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      Absorption, Metabolism and Excretion of Cranberry (Poly)phenols in Humans: A Dose Response Study and Assessment of Inter-Individual Variability

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          Abstract

          The beneficial health effects of cranberries have been attributed to their (poly)phenol content. Recent studies have investigated the absorption, metabolism and excretion of cranberry (poly)phenols; however, little is known about whether they follow a dose response in vivo at different levels of intake. An acute double-blind randomized controlled trial in 10 healthy men with cranberry juices containing 409, 787, 1238, 1534 and 1910 mg total (poly)phenols was performed. Blood and urine were analyzed by UPLC-Q-TOF-MS. Sixty metabolites were identified in plasma and urine including cinnamic acids, dihydrocinnamic, flavonols, benzoic acids, phenylacetic acids, benzaldehydes, valerolactones, hippuric acids, catechols, and pyrogallols. Total plasma, but not excreted urinary (poly)phenol metabolites, exhibited a linear dose response ( r 2 = 0.74, p < 0.05), driven by caffeic acid 4- O-ß- d-glucuronide, quercetin-3- O-ß- d-glucuronide, ferulic acid 4- O-ß- d-glucuronide, 2,5-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, ferulic acid, caffeic acid 3- O-ß- d-glucuronide, sinapic acid, ferulic acid 4- O-sulfate, 3-hydroxybenzoic acid, syringic acid, vanillic acid-4- O-sulfate, (4 R)-5-(3′-hydroxyphenyl)-γ-valerolactone-4′- O-sulfate, 4-methylgallic acid-3- O-sulfate, and isoferulic acid 3- O-sulfate (all r 2 ≥ 0.89, p < 0.05). Inter-individual variability of the plasma metabolite concentration was broad and dependent on the metabolite. Herein, we show that specific plasma (poly)phenol metabolites are linearly related to the amount of (poly)phenols consumed in cranberry juice. The large inter-individual variation in metabolite profile may be due to variations in the gut microbiome.

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          PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel.

          This study presents PKSolver, a freely available menu-driven add-in program for Microsoft Excel written in Visual Basic for Applications (VBA), for solving basic problems in pharmacokinetic (PK) and pharmacodynamic (PD) data analysis. The program provides a range of modules for PK and PD analysis including noncompartmental analysis (NCA), compartmental analysis (CA), and pharmacodynamic modeling. Two special built-in modules, multiple absorption sites (MAS) and enterohepatic circulation (EHC), were developed for fitting the double-peak concentration-time profile based on the classical one-compartment model. In addition, twenty frequently used pharmacokinetic functions were encoded as a macro and can be directly accessed in an Excel spreadsheet. To evaluate the program, a detailed comparison of modeling PK data using PKSolver and professional PK/PD software package WinNonlin and Scientist was performed. The results showed that the parameters estimated with PKSolver were satisfactory. In conclusion, the PKSolver simplified the PK and PD data analysis process and its output could be generated in Microsoft Word in the form of an integrated report. The program provides pharmacokinetic researchers with a fast and easy-to-use tool for routine and basic PK and PD data analysis with a more user-friendly interface. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.
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            Interaction between phenolics and gut microbiota: role in human health.

            Dietary phenolic compounds are often transformed before absorption. This transformation modulates their biological activity. Different studies have been carried out to understand gut microbiota transformations of particular polyphenol types and identify the responsible microorganisms. Although there are potentially thousands of different phenolic compounds in the diet, they are typically transformed to a much smaller number of metabolites. The aim of this review was to discuss the current information about the microbial degradation metabolites obtained from different phenolics and their formation pathways, identifying their differences and similarities. The modulation of gut microbial population by phenolics was also reviewed in order to understand the two-way phenolic-microbiota interaction. Clostridium and Eubacterium genera, which are phylogenetically associated, are other common elements involved in the metabolism of many phenolics. The health benefits from phenolic consumption should be attributed to their bioactive metabolites and also to the modulation of the intestinal bacterial population.
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              Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies.

              Polyphenols are abundant micronutrients in our diet, and evidence for their role in the prevention of degenerative diseases is emerging. Bioavailability differs greatly from one polyphenol to another, so that the most abundant polyphenols in our diet are not necessarily those leading to the highest concentrations of active metabolites in target tissues. Mean values for the maximal plasma concentration, the time to reach the maximal plasma concentration, the area under the plasma concentration-time curve, the elimination half-life, and the relative urinary excretion were calculated for 18 major polyphenols. We used data from 97 studies that investigated the kinetics and extent of polyphenol absorption among adults, after ingestion of a single dose of polyphenol provided as pure compound, plant extract, or whole food/beverage. The metabolites present in blood, resulting from digestive and hepatic activity, usually differ from the native compounds. The nature of the known metabolites is described when data are available. The plasma concentrations of total metabolites ranged from 0 to 4 mumol/L with an intake of 50 mg aglycone equivalents, and the relative urinary excretion ranged from 0.3% to 43% of the ingested dose, depending on the polyphenol. Gallic acid and isoflavones are the most well-absorbed polyphenols, followed by catechins, flavanones, and quercetin glucosides, but with different kinetics. The least well-absorbed polyphenols are the proanthocyanidins, the galloylated tea catechins, and the anthocyanins. Data are still too limited for assessment of hydroxycinnamic acids and other polyphenols. These data may be useful for the design and interpretation of intervention studies investigating the health effects of polyphenols.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                11 March 2017
                March 2017
                : 9
                : 3
                : 268
                Affiliations
                [1 ]Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, University of Düsseldorf, Moorenstrasse 5, Düsseldorf 40225, Germany; rodrigopedrofeliciano@ 123456gmail.com (R.P.F.); geoffrey.istas@ 123456kcl.ac.uk (G.I.); Christian.Heiss@ 123456med.uni-duesseldorf.de (C.H.)
                [2 ]Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King’s College London, Franklin Wilkins Building, 150 Stamford Street, London SE1 9NH, UK; charlotte.1.mills@ 123456kcl.ac.uk
                Author notes
                [* ]Correspondence: ana.rodriguez-mateos@ 123456kcl.ac.uk ; Tel.: +44-0-0207-848-4349
                Article
                nutrients-09-00268
                10.3390/nu9030268
                5372931
                28287476
                23fa1dce-1a9f-4205-89e6-538421551c32
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 02 February 2017
                : 08 March 2017
                Categories
                Article

                Nutrition & Dietetics
                cranberry,bioavailability,dose-response,kinetics,inter-individual variability

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