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. 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 Cmax, Tmax, AUC0−t, AUC0−∞, CL/F, V/F, t1/2, MRT, Ae, Ae(0–24), and Rmax were calculated from their plasma or urine concentrations. 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 (Cmax) for hesperetin and naringenin were 825.78±410.63 ng/ml (2731.8±1358.4 nmol/l) and 2009.51±770.82 ng/ml (7386.6±2833.4 nmol/l), respectively and the mean AUC0−∞ values were 4846.20±1675.99 ng h/ml and 9424.52±2960.52 ng h/ml for hesperetin and naringenin, respectively. The elimination half-life for hesperetin was found to be 3.05±0.91 h and for naringenin 2.31±0.40 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 3.26±0.44 and 5.81±0.81%, respectively. 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.

/pdf/pharmacokinetics-of-the-citrus-flavanone-aglycones-2ynwdxfqqw.pdf

Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects.

Naringenin, the predominant flavanone in grapefruit, mainly occurs as glycosides such as naringenin-7- rhamnoglucoside or naringenin-7-glucoside. This study compared kinetics of absorption of narin...

https://www.physiology.org/doi/pdf/10.1152/ajpgi.2000.279.6.G1148

Bioavailability of the flavanone naringenin and its glycosides in rats.

Publisher Summary The risks to humans of serious poisonous effects caused by natural phenols present in normal foods consumed under usual circumstances seem vanishingly small, as determined by experiment, as well as common sense and long-term observation. Conclusions involving evolution obviously are speculative, but some putative relationships appear worthy of discussion to clarify the durability of animal life and the threat of plant toxins generally or of phenols particularly. Phenols are probably the most important group of substances, useful in chemotaxonomic differentiation among plant species. Plants have evolved toxins to combat herbivores, but herbivores have also evolved to tolerate or avoid plant toxins. Phenol itself, and other small phenols, such as catechol, the cresols, guaiacol, orcinols, and pyrogallol, are commonly considered to be industrial chemicals. Gallic acid is widely distributed in plants, but the concentration is usually very low. The flavonoids contribute color, flavor, and processing characteristics important in food. The most often cited effect of phenols that is discussed in this chapter is the inhibition of catechol-O-methyltransferse (COMT) and competition for methyl groups by phenols that serve as a substrate for this enzyme. The chapter discusses that many plants contain secondary metabolites toxic or deterrent to members of the animal kingdom attempting to feed on them. Plant phenols that are highly toxic to animals are rarely found. The phenols that occur widely in plants or in large amounts in common food plants have very low acute oral toxicity and most are also of low toxicity when given parenterally.

Naturally Occurring Food Toxicants: Phenolic Substances of Plant Origin Common in Foods

Lipid-lowering efficacy of hesperetin metabolites in high-cholesterol fed rats.

An inverse association between flavonoid intake and coronary heart disease (CHD) has been suggested by a number of epidemiological studies (42,44,54,78). As a consequence, there is considerable interest in investigating the antiatherogenic nature of these compounds. Flavonoids are naturally occurring molecules abundant in fruit, vegetables, nuts, seeds, and beverages, such as tea and wine. Over 4000 different flavonoids have been identified in the human diet, where the daily intake ranges from levels as high as 1 g (59) to a more conservative estimate of 23 mg (43). Flavonoids are characterized by their polyphenolic structure (Fig. 1). Variations in this structure give rise to the major classes of flavonoids, including the flavonols, flavones, flavanones, catechins, anthocyanidins, isoflavones, dihydroflavonols, and chalcones. Naringenin belongs to the class of flavonoids called the flavanones. The flavanones are abundant in citrus fruits such as grapefruit (Citrus paradisi) and the oranges (Citrus sinensis). The role of naringenin and the related citrus flavanone hesperetin in the prevention and treatment of disease has recently received considerable attention (71), with particular interest in the use of these flavanones as anticancer (36) and antiatherogenic (85) compounds. This review focuses on the potential antiatherogenic roles of citrus flavonoids, with particular focus on naringenin.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1527-3466.1999.tb00011.x

Antiatherogenic Properties of Naringenin, a Citrus Flavonoid

1. The major biliary metabolites of flavanones in the rat have been identified by chromatographic and spectral methods.2. Evidence is presented that flavanones and flavanone glycosides, following oral or parenteral administration, undergo glucuronylation and are selectively excreted via the bile.3. Flavanone glycosides but not unconjugated aglycones may be excreted to a significant extent in bile.4. The percentage of parenterally administered flavanones excreted in bile varies inversely with the amount administered.

The bilary excretion of flavanones in the rat.

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The bilary excretion of flavanones in the rat.