Absorption and disposition of naringenin and quercetin after simultaneous administration via intestinal perfusion in mice.

As common constituents of tomatoes and other fruits and/or vegetables, naringenin and quercetin are usually ingested together, so for a clearer understanding of their bioavailability, metabolic fates and health benefits, it is more insightful to study them together. The purpose of the present work was to study how co-administration of naringenin and quercetin at realistic doses (3.5 µg ml(-1) and 2.36 µg ml(-1), respectively) influences their absorption and intestinal first-pass metabolism. A single-pass intestinal perfusion model in mice (n = 4-6) was used. Perfusate (every 10 minutes), blood (at 60 min) and bile samples were analysed by an UPLC-ESI-MS/MS method to evaluate the presence of the aglycones and their metabolites. Both naringenin and quercetin showed high permeability coefficients when administered separately (7.71 ± 0.82 × 10(-4) cm s(-1)vs. 7.30 ± 1.95 × 10(-4) cm s(-1), respectively), but these values decreased by 50% with co-administration (4.09 ± 0.89 × 10(-4) cm s(-1) for naringenin and 3.18 ± 0.45 × 10(-4) cm s(-1) for quercetin). Moreover, the level of phase II metabolites in perfusion, plasma and bile samples increased when naringenin and quercetin were administered together. The higher biliary excretion of these metabolites could thus favour the entero-hepatic recycling of the aglycones and metabolites. The results of this study may have several useful applications: to know and consider the possible interactions between polyphenols and drugs that use the same mechanism of absorption and elimination; when polyphenol-rich nutritional supplements are supplied, and in our regular diets to optimize the health benefits afforded by the biological activities of such aglycones and/or metabolites.

Metabolic profile of naringenin in the stomach and colon using liquid chromatography/electrospray ionization linear ion trap quadrupole-Orbitrap-mass spectrometry (LC-ESI-LTQ-Orbitrap-MS) and LC-ESI-MS/MS.

Several biological activities (antioxidant, anti-inflammatory, anticarcinogenic) are attributed to naringenin (NAR)-a predominant flavonoid of citrus fruit and tomato-despite its low bioavailability after ingestion. NAR undergoes extensive metabolism when crossing the gastrointestinal tract, resulting in enteric, hepatic and microbial metabolites, some of them with recognized beneficial effects on human health. This study sought to provide new insights into the metabolism of NAR in regions of the gastrointestinal tract where it has been less studied: the stomach and colon. With this purpose, liquid chromatography coupled with an electrospray ionization hybrid linear ion trap quadrupole Orbitrap mass spectrometry technique (LC-ESI-LTQ-Orbitrap-MS) was used for an accurate identification of NAR metabolites, and liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) on a triple quadrupole was used for their identification and quantification. The combination of both analytical techniques provided a broader metabolic profile of NAR. As far as we know, this is the first in-depth metabolic profiling study of NAR in the stomach of mice. Three of the metabolites determined using the LC-LTQ-Orbitrap could not be identified by LC-ESI-MS/MS in stomach perfusion samples: apigenin, 3-(4-hydroxyphenyl) propionic acid and phloroglucinol. The number of colonic metabolites determined using the LTQ-Orbitrap-MS was more than twice the number identified by LC-ESI-MS/MS.

High gastrointestinal permeability and local metabolism of naringenin: influence of antibiotic treatment on absorption and metabolism.

The present study aims to determine the permeability of naringenin in the stomach, small intestine and colon, to evaluate intestinal and hepatic first-pass metabolism, and to study the influence of the microbiota on the absorption and disposition of naringenin (3.5 µg/ml). A single-pass intestinal perfusion model in mice (n 4-6) was used. Perfusate (every 10 min), blood (at 60 min) and bile samples were taken and analysed to evaluate the presence of naringenin and its metabolites by an HPLC-MS/MS method. To study the influence of the microbiota on the bioavailability of naringenin, a group of animals received the antibiotic rifaximin (50 mg/kg per d) for 5 d, and naringenin permeability was determined in the colon. Naringenin was absorbed well throughout the gastrointestinal tract but mainly in the small intestine and colon (mean permeability coefficient 7.80 (SD 1.54) × 10(-4) cm/s and 5.49 (SD 1.86) × 10(-4) cm/s, respectively), at a level similar to the highly permeable compound, naproxen (6.39 (SD 1.23) × 10(-4) cm/s). According to the high amounts of metabolites found in the perfusate compared to the bile and plasma, naringenin underwent extensive intestinal first-pass metabolism, and the main metabolites excreted were sulfates (84.00 (SD 12.14)%), followed by glucuronides (8.40 (SD 5.67)%). Phase II metabolites were found in all perfusates from 5 min of sampling. Mice treated with rifaximin showed a decrease in naringenin permeability and in the amounts of 4-hydroxyhippuric acid and hippuric acid in the lumen. Naringenin was well absorbed throughout the gastrointestinal tract and its poor bioavailability was due mainly to high intestinal metabolism.