Gastrointestinal absorption of Heparin by lipidization or coadministration with penetration enhancers

A review with 93 references. Heparins are high molecular weight, hydrophilic polyanions, which are unstable under acidic conditions; and therefore they exhibit poor oral bioavailability. Consequently they must be administered via the parenteral route which is expensive, inconvenient, and limits use by outpatients. The development of an oral form of heparin is warranted. This review examined the literature, mostly published between January 2000 and January 2005, pertaining to the gastrointestinal absorption of heparin by lipidization or coadministration with penetration enhancers. A lipidization strategy that was examined involved conjugation of low molecular weight heparin with deoxycholic acid. The majority of studies examined the ability of different formulations, typically utilizing penetration enhancers, to improve heparin bioavailability. The penetration enhancers used included fatty acids, Labrasol™, Gelucire 44/14™, polycationic lipophilic-core dendrons, saponins, mono-N-carboxymethyl chitosan, Carbopol® 934P, a combination of thiolated polycarbophil and glutathione, polymeric nanoparticles, polymeric microparticles, sodium N-[8-(2-hydroxybenzoyl) amino]caprylate (SNAC), and sodium N-[10-(2-hydroxybenzoyl)amino]decanoate (SNAD). The variety of models used and doses of heparin/penetration enhancers applied, however, made it difficult to compare the results between studies. Nevertheless, all of the reviewed drug delivery systems showed therapeutic value and confirmation of the promising results obtained from animal studies, by progression to clinical trials, is necessary. Overall, progress has been made in the quest for an oral heparin formulation.

Gastrointestinal changes associated to heart failure

Over the last decade, several studies were conducted on the gastrointestinal changes associated to chronic heart failure. This article presents a literature review on the physiopathology and clinical consequences of pathological digestive changes of heart failure patients. Structural and functional abnormalities of the gastrointestinal tract, such as edema of absorptive mucosa and intestinal bacterial overgrowth, have been leading to serious clinical consequences. Some of these consequences are cardiac cachexia, systemic inflammatory activation and anemia. These conditions, alone or in combination, may lead to worsening of the pre-existing ventricular dysfunction. Although currently there is no therapy specifically earmarked for gastrointestinal changes associated to heart failure, the understanding of digestive abnormalities is germane for the prevention and management of systemic consequences.

Dietary modulation of the human colonic microbiota: updating the concept of prebiotics

Prebiotics are non-digestible (by the host) food ingredients that have a beneficial effect through their selective metabolism in the intestinal tract. Key to this is the specificity of microbial changes. The present paper reviews the concept in terms of three criteria: (a) resistance to gastric acidity, hydrolysis by mammalian enzymes and gastrointestinal absorption; (b) fermentation by intestinal microflora; (c) selective stimulation of the growth and/or activity of intestinal bacteria associated with health and wellbeing. The conclusion is that prebiotics that currently fulfil these three criteria are fructo-oligosaccharides, galacto-oligosaccharides and lactulose, although promise does exist with several other dietary carbohydrates. Given the range of food vehicles that may be fortified by prebiotics, their ability to confer positive microflora changes and the health aspects that may accrue, it is important that robust technologies to assay functionality are used. This would include a molecular-based approach to determine flora changes. The future use of prebiotics may allow species-level changes in the microbiota, an extrapolation into genera other than the bifidobacteria and lactobacilli, and allow preferential use in disease-prone areas of the body.

Impatto di rifaximina sul microbiota intestinale: selezione di bifidobatteri antibiotico resistenti

The ideal approach for the long term treatment of intestinal disorders, such as inflammatory bowel disease (IBD), is represented by a safe and well tolerated therapy able to reduce mucosal inflammation and maintain homeostasis of the intestinal microbiota. A combined therapy with antimicrobial agents, to reduce antigenic load, and immunomodulators, to ameliorate the dysregulated responses, followed by probiotic supplementation has been proposed. Because of the complementary mechanisms of action of antibiotics and probiotics, a combined therapeutic approach would give advantages in terms of enlargement of the antimicrobial spectrum, due to the barrier effect of probiotic bacteria, and limitation of some side effects of traditional chemiotherapy (i.e. indiscriminate decrease of aggressive and protective intestinal bacteria, altered absorption of nutrient elements, allergic and inflammatory reactions). Rifaximin (4-deoxy-4’-methylpyrido[1’,2’-1,2]imidazo[5,4-c]rifamycin SV) is a product of synthesis experiments designed to modify the parent compound, rifamycin, in order to achieve low gastrointestinal absorption while retaining good antibacterial activity. Both experimental and clinical pharmacology clearly show that this compound is a non systemic antibiotic with a broad spectrum of antibacterial action, covering Gram-positive and Gram-negative organisms, both aerobes and anaerobes. Being virtually non absorbed, its bioavailability within the gastrointestinal tract is rather high with intraluminal and faecal drug concentrations that largely exceed the MIC values observed in vitro against a wide range of pathogenic microorganisms. The gastrointestinal tract represents therefore the primary therapeutic target and gastrointestinal infections the main indication. The little value of rifaximin outside the enteric area minimizes both antimicrobial resistance and systemic adverse events. Fermented dairy products enriched with probiotic bacteria have developed into one of the most successful categories of functional foods. Probiotics are defined as “live microorganisms which, when administered in adequate amounts, confer a health benefit on the host” (FAO/WHO, 2002), and mainly include Lactobacillus and Bifidobacterium species. Probiotic bacteria exert a direct effect on the intestinal microbiota of the host and contribute to organoleptic, rheological and nutritional properties of food. Administration of pharmaceutical probiotic formula has been associated with therapeutic effects in treatment of diarrhoea, constipation, flatulence, enteropathogens colonization, gastroenteritis, hypercholesterolemia, IBD, such as ulcerative colitis (UC), Crohn’s disease, pouchitis and irritable bowel syndrome. Prerequisites for probiotics are to be effective and safe. The characteristics of an effective probiotic for gastrointestinal tract disorders are tolerance to upper gastrointestinal environment (resistance to digestion by enteric or pancreatic enzymes, gastric acid and bile), adhesion on intestinal surface to lengthen the retention time, ability to prevent the adherence, establishment and/or replication of pathogens, production of antimicrobial substances, degradation of toxic catabolites by bacterial detoxifying enzymatic activities, and modulation of the host immune responses. This study was carried out using a validated three-stage fermentative continuous system and it is aimed to investigate the effect of rifaximin on the colonic microbial flora of a healthy individual, in terms of bacterial composition and production of fermentative metabolic end products. Moreover, this is the first study that investigates in vitro the impact of the simultaneous administration of the antibiotic rifaximin and the probiotic B. lactis BI07 on the intestinal microbiota. Bacterial groups of interest were evaluated using culture-based methods and molecular culture-independent techniques (FISH, PCR-DGGE). Metabolic outputs in terms of SCFA profiles were determined by HPLC analysis. Collected data demonstrated that rifaximin as well as antibiotic and probiotic treatment did not change drastically the intestinal microflora, whereas bacteria belonging to Bifidobacterium and Lactobacillus significantly increase over the course of the treatment, suggesting a spontaneous upsurge of rifaximin resistance. These results are in agreement with a previous study, in which it has been demonstrated that rifaximin administration in patients with UC, affects the host with minor variations of the intestinal microflora, and that the microbiota is restored over a wash-out period. In particular, several Bifidobacterium rifaximin resistant mutants could be isolated during the antibiotic treatment, but they disappeared after the antibiotic suspension. Furthermore, bacteria belonging to Atopobium spp. and E. rectale/Clostridium cluster XIVa increased significantly after rifaximin and probiotic treatment. Atopobium genus and E. rectale/Clostridium cluster XIVa are saccharolytic, butyrate-producing bacteria, and for these characteristics they are widely considered health-promoting microorganisms. The absence of major variations in the intestinal microflora of a healthy individual and the significant increase in probiotic and health-promoting bacteria concentrations support the rationale of the administration of rifaximin as efficacious and non-dysbiosis promoting therapy and suggest the efficacy of an antibiotic/probiotic combined treatment in several gut pathologies, such as IBD. To assess the use of an antibiotic/probiotic combination for clinical management of intestinal disorders, genetic, proteomic and physiologic approaches were employed to elucidate molecular mechanisms determining rifaximin resistance in Bifidobacterium, and the expected interactions occurring in the gut between these bacteria and the drug. The ability of an antimicrobial agent to select resistance is a relevant factor that affects its usefulness and may diminish its useful life. Rifaximin resistance phenotype was easily acquired by all bifidobacteria analyzed [type strains of the most representative intestinal bifidobacterial species (B. infantis, B. breve, B. longum, B. adolescentis and B. bifidum) and three bifidobacteria included in a pharmaceutical probiotic preparation (B. lactis BI07, B. breve BBSF and B. longum BL04)] and persisted for more than 400 bacterial generations in the absence of selective pressure. Exclusion of any reversion phenomenon suggested two hypotheses: (i) stable and immobile genetic elements encode resistance; (ii) the drug moiety does not act as an inducer of the resistance phenotype, but enables selection of resistant mutants. Since point mutations in rpoB have been indicated as representing the principal factor determining rifampicin resistance in E. coli and M. tuberculosis, whether a similar mechanism also occurs in Bifidobacterium was verified. The analysis of a 129 bp rpoB core region of several wild-type and resistant bifidobacteria revealed five different types of miss-sense mutations in codons 513, 516, 522 and 529. Position 529 was a novel mutation site, not previously described, and position 522 appeared interesting for both the double point substitutions and the heterogeneous profile of nucleotide changes. The sequence heterogeneity of codon 522 in Bifidobacterium leads to hypothesize an indirect role of its encoded amino acid in the binding with the rifaximin moiety. These results demonstrated the chromosomal nature of rifaximin resistance in Bifidobacterium, minimizing risk factors for horizontal transmission of resistance elements between intestinal microbial species. Further proteomic and physiologic investigations were carried out using B. lactis BI07, component of a pharmaceutical probiotic preparation, as a model strain. The choice of this strain was determined based on the following elements: (i) B. lactis BI07 is able to survive and persist in the gut; (ii) a proteomic overview of this strain has been recently reported. The involvement of metabolic changes associated with rifaximin resistance was investigated by proteomic analysis performed with two-dimensional electrophoresis and mass spectrometry. Comparative proteomic mapping of BI07-wt and BI07-res revealed that most differences in protein expression patterns were genetically encoded rather than induced by antibiotic exposure. In particular, rifaximin resistance phenotype was characterized by increased expression levels of stress proteins. Overexpression of stress proteins was expected, as they represent a common non specific response by bacteria when stimulated by different shock conditions, including exposure to toxic agents like heavy metals, oxidants, acids, bile salts and antibiotics. Also, positive transcription regulators were found to be overexpressed in BI07-res, suggesting that bacteria could activate compensatory mechanisms to assist the transcription process in the presence of RNA polymerase inhibitors. Other differences in expression profiles were related to proteins involved in central metabolism; these modifications suggest metabolic disadvantages of resistant mutants in comparison with sensitive bifidobacteria in the gut environment, without selective pressure, explaining their disappearance from faeces of patients with UC after interruption of antibiotic treatment. The differences observed between BI07-wt e BI07-res proteomic patterns, as well as the high frequency of silent mutations reported for resistant mutants of Bifidobacterium could be the consequences of an increased mutation rate, mechanism which may lead to persistence of resistant bacteria in the population. However, the in vivo disappearance of resistant mutants in absence of selective pressure, allows excluding the upsurge of compensatory mutations without loss of resistance. Furthermore, the proteomic characterization of the resistant phenotype suggests that rifaximin resistance is associated with a reduced bacterial fitness in B. lactis BI07-res, supporting the hypothesis of a biological cost of antibiotic resistance in Bifidobacterium. The hypothesis of rifaximin inactivation by bacterial enzymatic activities was verified by using liquid chromatography coupled with tandem mass spectrometry. Neither chemical modifications nor degradation derivatives of the rifaximin moiety were detected. The exclusion of a biodegradation pattern for the drug was further supported by the quantitative recovery in BI07-res culture fractions of the total rifaximin amount (100 μg/ml) added to the culture medium. To confirm the main role of the mutation on the β chain of RNA polymerase in rifaximin resistance acquisition, transcription activity of crude enzymatic extracts of BI07-res cells was evaluated. Although the inhibition effects of rifaximin on in vitro transcription were definitely higher for BI07-wt than for BI07-res, a partial resistance of the mutated RNA polymerase at rifaximin concentrations > 10 μg/ml was supposed, on the basis of the calculated differences in inhibition percentages between BI07-wt and BI07-res. By considering the resistance of entire BI07-res cells to rifaximin concentrations > 100 μg/ml, supplementary resistance mechanisms may take place in vivo. A barrier for the rifaximin uptake in BI07-res cells was suggested in this study, on the basis of the major portion of the antibiotic found to be bound to the cellular pellet respect to the portion recovered in the cellular lysate. Related to this finding, a resistance mechanism involving changes of membrane permeability was supposed. A previous study supports this hypothesis, demonstrating the involvement of surface properties and permeability in natural resistance to rifampicin in mycobacteria, isolated from cases of human infection, which possessed a rifampicin-susceptible RNA polymerase. To understand the mechanism of membrane barrier, variations in percentage of saturated and unsaturated FAs and their methylation products in BI07-wt and BI07-res membranes were investigated. While saturated FAs confer rigidity to membrane and resistance to stress agents, such as antibiotics, a high level of lipid unsaturation is associated with high fluidity and susceptibility to stresses. Thus, the higher percentage of saturated FAs during the stationary phase of BI07-res could represent a defence mechanism of mutant cells to prevent the antibiotic uptake. Furthermore, the increase of CFAs such as dihydrosterculic acid during the stationary phase of BI07-res suggests that this CFA could be more suitable than its isomer lactobacillic acid to interact with and prevent the penetration of exogenous molecules including rifaximin. Finally, the impact of rifaximin on immune regulatory functions of the gut was evaluated. It has been suggested a potential anti-inflammatory effect of rifaximin, with reduced secretion of IFN-γ in a rodent model of colitis. Analogously, it has been reported a significant decrease in IL-8, MCP-1, MCP-3 e IL-10 levels in patients affected by pouchitis, treated with a combined therapy of rifaximin and ciprofloxacin. Since rifaximin enables in vivo and in vitro selection of Bifidobacterium resistant mutants with high frequency, the immunomodulation activities of rifaximin associated with a B. lactis resistant mutant were also taken into account. Data obtained from PBMC stimulation experiments suggest the following conclusions: (i) rifaximin does not exert any effect on production of IL-1β, IL-6 and IL-10, whereas it weakly stimulates production of TNF-α; (ii) B. lactis appears as a good inducer of IL-1β, IL-6 and TNF-α; (iii) combination of BI07-res and rifaximin exhibits a lower stimulation effect than BI07-res alone, especially for IL-6. These results confirm the potential anti-inflammatory effect of rifaximin, and are in agreement with several studies that report a transient pro-inflammatory response associated with probiotic administration. The understanding of the molecular factors determining rifaximin resistance in the genus Bifidobacterium assumes an applicative significance at pharmaceutical and medical level, as it represents the scientific basis to justify the simultaneous use of the antibiotic rifaximin and probiotic bifidobacteria in the clinical treatment of intestinal disorders.

Polycationic lipophilic-core dendrons as penetration enhancers for the oral administration of low molecular weight heparin

Two polycationic lipophilic-core carbohydrate-based dendrons 2a-b and five polycationic lipophilic-core peptide dendrons 3-6, containing four arginine or lysine terminal residues, were synthesized and then tested in rats as penetration enhancers for the oral delivery of low molecular weight heparin. Better results were obtained with dendrons containing terminal lysine residues than terminal arginine. A significant anti-factor Xa activity was obtained when low molecular weight heparin was coadministered with dendron 5. (c) 2005 Elsevier Ltd. All rights reserved.

The release of nicotine from chewing gum formulations

The first clinically proven nicotine replacement product to obtain regulatory approval was Nicorette® gum. It provides a convenient way of delivering nicotine directly to the buccal cavity, thus, circumventing 'first-pass' elimination following gastrointestinal absorption. Since launch, Nicorette® gum has been investigated in numerous studies (clinical) which are often difficult to compare due to large variations in study design and degree of sophistication. In order to standardise testing, in 2000 the European Pharmacopoeia introduced an apparatus to investigate the in vitro release of drug substances from medical chewing gum. With use of the chewing machine, the main aims of this project were to determine factors that could affect release from Nicorette® gum, to develop an in vitro in vivo correlation and to investigate formulation variables on release of nicotine from gums. A standard in vitro test method was developed. The gum was placed in the chewing chamber with 40 mL of artificial saliva at 37'C and chewed at 60 chews per minute. The chew rate, the type of dissolution medium used, pH, volume, temperature and the ionic strength of the dissolution medium were altered to investigate the effects on release in vitro. It was found that increasing the temperature of the dissolution media and the rate at which the gums were chewed resulted in a greater release of nicotine, whilst increasing the ionic strength of the dissolution medium to 80 mM resulted in a lower release. The addition of 0.1 % sodium Jauryl sulphate to the artificial saliva was found to double the release of nicotine compared to the use of artificial saliva and water alone. Although altering the dissolution volume and the starting pH did not affect the release. The increase in pH may be insufficient to provide optimal conditions for nicotine absorption (since the rate at which nicotine is transported through the buccal membrane was found to be higher at pH values greater than 8.6 where nicotine is predominately unionised). Using a time mapping function, it was also possible to establish a level A in vitro in vivo correlation. 4 mg Nicorette® gum was chewed at various chew rates in vitro and correlated to an in vivo chew-out study. All chew rates used in vitro could be successfully used for IVIVC purposes, however statistically, chew rates of 10 and 20 chews per minute performed better than all other chew rates. Finally a series of nicotine gums was made to investigate the effect of formulation variables on release of nicotine from the gum. Using a directly compressible gum base, in comparison to Nicorette® the gums crumbled when chewed in vitro, resulting in a faster release of nicotine. To investigate the effect of altering the gum base, the concentration of sodium salts, sugar syrup, the form of the active drug, the addition sequence and the incorporation of surfactant into the gum, the traditional manufacturing method was used to make a series of gum formulations. Results showed that the time of addition of the active drug, the incorporation of surfactants and using different gum base all increased the release of nicotine from the gum. In contrast, reducing the concentration of sodium carbonate resulted in a lower release. Using a stronger nicotine ion-exchange resin delayed the release of nicotine from the gum, whilst altering the concentration of sugar syrup had little effect on the release but altered the texture of the gum.

Produção de nanopartículas contendo peptídeos bioativos de microalgas

A produção de peptídeos bioativos de distintas fontes de proteínas vem ganhando espaço na produção científica e tecnológica, despertando interesse do setor empresarial. Paralelamente a isso, devido à elevada concentração de proteínas na biomassa das microalgas Spirulina e Chlorella, estas apresentam grande potencial para a extração de biocompostos com alto valor agregado, como biopeptídeos de microalgas. As proteínas são uma importante fonte de peptídeos bioativos, mas estes não estão ativos na proteína precursora e devem ser liberados para que apresentem efeitos fisiológicos desejados. Essa liberação pode ser feita através de hidrólise enzimática a partir de proteases, sendo um dos métodos mais utilizados para a produção destes biocompostos. Dentro deste contexto, vários estudos vêm mostrando o uso da tecnologia por secagem em spray dryer para a obtenção de nanopartículas que contenham compostos bioativos, sendo, essa técnica, amplamente utilizada para transformar líquidos em pós, podendo ser aplicada em materiais sensíveis à temperatura. Este estudo teve como objetivo obter peptídeos bioativos através da reação enzimática, tendo como substrato a biomassa de Spirulina sp. LEB 18 e Chlorella pyrenoidosa e, na sequência, obter nanopartículas contendo os biopeptídeos. Primeiramente, foram testadas as 3 proteases comerciais (Protemax 580 L, Protemax N 200 e pepsina) para a produção de hidrolisados proteicos de microalgas, para isso foram realizados 3 delineamentos compostos centrais para cada microalga em estudo (Chlorella e Spirulina). Os delineamentos utilizados foram do tipo 23 com três repetições no ponto central, variando-se a concentração de enzima (5 a 10 U.mL-1), a concentração de substrato (5 a 10 %) e o tempo de reação (60 a 240 min). Após, realizou-se 2 delineamentos compostos rotacionais do tipo 22 com pontos centrais, um para cada microalga, utilizando-se para a hidrólise a enzima Protemax 580L (5 U.mL-1) variando-se a concentração de substrato e tempo de reação, para todos ensaios estudou-se a solubilidade, capacidade de retenção de água, atividade antioxidante e digestibilidade. Foi selecionado um ensaio para cada microalga, levando em conta os melhores resultados. Então nova hidrólise enzimática foi realizada sendo o sistema reacional composto pela enzima Protemax 580 L (5 U.mL-1) e pela biomassa de Spirulina sp. LEB 18 ou Chlorella pyrenoidosa (4% de proteína) durante tempo de 200 min. Os hidrolisados foram purificados por filtração a vácuo com membranas millipores de diferentes tamanhos (0,45; 0,2 e 0,1 µm) e por colunas com membrana vertical Amicon® Ultra 0.5 (3K e 10K), sendo que após cada etapa, foi realizado teste de atividade antioxidante pelos métodos de poder redutor, DPPH e ABTS, a fim de verificar a permanência da atividade antioxidante. Utilizou-se nano spray dryer Büchi modelo B 90 para a secagem das amostras, sendo o tamanho das partículas obtidas analisados por microscopia eletrônica de varredura (MEV). Por fim, conclui-se que a biomassa de microalgas pode ser utilizada como fonte de produção de peptídeos bioativos com elevada atividade antioxidante e que dentre as microalgas estudadas, Spirulina sp. LEB 18 apresentou melhores resultados, em todas as análises realizadas, quando comparada com Chlorella pyrenoidosa. Esse estudo, também visou utilizar a nanobiotecnologia para obtenção de nanoparículas contendo os biopeptídeos, para tal, utilizou-se o nano Buchi Spray Dryer B-90, o qual gerou partículas nanométricas de 14 a 18 nm para o hidrolisado de Spirulina e de 72 a 108 nm para o hidrolisado de Chlorella.

Cloning and gastrointestinal expression of rat hephaestin: Relationship to other iron transport proteins

The membrane-bound ceruloplasmin homolog hephaestin plays a critical role in intestinal iron absorption. The aims of this study were to clone the rat hephaestin gene and to examine its expression in the gastrointestinal tract in relation to other genes encoding iron transport proteins. The rat hephaestin gene was isolated from intestinal mRNA and was found to encode a protein 96% identical to mouse hephaestin. Analysis by ribonuclease protection assay and Western blotting showed that hephaestin was expressed at high levels throughout the small intestine and colon. Immunofluorescence localized the hephaestin protein to the mature villus enterocytes with little or no expression in the crypts. Variations in iron status had a small but nonsignificant effect on hephaestin expression in the duodenum. The high sequence conservation between rat and mouse hephaestin is consistent with this protein playing a central role in intestinal iron absorption, although its precise function remains to be determined.

Casein and whey exert different effects on plasma amino acid profiles, gastrointestinal hormone secretion and appetite

Protein, generally agreed to be the most satiating macronutrient, may differ in its effects on appetite depending on the protein source and variation in digestion and absorption. We investigated the effects of two milk protein types, casein and whey, on food intake and subjective ratings of hunger and fullness, and on postprandial metabolite and gastrointestinal hormone responses. Two studies were undertaken. The first study showed that energy intake from a buffet meal ad libitum was significantly less 90 min after a 1700 kJ liquid preload containing 48 g whey, compared with an equivalent casein preload (P<0.05). In the second study, the same whey preload led to a 28 % increase in postprandial plasma amino acid concentrations over 3 h compared with casein (incremental area under the curve (iAUC), P<0.05). Plasma cholecystokinin (CCK) was increased by 60 % (iAUC, P<0.005), glucagon-like peptide (GLP)-1 by 65 % (iAUC, P<0.05) and glucose-dependent insulinotropic polypeptide by 36 % (iAUC, P<0.01) following the whey preload compared with the casein. Gastric emptying was influenced by protein type as evidenced by differing plasma paracetamol profiles with the two preloads. Greater subjective satiety followed the whey test meal (P<0.05). These results implicate post-absorptive increases in plasma amino acids together with both CCK and GLP-1 as potential mediators of the increased satiety response to whey and emphasise the importance of considering the impact of protein type on the appetite response to a mixed meal.

The fate of olive oil polyphenols in the gastrointestinal tract: implications of gastric and colonic microflora-dependent biotransformation

We have conducted a detailed investigation into the absorption, metabolism and microflora-dependent transformation of hydroxytyrosol ( HT), tyrosol (TYR) and their conjugated forms, such as oleuropein (OL). Conjugated forms underwent rapid hydrolysis under gastric conditions, resulting in significant increases in the amount of free HT and TYR entering the small intestine. Both HT and TYR transferred across human Caco-2 cell monolayers and rat segments of jejunum and ileum and were subject to classic phase I/II biotransformation. The major metabolites identified were an O-methylated derivative of HT, glucuronides of HT and TYR and a novel glutathionylated conjugate of HT. In contrast, there was no absorption of OL in either model. However, OL was rapidly degraded by the colonic microflora resulting in the formation of HT. Our study provides additional information regarding the breakdown of complex olive oil polyphenols in the GI tract, in particular the stomach and the large intestine.

Extra virgin olive oil phenolics: absorption, metabolism, and biological activities in the GI tract

Olive oil, a typical ingredient of the Mediterranean diet, possesses many beneficial health effects. The biological activities ascribed to olive oil consumption are associated in part to its phenolics constituents, and mainly linked to the direct or indirect antioxidant activity of olive oil phenolics and their metabolites, which are exerted more efficiently in the gastrointestinal (GI) tract, where dietary phenolics are more concentrated when compared to other organs. In this regard, we present a brief overview of the metabolism, biological activities, and anticancer properties of olive oil phenolics in the GI tract. Toxicology and Industrial Health 2009; 25: 285-293.