Skip to main content Accessibility help
×
Home

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

  • Naiara Orrego-Lagarón (a1), Miriam Martínez-Huélamo (a2) (a3), Anna Vallverdú-Queralt (a2) (a3), Rosa M. Lamuela-Raventos (a2) (a3) and Elvira Escribano-Ferrer (a1) (a3)...

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− 4cm/s and 5·49 (sd 1·86) × 10− 4cm/s, respectively), at a level similar to the highly permeable compound, naproxen (6·39 (sd 1·23) × 10− 4cm/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.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      High gastrointestinal permeability and local metabolism of naringenin: influence of antibiotic treatment on absorption and metabolism
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      High gastrointestinal permeability and local metabolism of naringenin: influence of antibiotic treatment on absorption and metabolism
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      High gastrointestinal permeability and local metabolism of naringenin: influence of antibiotic treatment on absorption and metabolism
      Available formats
      ×

Copyright

Corresponding author

* Corresponding author: E. Escribano-Ferrer, +34 9340 24578, email eescribano@ub.edu

References

Hide All
1 Xu, H, Kulkarni, KH, Singh, R, et al. (2009) Disposition of naringenin via glucuronidation pathway is affected by compensating efflux transporters of hydrophilic glucuronides. Mol Pharm 6, 17031715.
2 Yoshimura, M, Sano, A, Kamei, J, et al. (2009) Identification and quantification of metabolites of orally administered naringenin chalcone in rats. J Agric Food Chem 57, 64326437.
3 Felgines, C, Texier, O, Morand, C, et al. (2000) Bioavailability of the flavanone naringenin and its glycosides in rats. Am J Physiol Gastrointest Liver Physiol 279, G1148G1154.
4 Chabane, MN, Al Ahmad, A, Peluso, J, et al. (2009) Quercetin and naringenin transport across human intestinal Caco-2 cells. J Pharm Pharmacol 61, 14731483.
5 Amidon, GL, Lennernäs, H, Shah, VP, et al. (1995) A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 12, 413420.
6 Azuma, K, Ippoushi, K, Ito, H, et al. (2002) Combination of lipids and emulsifiers enhances the absorption of orally administered quercetin in rats. J Agric Food Chem 50, 17061712.
7 Jeong, EJ, Jia, X & Hu, M (2005) Disposition of formononetin via enteric recycling: metabolism and excretion in mouse intestinal perfusion and Caco-2 cell models. Mol Pharm 2, 319328.
8 Escribano, E, García Sala, X, Salamanca, J, et al. (2012) Single-pass intestinal perfusion to establish the intestinal permeability of model drugs in mouse. Int J Pharm 436, 472477.
9 Lieber, CS, Leo, MA, Mak, KM, et al. (2004) Model of non-alcoholic steatohepatitis. Am J Clin Nutr 79, 502509.
10 Vallverdú-Queralt, A, De Alvarenga, JF, Estruch, R, et al. (2013) Bioactive compounds present in the Mediterranean sofrito. Food Chem 41, 33653372.
11 Martínez-Huélamo, M, Tulipani, S & Torrado, X (2012) Validation of a new LC-MS/MS method for the detection and quantification of phenolic metabolites from tomato sauce in biological samples. J Agric Food Chem 60, 45424549.
12 Dahan, A, West, BT & Amidon, GL (2009) Segmental-dependent membrane permeability along the intestine following oral drug administration: evaluation of a triple single-pass intestinal perfusion (TSPIP) approach in the rat. Eur J Pharm Sci 36, 320329.
13 Eisen, EJ (1976) Results of growth curve analyses in mice and rats. J Anim Sci 42, 10081023.
14 Miglioli, PA, Allerberger, F, Calabró, GB, et al. (2001) Effects of daily oral administration of rifaximin and neomycin on faecal aerobic flora in rats. Pharmacol Res 44, 373375.
15 Scarpignato, C & Pelosini, I (2005) Rifaximin, a poorly absorbed antibiotic: pharmacology and clinical potential. Chemotherapy 51, Suppl. 1, S36S66.
16 Tulipani, S, Martinez-Huelamo, M, Rotches Ribalta, M, et al. (2012) Oil matrix effects on plasma exposure and urinary excretion of phenolic compounds from tomato sauces: evidence from a human pilot study. Food Chem 130, 581590.
17 Varma, MVS & Panchagnula, R (2005) Prediction of in vivo intestinal absorption enhancement on P-glycoprotein inhibition, from rat in situ permeability. J Pharm Sci 94, 16941704.
18 Zakeri-Milani, P, Valizadeh, H, Tajerzadeh, H, et al. (2007) Predicting human intestinal permeability using single-pass intestinal perfusion in rat. J Pharm Sci 10, 368379.
19 Sutton, SC, Rinaldi, MTS & Vukovinsky, KE (2001) Comparison of the gravimetric, phenol red, and 14C-PEG-3350 methods to determine water absorption in the rat single-pass intestinal perfusion model. AAPS Pharm Sci 3, 15.
20 Japar, D, Wu, SP, Hu, Y, et al. (2010) Significance and regional dependency of peptide transporter (PEPT) 1 in the intestinal permeability of glycylsarcosine: in situ single-pass perfusion studies in wild-type and Pept1 knockout mice. Drug Metab and Dispos 38, 17401746.
21 Incecayir, T, Tsume, Y & Amidon, GL (2013) Comparison of the permeability of metoprolol and labetalol in rat, mouse, and Caco-2 cells: use as a reference standard for BCS classification. Mol Pharm 10, 958966.
22 Masaoka, Y, Tanaka, Y, Kataoba, M, et al. (2006) Site of absorption after oral administration: assessment of membrane permeability and luminal concentration of drugs in each segment of gastrointestinal tract. Eur J Pharm Sci 29, 240250.
23 McConnell, EL, Basit, AW & Murdan, S (2008) Measurements of rat and mouse gastrointestinal pH, fluid and lymphoid tissue, and implications for in vivo experiments. J Pharm Pharm 60, 6370.
24 Komiya, I, Park, JY, Kamani, A, et al. (1980) Quantitative mechanistic studies in simultaneous fluid flow and intestinal absorption using steroids as model solutes. Int J Pharm 4, 249262.
25 Vallverdú-Queralt, A, Regueiro, J, Martinez-Huelamo, , et al. (2014) A comprehensive study on the phenolic profile of widely used culinary herbs and spices: rosemary, thyme, oregano, cinnamon, cumin and bay. Food Chem 154, 299307.
26 DrugBank (2014) DrugBank database (open data drug and drug target data base). http://www.drugbank.ca/drugs/DB03467 (accessed accessed May 2014).
27 Fagerholm, U, Johansson, M & Lennernäs, H (1996) Comparison between permeability coefficients in rat and human jejunum. Pharm Res 13, 13361342.
28 Takanaga, H, Ohnishi, A, Matsuo, H, et al. (1998) Inhibition of vinblastine efflux mediated by P-glycoprotein by grapefruit juice components in Caco-2 cells. Biol Pharm Bull 21, 10621066.
29 Bailey, DG, Malcolm, J, Arnold, O, et al. (1998) Grapefruit juice-drug interactions. Br J Clin Pharmacol 46, 101110.
30 Le Goff, N, Koffel, JC, Vandenschrieck, S, et al. (2002) Comparison of in vitro hepatic models for the prediction of metabolic interaction between simvastatin and naringenin. Eur J Drug Metab Pharmacokinet 27, 233241.
31 Le Goff-Klein, N, Koffel, JC, Jung, L, et al. (2005) In vitro inhibition of simvastatin metabolism, a HMG-CoA reductase inhibitor in human and rat liver by bergamottin, a component of grapefruit juice. Eur J Pharm Sci 18, 3135.
32 Hsiu, SL, Huang, TY, Hou, YC, et al. (2002) Comparison of metabolic pharmacokinetics of naringin and naringenin in rabbits. Life Sci 70, 14811489.
33 Chen, G, Zhang, D, Jing, N, et al. (2003) Human gastrointestinal sulfotransferases: identification and distribution. Toxicol Appl Pharmacol 187, 186197.
34 Gregory, P, Lewinsky, R, Gardner-Stephen, D, et al. (2004) Regulation of UDP glucuronosyltransferases in the gastrointestinal tract. Toxicol Appl Pharmacol 199, 354356.
35 Fang, T, Wang, Y, Ma, Y, et al. (2006) A rapid LC/MS/MS quantitation assay for naringin and its two metabolites in rats plasma. J Pharm Biomed Anal 40, 454459.
36 Manach, C, Scalbert, A, Morand, C, et al. (2004) Polyphenols: food sources and bioavailability. Am J Clin Nutr 79, 727747.
37 Rechner, AR, Smith, MA, Kuhnle, G, et al. (2004) Colonic metabolism of dietary polyphenols: influence of structure on microbial fermentation products. Free Radic Biol Med 36, 212225.
38 Possimiers, S, Bolca, S, Verstraete, W, et al. (2011) The intestinal microbiome: a separate organ inside the body with the metabolic potential to influence the bioactivity of botanicals. Fitoterapia 82, 5366.
39 Boto-Ordóñez, M, Rothwell, JA, Andres-Lacueva, C, et al. (2014) Prediction of the wine polyphenol metabolic space: an application of the Phenol-Explorer database. Mol Nutr Food Res 58, 466477.
40 Cong, D, Fong, AK, Lee, R, et al. (2001) Absorption of benzoic acid in segmental regions of the vascularly perfused rat small intestine preparation. Drug Metab Dispos 29, 15391547.
41 Gao, K, Xu, A, Krul, C, et al. (2006) Of the major phenolic acids formed during human microbial fermentation of tea, citrus, and soy flavonoid supplements, only 3, 4-dihydroxyphenylacetic acid has antiproliferative activity. J Nutr 136, 5257.
42 Aura, AM (2008) Microbial metabolism of dietary phenolic compounds in the colon. Phytochem Rev 7, 407429.
43 Serra, A, Macià, A, Romero, MP, et al. (2012) Metabolic pathway of the colonic metabolism of flavonoids (flavonols, flavones and flavonones) and phenolic acids. Food Chem 130, 383393.
44 Konishi, Y & Kobayashi, S (2004) Microbial metabolites of ingested caffeic acid are absorbed by the monocarboxylic acid transporter (MCT) in intestinal Caco-2 cell monolayers. J Agric Food Chem 52, 64186424.
45 Spoelstra, SF (1978) Degradation of tyrosine in anaerobically stored piggery wastes and in pig feces. Appl Environ Microbiol 36, 631638.
46 Lord, RS & Bradley, JA (2008) Clinical applications of urinary organic acids. Part 2. Dysbiosis markers. Altern Med Rev 13, 292306.
47 Gao, J, Gillilland, MIII & Owyang, C (2014) Rifaximin, gut microbes and mucosal inflammation: unravelling a complex relationship. Gut Microbes 5, 571575.
48 Miene, C, Weise, A & Glei, M (2011) Impact of polyphenol metabolites produced by colonic microbiota on expression of COX-2 and GSTT2 in human colon cells (LT97). Nutr Cancer 63, 653662.

Keywords

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed