Chronic consumption of orange juice modifies urinary excretion of flavanone gut-derived metabolites through gut microbiota modulation.

The metabolism and absorption of citrus flavanones are intrinsically linked to the gut microbiota, creating a bidirectional relationship where these compounds influence the microbiome, and in turn, the microbiota affects their metabolism. This study evaluates the effect of acute and chronic consumption of orange juice (OJ) on the urinary excretion of gut-derived flavanone metabolites and the gut microbiota. Health volunteers ingested 500 mL of OJ for 60 days in a single-arm human intervention study. Blood and feces were collected at baseline and after 60 days, with an additional 24-hour urine collection after a single dose on day 1 and day 63. LC-MS/MS analyzed urinary flavanone metabolites, while 16S rRNA sequencing characterized gut microbiota. Total urinary hesperetin conjugates excretion significantly decreased over 60 days, while gut-derived total phenolic acids, particularly three hydroxybenzoic acids, increased. Moreover, the heterogeneity of the total amount of flavanone conjugates, initially categorizing individuals into high-, medium- and low- urinary excretor profiles, shifted towards medium-excretor, except for five individuals who remained as low-excretors. This alteration was accompanied by a decrease in intestinal ß-glucosidase activity and a shift in the relative abundance of specific genera, such as decreases in Blautia, Eubacterium hallii, Anaerostipes, and Fusicatenibacter, among which, Blautia was associated with higher urinary flavanone conjugates excretion. Conversely, an increase in Prevotella was observed. In summary, chronic OJ consumption induced transient changes in gut microbiota and altered the metabolism of citrus flavanones, leading to distinct urinary excretion profiles of flavanone metabolites.

TiO2-MXene/PEDOT:PSS Composite as a Novel Electrochemical Sensing Platform for Sensitive Detection of Baicalein.

In this work, TiO2-MXene/poly (3,4-ethylenedioxythiophene): poly(styrenesulfonate) (PEDOT:PSS) composite was utilized as an electrode material for the sensitive electrochemical detection of baicalein. The in-situ growth of TiO2 nanoparticles on the surface of MXene nanosheets can effectively prevent their aggregation, thus presenting a significantly large specific surface area and abundant active sites. However, the partial oxidation of MXene after calcination could reduce its conductivity. To address this issue, herein, PEDOT:PSS films were introduced to disperse the TiO2-MXene materials. The uniform and dense films of PEDOT:PSS not only improved the conductivity and dispersion of TiO2-MXene but also enhanced its stability and electrocatalytic activity. With the advantages of a composite material, TiO2-MXene/PEDOT:PSS as an electrode material demonstrated excellent electrochemical sensing ability for baicalein determination, with a wide linear response ranging from 0.007 to 10.0 µM and a lower limit of detection of 2.33 nM. Furthermore, the prepared sensor displayed good repeatability, reproducibility, stability and selectivity, and presented satisfactory results for the determination of baicalein in human urine sample analysis.

Safety, tolerability, pharmacokinetics, and food effect of baicalein tablets in healthy Chinese subjects: A single-center, randomized, double-blind, placebo-controlled, single-dose phase I study.

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria baicalensis (Huang-Qin in Chinese) is a dry root of the perennial herb Scutellaria baicalensis Georgi, which has been used extensively in current prescriptions. Scutellaria baicalensis is an herb high in flavonoids, and baicalein is the one flavonoid found in the highest amount in Scutellaria baicalensis. AIM OF THE STUDY: Influenza virus could cause mild respiratory tract illness to severe pneumonia and even death. Baicalein has been proved to be one of the effective components against the influenza virus. However, there have been few reports on human trials of baicalein. The purpose of this study was to evaluate the safety of baicalein in vivo and analyze its pharmacokinetic characteristics. MATERIALS AND METHODS: Three randomized studies were conducted to evaluate the pharmacokinetics (PK), safety, tolerability, and food effects of baicalein tablets. In the 7-month single-dose safety study, 60 subjects were enrolled and randomized to receive 100-800 mg baicalein tablets or placebo. In the single-dose PK study, 40 subjects were enrolled and randomized to receive 200 mg, 400 mg, 600 mg, 800 mg baicalein tablets. In the study of food effect on PK of baicalein, an additional 10 subjects were enrolled in the 400 mg group, this part of the trial lasted for 7 months. Blood and urine samples for PK analysis were collected at a pre-specified time. PK properties in both fasted and fed states were evaluated, as well as safety and tolerability. RESULTS: Among the 80 subjects who were evaluable for the single-dose safety and tolerability, 56 adverse events (AEs) were observed in 32/80 subjects, of which 49 events were from 28/68 subjects in baicalein group and 7 events were from 4/12 subjects in placebo group. All AEs were mild and resolved without any medical intervention. The most common AEs were elevated high-sensitivity C-reactive protein (hs-CRP) level and high triglycerides. After a single administration of baicalein tablets (200 mg, 400 mg, 600 mg, or 800 mg), Cmax were 280.44, 628.80, 845.20, 489.55 ng/mL; AUC0-∞ were 2035.57, 2939.31, 4494.88, and 3754.43 h*ng/mL, respectively. And t1/2z ranged from 7.80 to 14.91 h. The exposure of baicalein and its metabolites increased in a less than dose-proportional manner. CONCLUSION: Baicalein tablets within the studied dose range were safe and well-tolerated in healthy Chinese subjects with no serious or severe adverse effects. Further investigation will be needed to assess the safety and efficacy in the target patients.

Stratification of Volunteers According to Flavanone Metabolite Excretion and Phase II Metabolism Profile after Single Doses of 'Pera' Orange and 'Moro' Blood Orange Juices.

Large interindividual variations in the biological response to citrus flavanones have been observed, and this could be associated with high variations in their bioavailability. The aim of this study was to identify the main determinants underlying interindividual differences in citrus flavanone metabolism and excretion. In a randomized cross-over study, non-obese and obese volunteers, aged 19-40 years, ingested single doses of Pera and Moro orange juices, and urine was collected for 24 h. A large difference in the recovery of the urinary flavanone phase II metabolites was observed, with hesperetin-sulfate and hesperetin-sulfo-O-glucuronide being the major metabolites. Subjects were stratified according to their total excretion of flavanone metabolites as high, medium, and low excretors, but the expected correlation with the microbiome was not observed at the genus level. A second stratification was proposed according to phase II flavanone metabolism, whereby participants were divided into two excretion groups: Profiles A and B. Profile B individuals showed greater biotransformation of hesperetin-sulfate to hesperetin-sulfo-O-glucuronide, as well as transformation of flavanone-monoglucuronide to the respective diglucuronides, suggestive of an influence of polymorphisms on UDP-glucuronosyltransferase. In conclusion, this study proposes a new stratification of volunteers based on their metabolic profiles. Gut microbiota composition and polymorphisms of phase II enzymes may be related to the interindividual variability of metabolism.

Beverages Based on Second Quality Citrus Fruits and Maqui Berry, a Source of Bioactive (Poly)phenols: Sorting Out Urine Metabolites upon a Longitudinal Study.

The intake of sugar-sweetened beverages has been associated with an augmented prevalence of metabolic diseases, namely, obesity, type II diabetes, and metabolic syndrome. On the other hand, nowadays, it is broadly accepted that foods and beverages rich in (poly)phenols could contribute to reducing the incidence of these pathologies. In this sense, the objective of the work was to revalue second quality citrus fruits for the development of new beverages, rich in anthocyanins and flavanones (maqui berry and second qualities citrus-based), and evaluate the influence of alternative sweeteners (sucralose, sucrose, or stevia), regarding the bioaccessibility and bioavailability of these bioactive compounds in the frame of a chronic (longitudinal) intervention. To fulfill this objective, a longitudinal study of the urinary excretion of anthocyanins and flavanones, after 2-months of ingestion of the developed maqui-citrus beverage, by 138 volunteers (n = 46 per beverage) and the analysis of the resulting phenolic metabolites by ultra-high performance liquid chromatography coupled to mass spectrometry (UHPLC-ESI-QqQ-MS/MS) was carried out. As major results, the bioavailable metabolites of caffeic acid (CA), catechol (CAT), 3,4-di-hydroxyphenylacetic acid (DHPAA), eriodictyol (E), homoeriodictyol (HE), hippuric acid (HA), naringenin (N), trans-ferulic acid (TFA), 2,4,6-tri-hydroxybenzaldehyde (THBA), trans-isoferulic acid (TIFA), and vanillic acid (VA) were detected. Accordingly, significantly different bioavailability was dependent on the sweetener used, allowing proposing stevia and, to a lower extent, sucralose, as valuable alternatives to sucrose.

Urinary Biomarkers for Orange Juice Consumption.

SCOPE: As orange juice belongs to one of the most consumed juices worldwide, a human study is performed to identify urinary biomarkers for the consumption of orange juice in order to differentiate between low, medium, and high intake. METHODS AND RESULTS: The 32 study participants abstained from citrus fruits, juices and products thereof, except for one portion of orange juice, for eight days. Throughout the study, spot urine samples are collected and quantitatively analyzed by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) regarding their content of several potential biomarkers for orange juice intake after enzymatic treatment with ß-glucuronidase. Proline betaine is determined as a long-term biomarker: based on its urinary excretion, orange juice consumption is traceable for at least 72 h after intake. Naringenin and hesperetin are identified as qualitative short-term biomarkers. Synephrine sulfate also showed a fast increase and decrease in a semi-quantitative approach. In the case of phloretin, no correlation between orange juice consumption and the urinary concentration is observed. CONCLUSION: Proline betaine is the most promising biomarker for orange juice consumption and allows to differentiate between low, medium, and high intake. Hesperetin and naringenin (as well as synephrine) are applicable as supporting biomarkers, whereas phloretin does not represent a reliable biomarker for orange juice consumption.

Metabolic profiling of mice plasma, bile, urine and feces after oral administration of two licorice flavonones.

ETHNOPHARMACOLOGICAL RELEVANCE: Licorice is an ancient food and medicinal plant. Liquiritigenin and liquiritin, two kinds of major flavonoes in licorice, are effective substances used as antioxidant, anti-inflammatory and tumor-suppressive food, cosmetics or medicines. However, their in vivo metabolites have not been fully explored. AIM OF STUDY: To clarify the metabolism of liquiritigenin and liquiritin in mice. MATERIALS AND METHODS: In this study, we developed a liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry approach to determine the metabolites in mice plasma, bile, urine and feces after oral administration of liquiritigenin or liquiritin. The structures of those metabolites were tentatively identified according to their fragment pathways, accurate masses, characteristic product ions, metabolism laws or reference standard matching. RESULTS: A total of 26 and 24 metabolites of liquiritigenin or liquiritin were respectively identified. The products related with apigenin, luteolin or quercetin were the major metabolites of liquiritigenin or liquiritin in mice. Seven main metabolic pathways including (de)hydrogenation, (de)hydroxylation, (de)glycosylation, (de)methoxylation, acetylation, glucuronidation and sulfation were summarized to tentatively explain their biotransformation. CONCLUSION: This study not only can provide the evidence for in vivo metabolites and pharmacokinetic mechanism of liquiritigenin and liquiritin, but also may lay the foundation for further development and utilization of liquiritigenin, liquiritin and then licorice.

Enhanced pseudotargeted analysis using a segment data dependent acquisition strategy by liquid chromatography-tandem mass spectrometry for a metabolomics study of liquiritin in the treatment of depression.

An enhanced pseudotargeted method using a segment data-dependent acquisition mode based on ultra-high performance liquid chromatography-tandem mass spectrometry was developed. This segment data dependent acquisition-based pseudotargeted method could improve the detection of co-eluted ions and extend the coverage of analytes. A set of 502 multiple reaction monitoring channels were obtained by this segment strategy, which was twice the number created by the traditional data-dependent acquisition mode. Compared with the untargeted method, the pseudotargeted profiling demonstrated higher sensitivity and higher precision. More than 90% of the metabolites detected by the enhanced pseudotargeted method had relative standard deviations less than 15%. The segment data dependent acquisition-based pseudotargeted method was successfully applied to the metabolomics study of the depressed rats with the treatment of liquiritin. Forty-seven differential metabolites were screened and five metabolic pathways were found to be related to depression including retinol metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine metabolism, terpenoid backbone biosynthesis, and lysine degradation. The segment data dependent acquisition-based pseudotargeted method widened the coverage of metabolites with good sensitivity and precision, which exhibited great potential in the discovery of differential metabolites in metabolomics studies.

Urinary flavanone concentrations as biomarkers of dietary flavanone intakes in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

In the present study, the aim was to investigate the correlation between the acute and habitual dietary intake of flavanones, their main food sources and the concentrations of aglycones naringenin and hesperetin in 24 h urine in a European population. A 24-h dietary recall (24-HDR) and a 24-h urine sample were collected the same day from a subsample of 475 people from four different countries of the European Prospective Investigation into Cancer and Nutrition study. Acute and habitual dietary data were captured through a standardised 24-HDR and a country/centre-specific validated dietary questionnaire (DQ). The intake of dietary flavanones was estimated using the Phenol-Explorer database. Urinary flavanones (naringenin and hesperetin) were analysed using tandem MS with a previous enzymatic hydrolysis. Weak partial correlation coefficients were found between urinary flavanone concentrations and both acute and habitual dietary flavanone intakes (Rpartial = 0·14-0·17). Partial correlations were stronger between urinary excretions and acute intakes of citrus fruit and juices (Rpartial ∼ 0·6) than with habitual intakes of citrus fruit and juices (Rpartial ∼ 0·24). In conclusion, according to our results, urinary excretion of flavanones can be considered a good biomarker of acute citrus intake. However, low associations between habitual flavanone intake and urinary excretion suggest a possible inaccurate estimation of their intake or a too sporadic intake. For assessing habitual exposures, multiple urinary collections may be needed. These results show that none of the approaches tested is ideal, and the use of both DQ and biomarkers can be recommended.

Determination of cis-diol-containing flavonoids in real samples using boronate affinity quantum dots coated with imprinted silica based on controllable oriented surface imprinting approach.

Novel boronate affinity imprinted quantum dots (BA-CdTe@MIPs QDs) were used to develop a selective and sensitive fluorescent nanosensor for determination of cis-diol-containing flavonoids such as quercetin (Qu), baicalein (Bai) and luteolin (Lut) based on controllable oriented surface imprinting approach. The boronate affinity imprinted silica was used as recognition elements. Under the optimum conditions, the imprinting factor (IF) for Qu, Bai and Lut was evaluated to be 9.42, 6.58 and 10.91, respectively. The results indicated that the boronate affinity quantum dots coated with imprinted silica were successfully prepared. The obtained BA-CdTe@MIPs QDs provided high selectivity and high sensitivity for cis-diol-containing flavonoids such as quercetin and luteolin. The BA-CdTe@MIPs QDs exhibited linear decrease in fluorescence intensity with the increase of concentration of quercetin in the 0.05-25 µM concentration range. The detection limit (LOD) is evaluated to be 0.02 µM. The obtained fluorescent nanosensor could be successfully applied to efficient detection of cis-diol-containing flavonoids in onion skin and human urine samples. The recoveries for the spiked onion skin and urine samples were evaluated to be 83.50-104.00% and 86.67-105.00%, respectively. Clearly, this study provides a rapid and efficient fluorescent detection tool for cis-diol-containing flavonoids in real samples.

Metabolite Profiling of Naringin in Rat Urine and Feces Using Stable Isotope-Labeling-Based Liquid Chromatography-Mass Spectrometry.

Naringin has been documented to possess various bioactivities. Due to thorny endogenous interferences, the metabolism pathways of naringin and exact amounts of derived phenolic catabolites have not been definitely assigned. In this work, stable isotope-labeling-based liquid chromatography-mass spectrometry methods were developed to eliminate the endogenous interferences. [2',3',5',6'-D4]-naringin was orally administrated to rats. Urine and feces samples were collected and then analyzed with ultrahigh-performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry (UHPLC-Q-TOF-MS/MS). A total of 21 flavonoid metabolites and 11 phenolic catabolites were screened. The metabolism and catabolism pathways were proposed. Furthermore, deuterated naringin and its main metabolites were determined with rapid resolution liquid chromatography tandem triple quadrupole mass spectrometry (RRLC-QqQ-MS/MS). The overall recovery of ingested deuterated naringin was calculated as 56.9% without endogenous interferences. The obtained results provide essential information for further pharmacological studies of naringin.

UFLC-Q-TOF-MS/MS-Based Screening and Identification of Flavonoids and Derived Metabolites in Human Urine after Oral Administration of Exocarpium Citri Grandis Extract.

Exocarpium Citri grandis (ECG) is an important Traditional Chinese Medicine (TCM) for the treatment of cough and phlegm, and the flavonoids contained were considered the main effective components. To date, the systematic chemical profiling of these flavonoids and derived in vivo metabolites in human have not been well investigated. ECG was extracted using boiling water and then provided to volunteers for oral administration. Following the ingestion, urine samples were collected from volunteers over 48 h. The extract and urine samples were analyzed using ultra-fast liquid chromatography/quadrupole-time-of-flight tandem mass spectrometry (UFLC-Q-TOF-MS/MS) system to screen and identify flavonoids and derived in vivo metabolites. A total of 18 flavonoids were identified in the ECG extract, and 20 metabolites, mainly glucuronide and sulfate conjugates, were screened in urine samples collected post consumption. The overall excretion of naringenin metabolites corresponded to 5.45% of intake and occurred mainly within 4-12 h after the ingestion. Meanwhile, another 29 phenolic catabolites were detected in urine. Obtained data revealed that flavonoids were abundant in the ECG extract, and these components underwent extensive phase II metabolism in humans. These results provided valuable information for further study of the pharmacology and mechanism of action of ECG.

Phosphorus doped graphitic carbon nitride nanosheets as fluorescence probe for the detection of baicalein.

Phosphorus doped graphitic carbon nitride (P-g-C3N4) nanosheets were synthesized by calcination. P-g-C3N4 nanosheets were characterized by XRD, XPS, TEM, fluorescence, ultraviolet-visible absorption and Fourier transform infrared spectroscopy. The fluorescence of the P-g-C3N4 nanosheets was gradually quenched with the increase in the concentration of baicalein at room temperature. The proposed probe was used for the determination of baicalein in the concentration 2.0-30µM with a detection limit of 53nM. The quenching mechanism was discussed. The P-g-C3N4 nanosheets have been successfully applied for effective and selective detection of baicalein in human urine samples and blood samples.

The Oral Bioavailability of 8-Prenylnaringenin from Hops (Humulus Lupulus L.) in Healthy Women and Men is Significantly Higher than that of its Positional Isomer 6-Prenylnaringenin in a Randomized Crossover Trial.

SCOPE: Prenylated chalcones and flavonoids from hop (Humulus lupulus L.), such as 6-prenylnaringenin (6-PN) and 8-prenylnaringenin (8-PN), are investigated for their health beneficial and anticancer activities. We, thus, compare the oral bioavailability and safety of 6-PN and 8-PN in healthy young women and men, and investigated their effects on peripheral blood mononuclear cells (PBMC). METHODS AND RESULTS: A double-blind, placebo-controlled, crossover trial is conducted with 16 healthy volunteers (eight women, eight men) given a single oral dose of 500 mg 6-PN, 8-PN, or placebo in random order. Maximum total concentrations of 6-PN and 8-PN in plasma (Cmax ; 543 and 2834 nmol L-1 ) and their respective area under the plasma concentration-time curve (AUC; 3635 and 15801 nmol L-1 × h) are significantly (5.2- and 4.3-fold) higher for 8-PN than for 6-PN (p Ë‚ 0.05). PBMC for ex vivo experiments are isolated from blood sampled before and 6 h after intake of 6-PN, 8-PN, or placebo. Despite the single-treatment regime and low blood concentrations, both 6-PN and 8-PN increase the survival of PBMC relative to control. CONCLUSION: 8-PN is significantly more bioavailable in healthy humans than its isomer 6-PN. Interestingly, 6-PN, despite being less bioavailable, is similarly effective as 8-PN in enhancing PBMC viability.

Association between different dietary polyphenol subclasses and the improvement in cardiometabolic risk factors: evidence from a randomized controlled clinical trial.

AIMS: Due to their different chemical structures and metabolism, polyphenol subclasses may have specific impact on cardiometabolic risk factors. Our aim was to evaluate whether the intake of different polyphenol subclasses is associated with clinical outcomes beneficially improved by polyphenols in a nutritional trial performed by our group (postprandial lipid response, glucose homeostasis, early insulin secretion and oxidative stress). METHODS: The present study is a secondary analysis of a nutritional intervention study with a diet naturally rich in polyphenols. The data are derived from 78 participants at high cardiovascular risk who completed the ETHERPATH trial. The associations between variations in polyphenol subclasses (phenolic acids, anthocyanidins, flavones, flavan-3-ols, flavonols and flavanones) and clinical outcomes beneficially influenced by polyphenols were firstly explored by Spearman's correlation. Thereafter, adjustment for gender, age and body mass index (BMI) was run. Linear regression analysis was used to assess the class of polyphenols that best predicted the outcome. RESULTS: Flavanone intake was inversely correlated with postprandial lipid response, whereas flavone intake was related to postchallenge glucose response. Anthocyanidins and flavan-3-ols associated positively with early insulin secretion. The decrease in urinary isoprostanes correlated with anthocyanidins, flavan-3-ols and flavonols. Correlations did not change after adjustment for gender, age, and BMI. Linear regression analysis showed an independent association between flavonols and urinary isoprostanes, whereas early insulin secretion was mainly associated with flavan-3-ols intake. CONCLUSIONS: The results of this study show that a polyphenol-rich diet may have a pleiotropic effect on cardiometabolic risk factors thanks to the specific action of different polyphenol subclasses.

Bioavailability of orange juice (poly)phenols: the impact of short-term cessation of training by male endurance athletes.

Background: Physical exercise has been reported to increase the bioavailability of citrus flavanones.Objective: We investigated the bioavailability of orange juice (OJ) (poly)phenols in endurance-trained males before and after cessation of training for 7 d.Design: Ten fit, endurance-trained males, with a mean ± SD maximal oxygen consumption of 58.2 ± 5.3 mL · kg-1 · min-1, followed a low (poly)phenol diet for 2 d before drinking 500 mL of OJ containing 398 µmol of (poly)phenols, of which 330 µmol was flavanones. After the volunteers stopped training for 7 d the feeding study was repeated. Urine samples were collected 12 h pre- and 24 h post-OJ consumption. Bioavailability was assessed by the quantitative analysis of urinary flavanone metabolites and (poly)phenol catabolites with the use of high-pressure liquid chromatography-high resolution mass spectrometry.Results: During training, 0-24-h urinary excretion of flavanone metabolites, mainly hesperetin-3'-O-glucuronide, hesperetin-3'-sulfate, naringenin-4'-O-glucuronide, naringenin-7-O-glucuronide, was equivalent to 4.2% of OJ flavanone intake. This increased significantly to 5.2% when OJ was consumed after the volunteers stopped training for 7 d. Overall, this trend, although not significant, was also observed with OJ-derived colonic catabolites, which, after supplementation in the trained state, were excreted in amounts equivalent to 51% of intake compared with 59% after cessation of training. However, urinary excretion of 3 colonic catabolites of bacterial origin, most notably, 3-(3'-hydroxy-4'-methoxyphenyl)hydracrylic acid, did increase significantly when OJ was consumed postcessation compared with precessation of training. Data were also obtained on interindividual variations in flavanone bioavailability.Conclusions: A 7-d cessation of endurance training enhanced, rather than reduced, the bioavailability of OJ flavanones. The biological significance of these differences and whether they extend to the bioavailability of other dietary (poly)phenols remain to be determined. Hesperetin-3'-O-glucuronide and the colonic microbiota-derived catabolite 3-(3'-hydroxy-4'-methoxyphenyl)hydracrylic acid are key biomarkers of the consumption of hesperetin-O-glycoside-containing OJ and other citrus products. This trial was registered at clinicaltrials.gov as NCT02627547.

Urinary metabolite profiling of flavonoids in Chinese volunteers after consumption of orange juice by UFLC-Q-TOF-MS/MS.

The metabolism of flavonoids derived from orange juice in Chinese volunteers has not been well investigated. With the ultra-fast liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry (UFLC-Q-TOF-MS/MS) system, orange juice-derived flavonoids, as well as metabolites contained in urine collected from healthy Chinese volunteers after consumption of 250mL orange juice, were systematically identified and quantified. Finally, a total of 9 flavonoids and 30 metabolites were detected. Obtained results revealed that flavonoids derived from orange juice underwent extensive phase II metabolism in human, mainly comprising glucuronidation and sulfation. The overall recovery of the primary flavonoid aglycones, i.e., naringenin and hesperetin, were both approximately equivalent 22% of intake, primarily occurred in 4-12h post consumption. Meanwhile, additional 35 phenolic catabolites were identified in urine collected post consumption. However, it is difficult to determine the exact amounts of phenolic catabolites derived from specific flavonoid due to the interference of diets and other flavonoids. This work would be valuable for the clarification of metabolic profiles for flavonoids in Chinese population.

Anthocyanins and Flavanones Are More Bioavailable than Previously Perceived: A Review of Recent Evidence.

This review considers recent investigations on the bioavailability of anthocyanins and flavanones. Both flavonoids are significant dietary components and are considered to be poorly bioavailable, as only low levels of phase II metabolites appear in the circulatory system and are excreted in urine. However, when lower molecular weight phenolic and aromatic ring-fission catabolites, produced primarily by the action of the colonic microbiota, are taken into account, it is evident that anthocyanins and flavanones are much more bioavailable than previously envisaged. The metabolic events to which these flavonoids are subjected as they pass along the gastrointestinal tract and are absorbed into the circulatory system prior to their rapid elimination by renal excretion are highlighted. Studies on the impact of other food components and the probiotic intake on flavonoid bioavailability are summarized, as is the bioactivity of metabolites and catabolites assayed using a variety of in vitro model systems.

Effects of Intestinal Microecology on Metabolism and Pharmacokinetics of Oral Wogonoside and Baicalin.

Baicalin and wogonoside are two of the most abundant flavonoid glycosides in the root of Scutellaria baicalensis Georgi, which is a widely used peroral herbal medicine with anticancer, antiviral, antibacterial and anti-inflammatory properties. In the present study, the effects of intestinal microecology on the metabolism and pharmacokinetics of orally administered baicalin and wogonoside were investigated by UPLC-QTOF/MS measurement of the difference in metabolites between normal and antibiotic-pretreated rats. In the antibiotic-pretreated rats, the plasma concentration-time profile and pharmacokinetic parameters of the two flavonoid glycosides and their relevant aglycone forms were significantly changed compared with those in normal rats. Further, hydrolysis and glucuronidated metabolites were not detected in the cecum contents and urine samples from antibiotic-pretreated rats. These results suggested that intestinal microbiota may play a key role in the pharmacokinetics and metabolism of peroral baicalin and wogonoside. According to our findings, it is recommended that the root of S. baicalensis should not be co-administered with antibiotics in clinical use.

Identification of Naringin Metabolites in Human Urine and Feces.

BACKGROUND AND OBJECTIVES: Naringin, an active flavanone glycoside, has been widely considered as a prospective antitussive and expectorant. The present study aimed to elucidate the metabolic profile of naringin in the human body. METHODS: Four male and three female volunteers (20-30 years old and 18.8-21.7 kg/m2 Body Mass Index) were orally administrated 320 mg naringin; their urine and feces were collected at different times and the corresponding metabolites were identified with a high resolution ultra-fast liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry (UFLC-Q-TOF-MS/MS) system. RESULTS: Sixteen conjugative metabolites and five polyphenols were identified. These detected metabolites varied in the types, relative responses, and excretion times among different individuals. CONCLUSIONS: The results revealed that naringin underwent extensive phase II metabolism in the human body and yielded an array of conjugated products. This study provided a reference for further clinical studies and in vivo metabolism of other flavonoids.