Effect of Water-Loading on the Performance of Polyethylene Glycol as a Marker of Small Intestinal Permeability

1995 ◽  
Vol 89 (3) ◽  
pp. 299-303 ◽  
Author(s):  
Tariq H. Iqbal ◽  
Mark A. Cox ◽  
Kenneth O. Lewis ◽  
Brian T. Cooper
Keyword(s):  
Polyethylene Glycol ◽  
Intestinal Permeability ◽  
Volume Of Distribution ◽  
Differential Rate ◽  
Water Loading ◽  
Collection Period ◽  
Small Intestinal ◽  
Renal Tubular ◽  
The Individual

1. Polyethylene glycol has been used extensively to measure small intestinal permeability in vivo. However, polyethylene glycol seems to traverse the intestinal mucosa in much greater quantities than sugar molecules of equivalent Mr. In addition, the recovery of the lowest Mr polymers of administered polyethylene glycol has been found to be both low and unreliable. 2. To compare the behaviour of a range of polyethylene glycol polymers with sugar probes in vivo, a combined polyethylene glycol/mannitol/lactulose probe was administered sequentially to healthy individuals in the fasted state and under conditions of water-loading. Timed hourly urine collections were made for 6 h. 3. Mannitol and lactulose recoveries were all within the normal range and were unaffected by coadministration of water. The lactulose/mannitol recovery ratios did not vary significantly over the 6 h collection period. In contrast, the recovery of total polyethylene glycol was significantly greater when subjects were water-loaded. Futhermore, proportionally greater quantities of polyethylene glycol Mr 370 than Mr 854 were recovered towards the end of the collection period than at the start. 4. Our results show that, in contrast to lactulose and mannitol, excretion of low—medium Mr polyethylene glycol polymers is highly dependent on coadministration of water. Futhermore, the differential rate of excretion of the low compared with the high Mr polyethylene glycol polymers suggests that the volume of distribution of the individual polymers may vary with Mr, and smaller polyethylene glycol molecules may undergo considerable renal tubular reabsorption.

Small intestinal efflux mediated by MRP2 and BCRP shifts sulfasalazine intestinal permeability from high to low, enabling its colonic targeting

2009 ◽  
Vol 297 (2) ◽  
pp. G371-G377 ◽  
Author(s):  
Arik Dahan ◽  
Gordon L. Amidon
Keyword(s):  
Intestinal Absorption ◽  
Intestinal Permeability ◽  
Oral Drug ◽  
Dependent Manner ◽  
Therapeutic Action ◽  
Cancer Resistance ◽  
High Permeability ◽  
Small Intestinal ◽  
Intestinal Efflux

Sulfasalazine is characterized by low intestinal absorption, which essentially enables its colonic targeting and therapeutic action. The mechanisms behind this low absorption have not yet been elucidated. The purpose of this study was to investigate the role of efflux transporters in the intestinal absorption of sulfasalazine as a potential mechanism for its low small-intestinal absorption and colonic targeting following oral administration. The effects of P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP) inhibitors on sulfasalazine bidirectional permeability were studied across Caco-2 cell monolayers, including dose-response analysis. Sulfasalazine in vivo permeability was then investigated in the rat jejunum by single-pass perfusion, in the presence vs. absence of inhibitors. Sulfasalazine exhibited 19-fold higher basolateral-to-apical (BL-AP) than apical-to-basolateral (AP-BL) Caco-2 permeability, indicative of net mucosal secretion. MRP2 inhibitors (MK-571 and indomethacin) and BCRP inhibitors [fumitremorgin C (FTC) and pantoprazole] significantly increased AP-BL and decreased BL-AP sulfasalazine Caco-2 transport in a concentration-dependent manner. No effect was observed with the P-gp inhibitors verapamil and quinidine. The IC50 values of the specific MRP2 and BCRP inhibitors MK-571 and FTC on sulfasalazine secretion were 21.5 and 2.0 μM, respectively. Simultaneous inhibition of MRP2 and BCRP completely abolished sulfasalazine Caco-2 efflux. Without inhibitors, sulfasalazine displayed low (vs. metoprolol) in vivo intestinal permeability in the rat model. MK-571 or FTC significantly increased sulfasalazine permeability, bringing it to the low-high permeability boundary. With both MK-571 and FTC present, sulfasalazine displayed high permeability. In conclusion, efflux transport mediated by MRP2 and BCRP, but not P-gp, shifts sulfasalazine permeability from high to low, thereby enabling its colonic targeting and therapeutic action. To our knowledge, this is the first demonstration of intestinal efflux acting in favor of oral drug delivery.

Diffusion of Polyethylene Glycol-400 across Lipid Barriers in Vitro

1993 ◽  
Vol 85 (1) ◽  
pp. 111-115 ◽  
Author(s):  
T. H. Iqbal ◽  
K. O. Lewis ◽  
B. T. Cooper
Keyword(s):  
Polyethylene Glycol ◽  
Petroleum Ether ◽  
Intestinal Permeability ◽  
Intestinal Wall ◽  
Water Soluble ◽  
Separate Experiment ◽  
Polyethylene Glycol 400 ◽  
Lipid Barriers

1. Polyethylene glycol has been used extensively as a probe to measure passive small-intestinal permeability in viro. However, there has been some uncertainty as to its suitability for use as an indicator of the permeation of water-soluble molecules across the intestinal wall because it seems to traverse the mucosa in much greater quantities than sugar molecules of equivalent Mr. 2. We have measured the permeation of polyethylene glycol-400 and lactulose from aqueous solution across pure lipid solvents in vitro. We found considerable transport of polyethylene glycol-400 across chloroform (1.03 g h−1 m−2) but no movement across petroleum ether. 3. However, in a separate experiment in which phospholipid (egg lecithin) was dissolved in the petroleum ether, permeation of polyethylene glycol-400 did occur (0.13 g h−1 m2), implying interaction of polyethylene glycol-400 with the phospholipid. No permeation of lactulose was seen in any of the experiments. 4. Our results suggest that, because of its interaction with lipid solvents, polyethylene glycol-400 is unsuitable as a probe to measure passive intestinal permeability in vivo.

scholarly journals Polyethylene glycol (PEG) as a marker of small intestinal permeability.

Gut ◽  
1995 ◽  
Vol 36 (6) ◽  
pp. 946-947 ◽  
Author(s):  
T H Iqbal ◽  
M A Cox ◽  
K O Lewis ◽  
B T Cooper
Keyword(s):  
Polyethylene Glycol ◽  
Intestinal Permeability ◽  
Small Intestinal

scholarly journals Enantiomers of flurbiprofen can distinguish key pathophysiological steps of NSAID enteropathy in the rat

Gut ◽  
1998 ◽  
Vol 43 (6) ◽  
pp. 775-782 ◽  
Author(s):  
T Mahmud ◽  
S Somasundaram ◽  
G Sigthorsson ◽  
R J Simpson ◽  
S Rafi ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Intestinal Permeability ◽  
Racemic Mixture ◽  
Mitochondrial Morphology ◽  
Intestinal Damage ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Nsaid Enteropathy ◽  
Small Intestinal

Background—Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage by a non-prostaglandin (PG) dependent “topical” action and by inhibiting cyclooxygenase.Aims—To discriminate between these two effects by studying some key pathophysiological steps in NSAID enteropathy following administration of (R)- and (S)-flurbiprofen, the racemic mixture, and an uncoupler, dinitrophenol.Methods—The effects of dinitrophenol, racemic, (R)-, and (S)-flurbiprofen on mitochondria were assessed in vitro and on key pathophysiological features of small intestinal damage in vivo (ultrastructure by electron microscopy, mucosal prostanoid concentrations, intestinal permeability, inflammation, and ulcer count) in rats.Results—All the drugs uncoupled mitochondrial oxidative phosphorylation in vitro, caused mitochondrial damage in vivo, and increased intestinal permeability. Dinitrophenol and (R)-flurbiprofen caused no significant decreases in mucosal prostanoid concentrations (apart from a decrease in thromboxane (TX) B2 concentrations following (R)-flurbiprofen) while racemic and (S)- flurbiprofen reduced mucosal prostanoids significantly (PGE, TXB2, and 6-keto-PGF1α concentrations by 73–95%). Intestinal inflammation was significantly greater following administration of (S)-flurbiprofen and racemate than with dinitrophenol and (R)-flurbiprofen. No small intestinal ulcers were found following dinitrophenol or (R)-flurbiprofen while both racemic and (S)-flurbiprofen caused numerous ulcers.Conclusions—Dinitrophenol and (R)-flurbiprofen show similarities in their actions to uncouple mitochondrial oxidative phosphorylation in vitro, alter mitochondrial morphology in vivo, increase intestinal permeability, and cause mild inflammation without ulcers. Concurrent severe decreases in mucosal prostanoids seem to be the driving force for the development of severe inflammation and ulcers.

scholarly journals Dietary calcium decreases but short-chain fructo-oligosaccharides increase colonic permeability in rats

2010 ◽  
Vol 104 (12) ◽  
pp. 1780-1786 ◽  
Author(s):  
Marloes A. A. Schepens ◽  
Anneke Rijnierse ◽  
Arjan J. Schonewille ◽  
Carolien Vink ◽  
Robert-Jan M. Brummer ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Intestinal Permeability ◽  
Control Diet ◽  
Short Chain ◽  
Gut Permeability ◽  
Colonic Tissue ◽  
Ussing Chambers ◽  
Small Intestinal ◽  
Gastrointestinal Permeability

An increased intestinal permeability is associated with several diseases. Nutrition can influence gut permeability. Previously, we showed that dietary Ca decreases whereas dietary short-chain fructo-oligosaccharides (scFOS) increase intestinal permeability in rats. However, it is unknown how and where in the gastrointestinal tract Ca and scFOS exert their effects. Rats were fed a Western low-Ca control diet, or a similar diet supplemented with either Ca or scFOS. Lactulose plus mannitol and Cr-EDTA were added to the diets to quantify small and total gastrointestinal permeability, respectively. Additionally, colonic tissue was mounted in Ussing chambers and exposed to faecal water of these rats. Dietary Ca immediately decreased urinary Cr-EDTA excretion by 24 % in Ca-fed rats compared with control rats. Dietary scFOS increased total Cr-EDTA permeability gradually with time, likely reflecting relatively slow gut microbiota adaptations, which finally resulted in a 30 % increase. The lactulose:mannitol ratio was 15 % higher for Ca-fed rats and 16 % lower for scFOS-fed rats compared with control rats. However, no dietary effect was present on individual urinary lactulose and mannitol excretion. The faecal waters did not influence colonic permeability in Ussing chambers. In conclusion, despite effects on the lactulose:mannitol ratio, individual lactulose values did not alter, indicating that diet did not influence small-intestinal permeability. Therefore, both nutrients affect permeability only in the colon: Ca decreases, while scFOS increase colonic permeability. As faecal water did not influence permeability in Ussing chambers, probably modulation of mucins and/or microbiota is important for the in vivo effects of dietary Ca and scFOS.

Acute increases of renal medullary osmolality stimulate endothelin release from the kidney

2007 ◽  
Vol 292 (1) ◽  
pp. F185-F191 ◽  
Author(s):  
Erika I. Boesen ◽  
David M. Pollock
Keyword(s):  
Excretion Rate ◽  
Renal Medulla ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Important Regulator ◽  
Collection Period ◽  
Renal Tubular ◽  
Urine Collection Period

Experiments conducted in vitro suggest that high osmolality stimulates endothelin production and release by renal tubular epithelial cells. Whether hyperosmotic solutions exert similar effects in vivo is unknown. Therefore, we tested the hypothesis that increasing renal medullary osmolality enhances urinary excretion of endothelin in anesthetized rats. Isosmotic NaCl (284 mosmol/kgH2O) was infused either intravenously (1.5 ml/h) or into the renal medullary interstitium (0.5 ml/h) during a 1-h equilibration period and 30-min baseline urine collection period, followed by either isosmotic or hyperosmotic NaCl (921 or 1,664 mosmol/kgH2O iv; 1,714 mosmol/kgH2O into renal medulla) for two further 30-min periods. Compared with isosmotic NaCl, infusion of hyperosmotic NaCl into the renal medulla significantly increased the endothelin excretion rate ( P < 0.05; from 0.30 ± 0.02 to 0.49 ± 0.03 fmol/min). Intravenous infusion of hyperosmotic NaCl also significantly increased endothelin excretion rate in a concentration-dependent manner (from 0.79 ± 0.07 to 1.77 ± 0.16 fmol/min and 0.59 ± 0.04 to 1.11 ± 0.08 fmol/min for 1,664 and 921 mosmol/kgH2O, respectively). To differentiate between effects of osmolality and NaCl, similar experiments were performed using mannitol solutions. Compared with isosmotic mannitol, medullary interstitial infusion of hyperosmotic mannitol (1,820 mosmol/kgH2O) significantly increased endothelin excretion rate ( P < 0.05; from 0.54 ± 0.03 to 0.94 ± 0.12 fmol/min). Thus exposing the renal medulla to hyperosmotic concentrations of either NaCl or mannitol stimulates endothelin release in vivo, consistent with medullary osmolality being an important regulator of renal endothelin synthesis.

Co-delivery of Doxorubicin and D-α-Tocopherol Polyethylene Glycol 1000 Succinate by Magnetic Nanoparticles

2018 ◽  
Vol 18 (8) ◽  
pp. 1138-1147 ◽  
Author(s):  
Esra Metin ◽  
Pelin Mutlu ◽  
Ufuk Gündüz
Keyword(s):  
Breast Cancer ◽  
Polyethylene Glycol ◽  
Magnetic Nanoparticles ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Drug Loading ◽  
Gravimetric Analysis ◽  
Polyethylene Glycol 1000 ◽  
Mcf 7

Background: Although conventional chemotherapy is the most common method for cancer treatment, it has several side effects such as neuropathy, alopecia and cardiotoxicity. Since the drugs are given to body systemically, normal cells are also affected, just like cancer cells. However, in recent years, targeted drug delivery has been developed to overcome these drawbacks. Objective: The aim of this study was targeted co-delivery of doxorubicin (Dox) which is an anticancer agent and D-α-Tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS or simply TPGS) to breast cancer cells. For this purpose, Magnetic Nanoparticles (MNPs) were synthesized and coated with Oleic Acid (OA). Coated nanoparticles were encapsulated in Poly Lactic-co-Glycolic Acid (PLGA) and TPGS polymers and loaded with Dox. The Nanoparticles (NPs) were characterized by Fourier Transform Infrared (FTIR) spectroscopy, zetapotential analysis, Dynamic Light Scattering (DLS) analysis, Thermal Gravimetric Analysis (TGA) and Scanning Electron Microscope (SEM) analysis. Results: The results showed that NPs were spherical, superparamagnetic and in the desired range for use in drug targeting. The targetability of NPs was confirmed. Moreover, TPGS and Dox loading was shown by TGA and FTIR analyses. NPs were internalized by cells and the cytotoxic effect of drug loaded NPs on sensitive (MCF-7) and drug-resistant (MCF-7/Dox) cells were examined. It was seen that the presence of TPGS increased cytotoxicity significantly. TPGS also enhanced drug loading efficiency, release rate, cellular internalization. In MCF- 7/Dox cells, the drug resistance seems to be decreased when Dox is loaded onto TPGS containing NPs. Conclusion: This magnetic PLGA nanoparticle system is important for new generation targeted chemotherapy and could be used for breast cancer treatment after in vivo tests.

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