Interactions of the Flavonoid Naringenin in the Gastrointestinal Tract and the Influence of Glycosylation

Choudhury, Rahela; Chowrimootoo, George; Srai, K; Debnam, ES; Rice‐Evans, Catherine

doi:10.1006/bbrc.1999.1695

Cited by 105 publications

(80 citation statements)

References 21 publications

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“…In the present study, hesperidin metabolites recovered in plasma were identified as glucuronides of hesperetin, among which a low part was also sulphated. To our knowledge, the nature of the metabolites of flavanones in human plasma has never been described in the literature, but our results are in agreement with the findings of animal studies (Peng et al, 1998;Choudhury et al, 1999;Felgines et al, 2000). Besides, the presence of glucuronides of flavanones has been reported in human urine (Fuhr & Kummert, 1995;Ameer et al, 1996;Lee & Reidenberg, 1998).…”

Section: Discussionsupporting

confidence: 92%

Bioavailability in humans of the flavanones hesperidin and narirutin after the ingestion of two doses of orange juice

Manach¹,

Morand²,

et al. 2003

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Objective: Flavanones are polyphenols specific of citrus fruits, where they are present in high amounts. Although citrus fruits and juices are widely consumed in the world, little information has been published on flavanone bioavailability in humans. The aim of the present study was to determine the nature of the circulating metabolites, the plasma kinetics and the urinary excretion patterns of the flavanones, hesperidin and narirutin. Design: After an overnight fast, five healthy volunteers ingested 0.5 or 1 l of a commercial orange juice providing 444 mg=l hesperidin and 96.4 mg=l narirutin, together with a polyphenol-free breakfast. Blood was sampled at 10 different timepoints over a 24 h period. Urine was collected for 48 h, in five fractions. Results: Flavanones metabolites appeared in plasma 3 h after the juice ingestion, reached a peak between 5 and 7 h, then returned to baseline at 24 h. The peak plasma concentration of hesperetin was 0.46 AE 0.07 mmol=l and 1.28 AE 0.13 mmol=l after the 0.5 and 1 l intake, respectively. It was lower for naringenin: 0.20 AE 0.04 mmol=l after the 1 l dose. The circulating forms of hesperetin were glucuronides (87%) and sulphoglucuronides (13%). For both flavanones, the urinary excretion was nearly complete 24 h after the orange juice ingestion. The relative urinary excretion was similar for hesperetin and naringenin and did not depend on the dose: values ranged from 4.1 AE 1.2 to 7.9 AE 1.7% of the intake. Conclusions: In case of a moderate or high consumption of orange juice, flavanones may represent an important part of the pool of total polyphenols present in plasma.

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Section: Discussionsupporting

confidence: 92%

Bioavailability in humans of the flavanones hesperidin and narirutin after the ingestion of two doses of orange juice

Manach¹,

Morand²,

et al. 2003

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“…Secondary objective of the study was also to improve their absorption rate and to decrease the inter-individual variability of the pharmacokinetic parameters concerning the rate and extent of absorption. Different animal and human studies indicate that the flavanone glycosides hesperidin and naringin, are most likely hydrolyzed by colonic bacteria into their flavanone aglycones, hesperetin and naringenin which are subsequently absorbed into the systematic circulation as glucuronides and sulphoglucuronides (Hacket et al, 1979;Bokkenheuser et al, 1987;Fuhr and Kummert, 1995;Jang and Kim, 1996;Choudhury et al, 1999;Hollman et al, 1999;Felgines et al, 2000;Erlund et al, 2001;Nielsen et al, 2006). However, trace amounts of the flavanone glycosides, for example, naringin, can be absorbed intact (Ishii et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Flavonoid glycosides, bearing rutinose groups, are hydrolyzed only in the distal part of the intestine and the colon by colonic bacteria, in contrast to flavonoid glucosides, bearing a glucose moiety, which are hydrolyzed already in the small intestine by beta-glucosidases. The released aglycones, hesperetin and naringenin, are recovered in plasma as glucuronides and sulphoglucuronides (Hacket et al, 1979;Fuhr and Kummert, 1995;Jang and Kim, 1996;Choudhury et al, 1999;Felgines et al, 2000;Nielsen et al, 2006). Different studies indicate that the aglycone release is the rate-limiting step for their absorption (Manach et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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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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“…In fact, i.v. naringenin-7-glucoside was excreted in urine mostly as its native glucoside form in a rat model (29). Despite the promising results using flavonoids in the reversal of BCRP-mediated drug resistance, we must bear in mind that that coadministration or intake of flavonoids with BCRP-substrate antitumor agents may result in the alteration of their pharmacokinetics and may increase the toxicity of the antitumor drugs in the recipient patients.…”

Section: Discussionmentioning

confidence: 99%

Phytoestrogens/Flavonoids Reverse Breast Cancer Resistance Protein/ABCG2-Mediated Multidrug Resistance

et al. 2004

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Interactions of the Flavonoid Naringenin in the Gastrointestinal Tract and the Influence of Glycosylation

Cited by 105 publications

References 21 publications

Bioavailability in humans of the flavanones hesperidin and narirutin after the ingestion of two doses of orange juice

Bioavailability in humans of the flavanones hesperidin and narirutin after the ingestion of two doses of orange juice

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

Phytoestrogens/Flavonoids Reverse Breast Cancer Resistance Protein/ABCG2-Mediated Multidrug Resistance

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