title: High gastrointestinal permeability and local metabolism of naringenin: influence of antibiotic treatment on absorption and metabolism.
abstract: 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.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology,Faculty of Pharmacy, University of Barcelona, Avgda Joan XXIII s/n,E-08028Barcelona,Spain.
authors.forename: Naiara
authors.initials: N
authors.lastname: Orrego-Lagarón
authors.affiliation: Nutrition and Food Science Department, XaRTA, INSA, Faculty of Pharmacy, University of Barcelona,E-08028Barcelona,Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Martínez-Huélamo
authors.affiliation: Nutrition and Food Science Department, XaRTA, INSA, Faculty of Pharmacy, University of Barcelona,E-08028Barcelona,Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Vallverdú-Queralt
authors.affiliation: Nutrition and Food Science Department, XaRTA, INSA, Faculty of Pharmacy, University of Barcelona,E-08028Barcelona,Spain.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Lamuela-Raventos
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology,Faculty of Pharmacy, University of Barcelona, Avgda Joan XXIII s/n,E-08028Barcelona,Spain.
authors.forename: Elvira
authors.initials: E
authors.lastname: Escribano-Ferrer
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D044950:Flavanones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism; D006626:Hippurates / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D008297:Male; D051379:Mice; D010477:Perfusion; D059808:Polyphenols / Q000097:blood; D012294:Rifamycins / Q000494:pharmacology*; D000078262:Rifaximin; D053719:Tandem Mass Spectrometry
chemical_list: D000900:Anti-Bacterial Agents; D044950:Flavanones; D006626:Hippurates; D059808:Polyphenols; D012294:Rifamycins; C056283:4-hydroxyhippuric acid; C005273:naringenin; D000078262:Rifaximin; C030514:hippuric acid
keywords: Gastrointestinal tract; In situ single-pass perfusion; Metabolism; Naringenin; Rifaximin