin, lead to their rapid absorption as their conjugated forms. The cumulative urinary recovery data indicated low bioavailability for both flavanone aglycones, owing to extensive first-pass metabolism partly by cleavage of the C-ring by the enzymes of intestinal bacteria leading to degradation products such as phenolic acids.

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Polyvinylpyrrolidone (PVP) and poly(ethylene glycol) (PEG) solid dispersion systems with flavanone glycosides, naringin and hesperidin, and their aglycones, naringenin and hesperetin, were prepared, using solvent evaporation method, to enhance their dissolution rates that may affect their bioavailability. Drug release of both flavanone glycosides and their aglycones was directly affected by the physical state of solid dispersions. Powder-XRD technique in combination with scanning and transmission electron microscopy revealed that PVP polymer formed amorphous nanodispersion systems with flavanone aglycones, while such systems could not be formed with their glycosides, which are bulkier molecules. Fourier transform infrared spectra suggest the presence of hydrogen bonds between PVP carbonyl groups and hydroxyl groups of both flavanone aglycones. These interactions prevent the crystallization of naringenin and hesperetin aglycones in PVP matrix. On the other hand, the ability of PEG carrier to form hydrogen bonds with flavanone glycosides or aglycones was limited, and as a result both flavanone glycosides and their aglycones remain in the crystalline form. For this reason, the solubility enhancement of PEG solid dispersions was lower than when PVP was used as drug carrier. At pH 6.8, the % release of naringenin and hesperetin from PVP/naringeninhesperetin (80/20 w/w) solid dispersion was 100% while in PEG solid dispersions, it was not higher than 60 -70%.

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