scholarly journals Utilization of Sodium Nitroprusside as an Intestinal Permeation Enhancer for Lipophilic Drug Absorption Improvement in the Rat Proximal Intestine

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6396
Author(s):  
Hisanao Kishimoto ◽  
Kaori Miyazaki ◽  
Hiroshi Tedzuka ◽  
Ryosuke Ozawa ◽  
Hanai Kobayashi ◽  
...  
Keyword(s):  
Small Intestine ◽  
Sodium Nitroprusside ◽  
Membrane Permeability ◽  
Drug Absorption ◽  
Complex Structure ◽  
Proximal Region ◽  
Drug Candidate ◽  
Drug Bioavailability ◽  
Absorption Enhancers ◽  
Lipophilic Drug

As advanced synthetic technology has enabled drug candidate development with complex structure, resulting in low solubility and membrane permeability, the strategies to improve poorly absorbed drug bioavailability have attracted the attention of pharmaceutical companies. It has been demonstrated that nitric oxide (NO), a vital signaling molecule that plays an important role in various physiological systems, affects intestinal drug absorption. However, NO and its oxidants are directly toxic to the gastrointestinal tract, thereby limiting their potential clinical application as absorption enhancers. In this study, we show that sodium nitroprusside (SNP), an FDA-approved vasodilator, enhances the intestinal absorption of lipophilic drugs in the proximal parts of the small intestine in rats. The SNP pretreatment of the rat gastrointestinal sacs significantly increased griseofulvin and flurbiprofen permeation in the duodenum and jejunum but not in the ileum and colon. These SNP-related enhancement effects were attenuated by the co-pretreatment with dithiothreitol or c-PTIO, an NO scavenger. The permeation-enhancing effects were not observed in the case of antipyrine, theophylline, and propranolol in the duodenum and jejunum. Furthermore, the SNP treatment significantly increased acidic glycoprotein release from the mucosal layers specifically in the duodenum and jejunum but not in the ileum and colon. These results suggest that SNP increases lipophilic drug membrane permeability specifically in the proximal region of the small intestine through disruption of the mucosal layer.

scholarly journals The Advantages of the Ussing Chamber in Drug Absorption Studies

2005 ◽  
Vol 10 (5) ◽  
pp. 517-523 ◽  
Author(s):  
Yasumasa Gotoh ◽  
Noboru Kamada ◽  
Denichi Momose
Keyword(s):  
Small Intestine ◽  
Membrane Permeability ◽  
Drug Absorption ◽  
Ussing Chamber ◽  
In Vivo Studies ◽  
Glycoprotein P ◽  
Absorption Studies ◽  
High Concentrations ◽  
Absorption Percentage

By adding high concentrations of test drugs to an Ussing chamber with rat jejunum, we established a systemthat yields very high correlations between the rat absorption percentage and the membrane permeability, and that can accurately predict the absorption percentage for rats. An advantage of this technique is that, unlike the results obtained using Caco-2, the slope of the absorption/membrane-permeability curve is gentle, which facilitates a more exact prediction of the absorption percentage. In addition, the results obtained with this technique demonstrated that it could be used to evaluate the absorption percentage of drugs with an affinity for P-glycoprotein (P-gp), which cannot be assessed using Caco-2. Thismethod also allows for cassette screening, whichwould facilitate evaluation of the contribution of P-gp to absorption in the small intestine. Cassette screening showed that absorption of fexofenadinewas unaffected by combinationwith the P-gp substrate ketoconazole. Consistent with this finding, in vivo studies showed that ketoconazole did not affect the Fa Fg for fexofenadine, a pharmacokinetic parameter that reflects absorption and bioavailability in the small intestine. This confirms the usefulness of the Ussing chamber for cassette screening and also suggests that intestinal P-gp has a minimal contribution to drug absorption.

scholarly journals Generation of tetracycline-controllable CYP3A4-expressing Caco-2 cells by the piggyBac transposon system

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Moe Ichikawa ◽  
Hiroki Akamine ◽  
Michika Murata ◽  
Sumito Ito ◽  
Kazuo Takayama ◽  
...  
Keyword(s):  
Small Intestine ◽  
Drug Absorption ◽  
Cell Model ◽  
Negative Effects ◽  
Piggybac Transposon ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme ◽  
Cyp3a4 Expression

AbstractCaco-2 cells are widely used as an in vitro intestinal epithelial cell model because they can form a monolayer and predict drug absorption with high accuracy. However, Caco-2 cells hardly express cytochrome P450 (CYP), a drug-metabolizing enzyme. It is known that CYP3A4 is the dominant drug-metabolizing enzyme in human small intestine. In this study, we generated CYP3A4-expressing Caco-2 (CYP3A4-Caco-2) cells and attempted to establish a model that can simultaneously evaluate drug absorption and metabolism. CYP3A4-Caco-2 cells were generated by piggyBac transposon vectors. A tetracycline-controllable CYP3A4 expression cassette (tet-on system) was stably transduced into Caco-2 cells, thus regulating the levels of CYP3A4 expression depending on the doxycycline concentration. The CYP3A4 expression levels in CYP3A4-Caco-2 cells cultured in the presence of doxycycline were similar to or higher than those of adult small intestine. The CYP3A4-Caco-2 cells had enough ability to metabolize midazolam, a substrate of CYP3A4. CYP3A4 overexpression had no negative effects on cell proliferation, barrier function, and P-glycoprotein activity in Caco-2 cells. Thus, we succeeded in establishing Caco-2 cells with CYP3A4 metabolizing activity comparable to in vivo human intestinal tissue. This cell line would be useful in pharmaceutical studies as a model that can simultaneously evaluate drug absorption and metabolism.

Carbohydrase activity in the pancreatic tissue and small intestine mucosa of sheep fed dried-grass or ground maize-based diets

1985 ◽  
Vol 104 (2) ◽  
pp. 435-443 ◽  
Author(s):  
A. N. Janes ◽  
T. E. C. Weekes ◽  
D. G. Armstrong
Keyword(s):  
Small Intestine ◽  
Amylase Activity ◽  
Total Activity ◽  
Pancreatic Tissue ◽  
Proximal Region ◽  
Small Intestinal Mucosa ◽  
Intestine Mucosa ◽  
Ruminant Animals ◽  
Specific Activities ◽  
Small Intestinal

SummaryTwo groups of six sheep were fed either dried-grass or ground maize-based diets for at least 4 weeks before slaughter. Samples of the small intestinal mucosa and spancreatic tissue were assayed for a-amylase, glucoamylase, maltase and oligo-l,6-glucosidase.The pancreatic tissue contained high activities of α-amylase and much lower activities of glucoamylase, maltase and oligo-1,6-glucosidase. There was no effect of diet on the specific activities of any of these enzymes in the pancreatic tissue.The activity of α-amylase adsorbed on to the mucosa of the small intestine was greatest in the proximal region of the small intestine, the activity generally declining with increasing distance away from the pylorus. There was no diet effect on the absorbed α-amylase activity.Similar patterns of distribution along the small intestine were observed for maltase, glucoamylase and oligo-1,6-glucosidase with the highest activities in t he jejunum. There was no overall effect of diet on glucoamylase or maltase specific activities and glucoamylase total activity, although the total activities of maltase and oligo-1,6-glucosidase were significantly greater for the sheep fed the ground maize-based diet (P < 0·05).It is suggested that ruminant animals may be capable of digesting large amounts of starch in the small intestine through an adaptation in the activity of the host carbohydrases.

Absorption Properties of Luteolin and Apigenin in Genkwa Flos Using In Situ Single-Pass Intestinal Perfusion System in the Rat

2017 ◽  
Vol 45 (08) ◽  
pp. 1745-1759 ◽  
Author(s):  
Xin He ◽  
Zi-Jing Song ◽  
Cui-Ping Jiang ◽  
Chun-Feng Zhang
Keyword(s):  
Small Intestine ◽  
Intestinal Absorption ◽  
Rat Model ◽  
Clinical Effectiveness ◽  
Intestinal Perfusion ◽  
Flower Bud ◽  
Transport Pathway ◽  
Absorption Enhancers ◽  
Single Pass

The flower bud of Daphne genkwa (Genkwa Flos) is a commonly used herbal medicine in Asian countries. Luteolin and apigenin are two recognized active flavonoids in Genkwa Flos. The aim of this study was to investigate the intestinal absorption mechanisms of Genkwa Flos flavonoids using in situ single-pass intestinal perfusion rat model. Using HPLC, we determined its major effective flavonoids luteolin, apigenin, as well as, hydroxygenkwanin and genkwanin in biological samples. The intestinal absorption mechanisms of the total flavonoids in Genkwa Flos (TFG) were investigated using in situ single-pass intestinal perfusion rat model. Comparing the TFG absorption rate in different intestinal segments, data showed that the small intestine absorption was significantly higher than that of the colon ([Formula: see text]). Compared with duodenum and ileum, the jejunum was the best small intestinal site for TFG absorption. The high TFG concentration (61.48[Formula: see text][Formula: see text]g/ml) yielded the highest permeability ([Formula: see text]). Subsequently, three membrane protein inhibitors (verapamil, pantoprazole and probenecid) were used to explore the TFG absorption pathways. Data showed probenecid, a multidrug resistance protein (or MRP) inhibitor, effectively enhanced the TFG absorption ([Formula: see text]). Furthermore, by comparing commonly used natural absorption enhancers on TFG, it was observed that camphor was the most effective. In Situ single-pass intestinal perfusion experiment shows that TFG absorption is much higher in the small intestine than in the colon, and the TFG is absorbed mainly via an active transport pathway with MRP-mediated efflux mechanism. Camphor obviously enhanced the TFG absorption, and this could be an effective TFG formulation preparation method to increase clinical effectiveness after Genkwa Flos administration. Our study elucidated the TFG absorption mechanisms, and provided new information for its formulation preparation.

Effects of pharmaceutical excipients on membrane permeability in rat small intestine

2013 ◽  
Vol 453 (2) ◽  
pp. 363-370 ◽  
Author(s):  
Yusuke Takizawa ◽  
Hisanao Kishimoto ◽  
Minami Nakagawa ◽  
Nasa Sakamoto ◽  
Yoshifusa Tobe ◽  
...  
Keyword(s):  
Small Intestine ◽  
Membrane Permeability ◽  
Rat Small Intestine ◽  
Pharmaceutical Excipients

scholarly journals Protective Effect of Sodium Nitroprusside on the Rat Small Intestine Transplanted Mucosa

2015 ◽  
Vol 2015 ◽  
pp. 1-6
Author(s):  
Feng-Hua Chen ◽  
Ke Li ◽  
Lu Yin ◽  
Chun-Qiu Chen ◽  
Zhao-Wen Yan ◽  
...  
Keyword(s):  
Small Intestine ◽  
Molecular Markers ◽  
Protective Effect ◽  
Sodium Nitroprusside ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Small Bowel Transplantation ◽  
Mucosal Barrier ◽  
No Donor

The intestinal mucosal epithelium is extremely susceptible to even brief periods of ischemia. Mucosal barrier damage, which is associated with ischemia/reperfusion (I/R) injury and consequently bacterial translocation, remains a major obstacle for clinically successful small bowel transplantation (SBT). Previous studies have demonstrated a protective effect of nitric oxide (NO) on other transplanted organs and NO mediated intestinal protection has also been reportedin vitro. The aim of this study was to evaluate the effect of sodium nitroprusside (SNP), NO donor, on graft mucosal histology and molecular markers of function after SBT in rats. We used SNP in different period of heterotopic SBT rats. The groups consisted of SBT, pre-SNP group, and post-SNP group. Interestingly, the pre-SNP graft samples exhibited less damage compared to the SBT and post-SNP samples. In addition, mucosal samples from the pre-SNP group showed higher Na+-K+-ATPase activity and higher levels of laminin expression compared to the SBT and post-SNP samples. The findings of the present study reveal that SNP given before graft ischemia/reperfusion injury has a protective effect on mucosal histology and molecular markers of function in the transplanted small intestine.

scholarly journals Mitigation of salinity stress in canola plants by sodium nitroprusside application

2018 ◽  
Vol 16 (3) ◽  
pp. e0802 ◽  
Author(s):  
Saad Farouk ◽  
Sally A. Arafa
Keyword(s):  
Hydrogen Peroxide ◽  
Lipid Peroxidation ◽  
Sodium Chloride ◽  
Plant Growth ◽  
Sodium Nitroprusside ◽  
Membrane Permeability ◽  
Salinity Stress ◽  
Growth Yield ◽  
Growth And Yield ◽  
Anatomical Changes

Salinity is a global issue threatening land productivity and food production. The present study aimed to examine the role of sodium nitroprusside (SNP) on the alleviation of NaCl stress on different parameters of canola (Brassica napus L.) plant growth, yield as well as its physiological and anatomical characteristics. Canola plants were grown under greenhouse conditions in plastic pots and were exposed to 100 mM NaCl. At 50 and 70 days from sown, plants were sprayed with SNP (50 and 100 µM) solutions under normal or salinity condition. Growth and yield characters as well as some biochemical and anatomical changes were investigated under the experimental conditions. Salinity stress caused an extremely vital decline in plant growth and yield components. A significant increase was found in membrane permeability, lipid peroxidation, hydrogen peroxide, sodium, chloride, proline, soluble sugars, ascorbic and phenol in canola plants under salinity stress. Under normal conditions, SNP application significantly increased all studies characters, except sodium, chloride, hydrogen peroxide, lipid peroxidation, membrane permeability that markedly reduced. Application of SNP to salt-affected plants mitigated the injuries of salinity on plant growth, yield, and improved anatomical changes. The present investigation demonstrated that SNP has the potential to alleviate the salinity injurious on canola plants.

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