Absorption and Intestinal Metabolic Profile of Oleocanthal in Rats

Oleocanthal (OLC), a phenolic compound of extra virgin olive oil (EVOO), has emerged as a potential therapeutic agent against a variety of diseases due to its anti-inflammatory activity. The aim of the present study is to explore its in vivo intestinal absorption and metabolism. An in situ perfusion technique in rats was used, involving simultaneous sampling from the luminal perfusate and mesenteric blood. Samples were analysed by UHPLC–MS–MS for the presence of oleocanthal (OLC) and its metabolites. OLC was mostly metabolized by phase I metabolism, undergoing hydration, hydrogenation and hydroxylation. Phase II reactions (glucuronidation of hydrogenated OLC and hydrated metabolites) were observed in plasma samples. OLC was poorly absorbed in the intestine, as indicated by the low effective permeability coefficient (2.23 ± 3.16 × 10−5 cm/s) and apparent permeability coefficient (4.12 ± 2.33 × 10−6 cm/s) obtained relative to the values of the highly permeable reference compound levofloxacin (LEV). The extent of OLC absorption reflected by the area under the mesenteric blood-time curve normalized by the inlet concentration (AUC) was also lower than that of LEV (0.25 ± 0.04 vs. 0.64 ± 0.03, respectively). These results, together with the observed intestinal metabolism, suggest that OLC has a moderate-to-low oral absorption; but higher levels of OLC are expected to reach human plasma vs. rat plasma.

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Permeability to albumin in isolated coronary venules

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.265.2.h543 ◽

1993 ◽

Vol 265 (2) ◽

pp. H543-H552 ◽

Cited By ~ 7

Author(s):

Y. Yuan ◽

W. M. Chilian ◽

H. J. Granger ◽

D. C. Zawieja

Keyword(s):

Permeability Coefficient ◽

Filtration Rate ◽

Intraluminal Pressure ◽

Apparent Permeability ◽

Filtration Pressure ◽

Diffusive Permeability ◽

Apparent Permeability Coefficient ◽

Chemical Conditions ◽

Physical And Chemical ◽

Intravascular Pressure

This study reports measurements of albumin permeability in isolated coronary venules. The isolated microvessel technique allows the quantification of transmural exchange of macromolecules under tightly controlled physical and chemical conditions. Transvenular exchange of albumin was studied in isolated coronary venules during alterations in filtration rate caused by changes in intravascular pressure. The apparent permeability coefficient of albumin (Pa) at an intraluminal pressure of 11 cmH2O was 3.92 +/- 0.43 x 10(-6) cm/s. Elevating intraluminal pressure to 16 and 21 cmH2O increased Pa to 5.13 +/- 0.57 x 10(-6) and 6.78 +/- 0.66 x 10(-6) cm/s, respectively. Calculation of the true diffusive permeability coefficient of albumin (Pd) at zero filtration rate was 1.54 x 10(-6) cm/s. The product of hydraulic conductance (Lp) and (1 - sigma), where sigma is the solute reflection coefficient, was 3.25 x 10(-7) cm.s-1 x cmH2O-1. At a net filtration pressure of 4-5 cmH2O, diffusion accounts for > 60% of total albumin transport across the venular wall. Transmural albumin flux is very sensitive to filtration rate, rising 6.7% for each cmH2O elevation of net filtration pressure. At 11 cmH2O net filtration pressure, convection accounts for nearly 70% of net albumin extravasation from the venular lumen. We suggest that the isolated coronary venule is a suitable preparation for the study of solute exchange in the heart.

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Oleacein Intestinal Permeation and Metabolism in Rats Using an In Situ Perfusion Technique

Pharmaceutics ◽

10.3390/pharmaceutics13050719 ◽

2021 ◽

Vol 13 (5) ◽

pp. 719

Author(s):

Anallely López-Yerena ◽

Maria Pérez ◽

Anna Vallverdú-Queralt ◽

Eleftherios Miliarakis ◽

Rosa M. Lamuela-Raventós ◽

...

Keyword(s):

Intestinal Permeability ◽

Model Compound ◽

Virgin Olive Oil ◽

Extra Virgin Olive Oil ◽

Perfusion Technique ◽

In Situ Perfusion ◽

First Pass ◽

Health Promoting ◽

Intestinal Permeation

Oleacein (OLEA) is one of the most important phenolic compounds in extra virgin olive oil in terms of concentration and health-promoting properties, yet there are insufficient data on its absorption and metabolism. Several non-human models have been developed to assess the intestinal permeability of drugs, among them, single-pass intestinal perfusion (SPIP), which is commonly used to investigate the trans-membrane transport of drugs in situ. In this study, the SPIP model and simultaneous luminal blood sampling were used to study the absorption and metabolism of OLEA in rats. Samples of intestinal fluid and mesenteric blood were taken at different times and the ileum segment was excised at the end of the experiment for analysis by LC–ESI–LTQ–Orbitrap–MS. OLEA was mostly metabolized by phase I reactions, undergoing hydrolysis and oxidation, and metabolite levels were much higher in the plasma than in the lumen. The large number of metabolites identified and their relatively high abundance indicates an important intestinal first-pass effect during absorption. According to the results, OLEA is well absorbed in the intestine, with an intestinal permeability similar to that of the highly permeable model compound naproxen. No significant differences were found in the percentage of absorbed OLEA and naproxen (48.98 ± 12.27% and 43.96 ± 7.58%, respectively).

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LC478, a Novel Di-Substituted Adamantyl Derivative, Enhances the Oral Bioavailability of Docetaxel in Rats

Pharmaceutics ◽

10.3390/pharmaceutics11030135 ◽

2019 ◽

Vol 11 (3) ◽

pp. 135 ◽

Cited By ~ 1

Author(s):

Seung Han ◽

Qili Lu ◽

Kyeong Lee ◽

Young Choi

Keyword(s):

Oral Bioavailability ◽

Oral Absorption ◽

Ussing Chamber ◽

Absolute Bioavailability ◽

Time Curve ◽

Glycoprotein P ◽

Dose Concentration ◽

Chamber Studies

P-glycoprotein (P-gp)-mediated efflux of docetaxel in the gastrointestinal tract mainly impedes its oral chemotherapy. Recently, LC478, a novel di-substituted adamantyl derivative, was identified as a non-cytotoxic P-gp inhibitor in vitro. Here, we assessed whether LC478 enhances the oral bioavailability of docetaxel in vitro and in vivo. LC478 inhibited P-gp mediated efflux of docetaxel in Caco-2 cells. In addition, 100 mg/kg of LC478 increased intestinal absorption of docetaxel, which led to an increase in area under plasma concentration-time curve (AUC) and absolute bioavailability of docetaxel in rats. According to U.S. FDA criteria (I, an inhibitor concentration in vivo tissue)/(IC50, inhibitory constant in vitro) >10 determines P-gp inhibition between in vitro and in vivo. The values 15.6–20.5, from (LC478 concentration in intestine, 9.37–12.3 μM)/(IC50 of LC478 on P-gp inhibition in Caco-2 cell, 0.601 μM) suggested that 100 mg/kg of LC478 sufficiently inhibited P-gp to enhance oral absorption of docetaxel. Moreover, LC478 inhibited P-gp mediated efflux of docetaxel in the ussing chamber studies using rat small intestines. Our study demonstrated that the feasibility of LC478 as an ideal enhancer of docetaxel bioavailability by P-gp inhibition in dose (concentration)-dependent manners.

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Biological Relevance of Extra Virgin Olive Oil Polyphenols Metabolites

Antioxidants ◽

10.3390/antiox7120170 ◽

2018 ◽

Vol 7 (12) ◽

pp. 170 ◽

Cited By ~ 40

Author(s):

Gabriele Serreli ◽

Monica Deiana

Keyword(s):

Olive Oil ◽

Intracellular Signaling ◽

Cellular Response ◽

Virgin Olive Oil ◽

Extra Virgin Olive Oil ◽

Main Concern ◽

Beneficial Effects ◽

Positive Effects

Extra virgin olive oil (EVOO) polyphenols beneficial effects have widely been debated throughout the last three decades, with greater attention to hydroxytyrosol and tyrosol, which are by far the most studied. The main concern about the evaluation of EVOO phenols activities in vitro and in vivo is that the absorption and metabolism of these compounds once ingested lead to the production of different metabolites in the human body. EVOO phenols in the ingested forms are less concentrated in human tissues than their glucuronide, sulfate and methyl metabolites; on the other hand, metabolites may undergo deconjugation before entering the cells and thus act as free forms or may be reformed inside the cells so acting as conjugated forms. In most in vitro studies the presence of methyl/sulfate/glucuronide functional groups does not seem to inhibit biological activity. Parent compounds and metabolites have been shown to reach tissue concentrations useful to exert beneficial effects others than antioxidant and scavenging properties, by modulating intracellular signaling and improving cellular response to oxidative stress and pro-inflammatory stimuli. This review aims to give an overview on the reported evidence of the positive effects exerted by the main EVOO polyphenols metabolites in comparison with the parent compounds.

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Development and In Vitro Evaluation of a Mucoadhesive Oral Deliverv System for Antisense Oliaonucleotides

Scientia Pharmaceutica ◽

10.3797/scipharm.aut-03-17 ◽

2003 ◽

Vol 71 (3) ◽

pp. 165-177 ◽

Cited By ~ 2

Author(s):

Andreas Bernkop-Schnürch ◽

Julia Telsnig ◽

Margit Hornof

Keyword(s):

Delivery System ◽

Permeability Coefficient ◽

Enzymatic Degradation ◽

Phosphorothioate Oligonucleotide ◽

Apparent Permeability ◽

Release Studies ◽

Apparent Permeability Coefficient ◽

Permeation Studies ◽

Membrane Bound

It was the aim of this study to develop an oral phosphorothioate oligodeoxynucleotide (PS-ODN) drug delivery system and to evaluate its properties in vitro. Results demonstrated that the 16-mer phosphorothioate oligonucleotide used was completely stable towards enzymatic degradation by secreted and membrane bound intestinal enzymes. Permeation studies with freshly excised intestinal mucosa showed a comparatively high uptake of the PS-ODN with an apparent permeability coefficient (Papp) of 8.35 ± 1.24 x 10-6 cm/sec. The PS-ODN was incorporated in a poly(acrylic acid)-cysteine carrier matrix system exhibiting high cohesive and mucoadhesive properties. Release studies demonstrated that a controlled and sustained PS-ODN release out of this delivery system could be achieved. Because of these features, the dosage form developed within this study seems to represent a promising novel tool for oral PS-ODN delivery.

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Histamine increases venular permeability via a phospholipase C-NO synthase-guanylate cyclase cascade

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.264.5.h1734 ◽

1993 ◽

Vol 264 (5) ◽

pp. H1734-H1739 ◽

Cited By ~ 38

Author(s):

Y. Yuan ◽

H. J. Granger ◽

D. C. Zawieja ◽

D. V. DeFily ◽

W. M. Chilian

Keyword(s):

Phospholipase C ◽

Guanylate Cyclase ◽

Permeability Coefficient ◽

Direct Action ◽

No Synthase ◽

Constant Flow ◽

Apparent Permeability ◽

Apparent Permeability Coefficient ◽

Synthase Inhibitor ◽

Ly 83583

In this study, we hypothesized that histaminergic increases in venular permeability result from a cascade triggered by activation of phospholipase C (PLC), inducing the synthesis of nitric oxide (NO) and activating guanylate cyclase. The apparent permeability coefficient to albumin (Pa) was measured in isolated porcine coronary venules subjected to constant flow and hydrostatic and oncotic pressures. Histamine (2.5, 5, and 10 microM) transiently and progressively increased Pa. The PLC inhibitor 2-nitro-4-carboxyphenyl N,N-diphenylcarbamate (NCDC; 100 microM) decreased baseline permeability and abolished the effect of histamine. The NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 10 microM) and the guanylate cyclase inhibitor 6-anilinoquinoline-5,8-quinone (LY 83583; 10 microM) also blocked the histamine-induced hyperpermeability. L-Arginine (3 mM) reversed the inhibition by L-NMMA. NG-monomethyl-D-arginine did not influence the effect of histamine. Furthermore, sodium nitroprusside (10 microM) augmented Pa by two- to threefold; this effect was blocked in the presence of LY 83583 but not altered in the presence of NCDC. The results suggest that histamine increases coronary venular permeability by a direct action on the venular endothelial cells through a PLC-NO synthase-guanylate cyclase-signaling cascade.

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Active amino acid absorption by proximal convoluted and proximal straight tubules

AJP Renal Physiology ◽

10.1152/ajprenal.1979.236.2.f149 ◽

1979 ◽

Vol 236 (2) ◽

pp. F149-F162 ◽

Cited By ~ 4

Author(s):

D. W. Barfuss ◽

J. A. Schafer

Keyword(s):

Permeability Coefficient ◽

Rabbit Kidney ◽

Apparent Permeability ◽

Nonlinear Fitting ◽

Luminal Membrane ◽

Straight Tubules ◽

Apparent Permeability Coefficient ◽

Active Amino Acid ◽

The Mean ◽

The Relationship

Transport of glycine and alpha-aminoisobutyric acid (AIB) was studied in proximal convoluted (PCT) and proximal straight (PST) tubules isolated from rabbit kidney. In both segments, unidirectional lumen-to-bath fluxes (J1 leads to b) (pmol min-1mm-1) of glycine and AIB exceeded corresponding bath-to-lumen fluxes (Jb leads to 1), which demonstrated that both were actively absorbed. During J1 leads to b measurements, intracellular concentrations of both amino acids were greater than the luminal concentration, indicating that the site of active transport was the luminal membrane. Replacement of Na+ by choline in both perfusate and bath (PCT) or perfusate alone (PST) reduced J1 leads to b for glycine to equal Jb leads to 1. Nonlinear fitting of the relationship between J1 leads to b and the mean luminal glycine concentration according to Michaelis-Menten kinetics gave Jmax values of 28.5 (PCT) and 2.5 (PST) pmol min-1 mm-1, and Km values of 11.8 (PCT) and 0.7 (PST) mM. There was a parallel, Na+-independent, nonsaturable component of J1 leads to b characterized by an apparent permeability coefficient of 0.19 micron/s in the PCT and 0.04 micron/s in the PST.

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Benefit of Oleuropein Aglycone for Alzheimer’s Disease by Promoting Autophagy

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/5010741 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 27

Author(s):

Joaquín G. Cordero ◽

Ramón García-Escudero ◽

Jesús Avila ◽

Ricardo Gargini ◽

Vega García-Escudero

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Olive Oil ◽

Virgin Olive Oil ◽

Extra Virgin Olive Oil ◽

Autophagy Gene ◽

Potential Benefits ◽

And Oxidative Stress

Alzheimer’s disease is a proteinopathy characterized by accumulation of hyperphosphorylated Tau and β-amyloid. Autophagy is a physiological process by which aggregated proteins and damaged organelles are eliminated through lysosomal digestion. Autophagy deficiency has been demonstrated in Alzheimer’s patients impairing effective elimination of aggregates and damaged mitochondria, leading to their accumulation, increasing their toxicity and oxidative stress. In the present study, we demonstrated by microarray analysis the downregulation of fundamental autophagy and mitophagy pathways in Alzheimer’s patients. The benefits of the Mediterranean diet on Alzheimer’s disease and cognitive impairment are well known, attributing this effect to several polyphenols, such as oleuropein aglycone (OLE), present in extra virgin olive oil. OLE is able to induce autophagy, achieving a decrease of aggregated proteins and a reduction of cognitive impairment in vivo. This effect is caused by the modulation of several pathways including the AMPK/mTOR axis and the activation of autophagy gene expression mediated by sirtuins and histone acetylation or EB transcription factor. We propose that supplementation of diet with extra virgin olive oil might have potential benefits for Alzheimer’s patients by the induction of autophagy by OLE.

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