Evaluation of an oral carrier system in rats: bioavailability and gastrointestinal absorption properties of curcumin encapsulated PBCA nanoparticles

NASA Astrophysics Data System (ADS)

Sun, Min; Zhao, Lixia; Guo, Chenyu; Cao, Fengliang; Chen, Huanlei; Zhao, Liyan; Tan, Qi; Zhu, Xiuqing; Zhu, Fanping; Ding, Tingting; Zhai, Yingjie; Zhai, Guangxi

2012-02-01

A new oral delivery system, polybutylcyanoacrylate nanoparticles (PBCNs), was introduced to improve the oral bioavailability of curcumin (CUR), a poorly soluble drug. The formulation was optimized by orthogonal design and the optimal PBCNs loading CUR exhibited a spherical shape under transmission electron microscopy with a range of 40-400 nm. Physicochemical state of CUR in PBCN was investigated by X-ray diffraction and the possible structure changes occurring in CUR after conjugating with polybutylcyanoacrylate were studied with FTIR. The results indicated that CUR in PBCN was in a non-crystalline state and CUR was encapsulated in PBCN without chemical reaction. The oral pharmacokinetic study was conducted in rats and the relative bioavailability of CUR encapsulated PBCNs to the crude CUR was more than 800%. The in situ absorption experiment in rat intestine indicated the absorption was first order with passive diffusion mechanism. The absorption results in various segments of intestine showed that the main absorption sites were ileum and colon. It can be concluded that PBCNs as an oral carrier can significantly improve the oral absorption of a poorly soluble drug.

[Improvement and prediction of intestinal drug absorption].

PubMed

Miyake, Masateru

2013-01-01

The suppository preparation, which can improve the absorption of poorly absorbable drugs safer than commercially available suppositories, was developed by utilizing sodium laurate and taurine. Additionally, the novel oral absorption-improving system was also established by utilizing polyamines and bile acids. Furthermore, to evaluate the efficacy of these new formulations and estimate the absorbability of new drug candidates in humans, the in vitro prediction system utilizing an isolated human intestinal tissues was developed and successfully predicted the fraction of dose absorbed for several model drugs. These findings would contribute to the development of new dosage forms and new drugs for oral administration.

Absorption enhancement studies of clopidogrel hydrogen sulphate in rat everted gut sacs.

PubMed

Lassoued, Mohamed Ali; Sfar, Souad; Bouraoui, Abderrahman; Khemiss, Fathia

2012-04-01

Clopidogrel, a thienopyridine antiplatelet agent, is a poor aqueous soluble compound and a P-glycoprotein (P-gp) efflux pump substrate. These two factors are responsible for its incomplete intestinal absorption. In this study, we have attempted to enhance the absorption of clopidogrel by improving its solubility and by inhibiting intestinal P-gp activity.   Solubility enhancement was achieved by preparing solid dispersions. Quinidine and naringin were selected as P-gp inhibitors, whilst tartaric acid was selected as the intestinal absorption enhancer. Absorption studies were performed using the everted gut sac model prepared from rat jejunum. The determination of clopidogrel was performed by high performance liquid chromatography. We noticed an enhancement of clopidogrel absorption by improving its solubility or by inhibiting the P-gp activity. The greatest results were obtained for solid dispersions in the presence of P-gp inhibitors at their highest concentrations, with an absorption improvement of 3.41- and 3.91-fold for naringin (15mg/kg) and quinidine (200µm), respectively. However, no clopidogrel absorption enhancement occurred in the presence of tartaric acid. Naringin, a natural compound which has no undesirable side effects as compared with quinidine, could be used as a pharmaceutical excipient in the presence of clopidogrel solid dispersions to increase clopidogrel intestinal absorption and therefore its oral bioavailability. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

Transport of sennosides and sennidines from Cassia angustifolia and Cassia senna across Caco-2 monolayers--an in vitro model for intestinal absorption.

PubMed

Waltenberger, B; Avula, B; Ganzera, M; Khan, I A; Stuppner, H; Khan, S I

2008-05-01

Laxative effects of Senna preparations are mainly mediated by rheinanthrone, a metabolite formed in the intestinal flora from dianthrones. Nevertheless, it was not clear whether dianthrones are bioavailable at all and contribute to the overall effects of this important medicinal plant. Using the Caco-2 human colonic cell line as an in vitro model of the human intestinal mucosal barrier, the bioavailability of dianthrones was studied in apical to basolateral (absorptive) and basolateral to apical (secretive) direction. Permeability coefficients (P(c)) and percent transport were calculated based on quantitations by HPLC. From the data obtained it was concluded that sennosides A and B, as well as their aglycones sennidine A and B are transported through the Caco-2 monolayers in a concentration-dependent manner and their transport was linear with time. The absorption in apical to basolateral direction was poor and P(c) values were comparable to mannitol. The transport was higher in the secretory direction, indicating a significant efflux (e.g. by efflux pumps) of the (poorly) absorbed compounds in the intestinal lumen again. Our findings support the general understanding that the laxative effects of Senna are explainable mainly by metabolites and not by the natively present dianthrones.

Mechanism of enhanced oral absorption of morin by phospholipid complex based self-nanoemulsifying drug delivery system.

PubMed

Zhang, Jinjie; Li, Jianbo; Ju, Yuan; Fu, Yao; Gong, Tao; Zhang, Zhirong

2015-02-02

Phospholipid complex (PLC) based self-nanoemulsifying drug delivery system (PLC-SNEDDS) has been developed for efficient delivery of drugs with poor solubility and low permeability. In the present study, a BCS class IV drug and a P-glycoprotein (P-gp) substrate, morin, was selected as the model drug to elucidate the oral absorption mechanism of PLC-SNEDDS. PLC-SNEDDS was superior to PLC in protecting morin from degradation by intestinal enzymes in vitro. In situ perfusion study showed increased intestinal permeability by PLC was duodenum-specific. In contrast, PLC-SNEDDS increased morin permeability in all intestinal segments and induced a change in the main absorption site of morin from colon to ileum. Moreover, ileum conducted the lymphatic transport of PLC-SNEDDS, which was proven by microscopic intestinal visualization of Nile red labeled PLC-SNEDDS and lymph fluids in vivo. Low cytotoxicity and increased Caco-2 cell uptake suggested a safe and efficient delivery of PLC-SNEDDS. The increased membrane fluidity and disrupted actin filaments were closely associated with the increased cell uptake of PLC-SNEDDS. PLC-SNEDDS could be internalized into enterocytes as an intact form in a cholesterol-dependent manner via clathrin-mediated endocytosis and macropinocytosis. The enhanced oral absorption of morin was attributed to the P-gp inhibition by Cremophor RH and the intact internalization of M-PLC-SNEDDS into Caco-2 cells bypassing P-gp recognition. Our findings thus provide new insights into the development of novel nanoemulsions for poorly absorbed drugs.

Absorption and Transport of Sea Cucumber Saponins from Apostichopus japonicus.

PubMed

Li, Shuai; Wang, Yuanhong; Jiang, Tingfu; Wang, Han; Yang, Shuang; Lv, Zhihua

2016-06-17

The present study is focused on the intestinal absorption of sea cucumber saponins. We determined the pharmacokinetic characteristics and bioavailability of Echinoside A and Holotoxin A₁; the findings indicated that the bioavailability of Holotoxin A₁ was lower than Echinoside A. We inferred that the differences in chemical structure between compounds was a factor that explained their different characteristics of transport across the intestine. In order to confirm the absorption characteristics of Echinoside A and Holotoxin A₁, we examined their transport across Caco-2 cell monolayer and effective permeability by single-pass intestinal perfusion. The results of Caco-2 cell model indicate that Echinoside A is transported by passive diffusion, and not influenced by the exocytosis of P-glycoprotein (P-gp, expressed in the apical side of Caco-2 monolayers as the classic inhibitor). The intestinal perfusion also demonstrated well the absorption of Echinoside A and poor absorption of Holotoxin A₁, which matched up with the result of the Caco-2 cell model. The results demonstrated our conjecture and provides fundamental information on the relationship between the chemical structure of these sea cucumber saponins and their absorption characteristics, and we believe that our findings build a foundation for the further metabolism study of sea cucumber saponins and contribute to the further clinical research of saponins.

In vitro solubility, dissolution and permeability studies combined with semi-mechanistic modeling to investigate the intestinal absorption of desvenlafaxine from an immediate- and extended release formulation.

PubMed

Franek, F; Jarlfors, A; Larsen, F; Holm, P; Steffansen, B

2015-09-18

Desvenlafaxine is a biopharmaceutics classification system (BCS) class 1 (high solubility, high permeability) and biopharmaceutical drug disposition classification system (BDDCS) class 3, (high solubility, poor metabolism; implying low permeability) compound. Thus the rate-limiting step for desvenlafaxine absorption (i.e. intestinal dissolution or permeation) is not fully clarified. The aim of this study was to investigate whether dissolution and/or intestinal permeability rate-limit desvenlafaxine absorption from an immediate-release formulation (IRF) and Pristiq(®), an extended release formulation (ERF). Semi-mechanistic models of desvenlafaxine were built (using SimCyp(®)) by combining in vitro data on dissolution and permeation (mechanistic part of model) with clinical data (obtained from literature) on distribution and clearance (non-mechanistic part of model). The model predictions of desvenlafaxine pharmacokinetics after IRF and ERF administration were compared with published clinical data from 14 trials. Desvenlafaxine in vivo dissolution from the IRF and ERF was predicted from in vitro solubility studies and biorelevant dissolution studies (using the USP3 dissolution apparatus), respectively. Desvenlafaxine apparent permeability (Papp) at varying apical pH was investigated using the Caco-2 cell line and extrapolated to effective intestinal permeability (Peff) in human duodenum, jejunum, ileum and colon. Desvenlafaxine pKa-values and octanol-water partition coefficients (Do:w) were determined experimentally. Due to predicted rapid dissolution after IRF administration, desvenlafaxine was predicted to be available for permeation in the duodenum. Desvenlafaxine Do:w and Papp increased approximately 13-fold when increasing apical pH from 5.5 to 7.4. Desvenlafaxine Peff thus increased with pH down the small intestine. Consequently, desvenlafaxine absorption from an IRF appears rate-limited by low Peff in the upper small intestine, which "delays" the predicted time to the maximal plasma concentration (tmax), consistent with clinical data. Conversely, desvenlafaxine absorption from the ERF appears rate-limited by dissolution due to the formulation, which tends to negate the influence of pH-dependent permeability on absorption. We suggest that desvenlafaxine Peff is mainly driven by transcellular diffusion of the unionized form. In the case of desvenlafaxine, poor metabolism does not imply low intestinal permeability, as indicated by the BDDCS, merely low duodenal/jejunal permeability. Copyright © 2015 Elsevier B.V. All rights reserved.

Denatured globular protein and bile salt-coated nanoparticles for poorly water-soluble drugs: Penetration across the intestinal epithelial barrier into the circulation system and enhanced oral bioavailability.

PubMed

He, Wei; Yang, Ke; Fan, Lifang; Lv, Yaqi; Jin, Zhu; Zhu, Shumin; Qin, Chao; Wang, Yiao; Yin, Lifang

2015-11-10

Oral drug delivery is the most preferred route for patients; however, the low solubility of drugs and the resultant poor absorption compromise the benefits of oral administration. On the other hand, for years, the overwhelmingly accepted mechanism for enhanced oral absorption using lipid nanocarriers was based on the process of lipid digestion and drug solubilization in the small intestine. Few reports indicated that other bypass pathways are involved in drug absorption in the gastrointestinal tract (GIT) for oral delivery of nanocarriers. Herein, we report a new nanoemulsion system with a denatured globular protein with a diameter of 30 nm, soybean protein isolates (SPI), and bile salt as emulsifiers, aiming to enhance the absorption of insoluble drugs and explore other pathways for absorption. A BCS class II drug, fenofibrate (FB), was used as the model drug. The SPI and bile salt-coated Ns with a diameter of approximately 150 nm were prepared via a high-pressure homogenizing procedure. Interestingly, the present Ns could be converted to solid dosage form using fluid-bed coating technology, maintaining a nanoscale size. Most importantly, in a model of in situ rat intestinal perfusion, Ns could penetrate across the intestinal epithelial barrier into the systemic circulation and then obtain biodistribution into other tissues. In addition, Ns significantly improved FB oral absorption, exhibited as a greater than 2- and 2.5-fold increase in Cmax and AUC0-t, respectively, compared to the suspension formulation. Overall, the present Ns are promising nanocarriers for the oral delivery of insoluble drugs, and the penetration of intact Ns across the GIT barrier into systemic circulation may be a new strategy for improved drug absorption with the use of nanocarriers. Copyright © 2015 Elsevier B.V. All rights reserved.

Nanostructured lipid carriers versus microemulsions for delivery of the poorly water-soluble drug luteolin.

PubMed

Liu, Ying; Wang, Lan; Zhao, Yiqing; He, Man; Zhang, Xin; Niu, Mengmeng; Feng, Nianping

2014-12-10

Nanostructured lipid carriers and microemulsions effectively deliver poorly water-soluble drugs. However, few studies have investigated their ability and difference in improving drug bioavailability, especially the factors contributed to the difference. Thus, this study was aimed at investigating their efficiency in bioavailability enhancement based on studying two key processes that occur in NLC and ME during traverse along the intestinal tract: the solubilization process and the intestinal permeability process. The nanostructured lipid carriers and microemulsions had the same composition except that the former were prepared with solid lipids and the latter with liquid lipids; both were evaluated for particle size and zeta potential. Transmission electron microscopy, differential scanning calorimetry, and X-ray diffraction were performed to characterize their properties. Furthermore, in vitro drug release, in situ intestinal absorption, and in vitro lipolysis were studied. The bioavailability of luteolin delivered using nanostructured lipid carriers in rats was compared with that delivered using microemulsions and suspensions. The in vitro analysis revealed different release mechanisms for luteolin in nanostructured lipid carriers and microemulsions, although the in situ intestinal absorption was similar. The in vitro lipolysis data indicated that digestion speed and extent were higher for microemulsions than for nanostructured lipid carriers, and that more of the former partitioned to the aqueous phase. The in vivo bioavailability analysis in rats indicated that the oral absorption and bioavailability of luteolin delivered using nanostructured lipid carriers and microemulsions were higher than those of luteolin suspensions. Nanostructured lipid carriers and microemulsions improved luteolin's oral bioavailability in rats. The rapid lipid digestion and much more drug solubilized available for absorption in microemulsions may contribute to better absorption and higher bioavailability. Copyright © 2014 Elsevier B.V. All rights reserved.

Urinary excretion of polyethylene glycol 3350 during colonoscopy preparation.

PubMed

Rothfuss, K S; Bode, J C; Stange, E F; Parlesak, A

2006-02-01

Whole gut lavage with a polyethylene glycol electrolyte solution (PEG) is a common bowel cleansing method for diagnostic and therapeutic colon interventions. Absorption of orally administered PEG from the gastrointestinal tract in healthy human beings is generally considered to be poor. In patients with inflammatory bowel disease (IBD), intestinal permeability and PEG absorption were previously reported to be higher than in normal subjects. In the current study, we investigated the absorption of PEG 3350 in patients undergoing routine gut lavage. Urine specimens were collected for 8 hours in 24 patients undergoing bowel cleansing with PEG 3350 for colonoscopy. The urinary excretion of PEG 3350, measured by size exclusion chromatography, ranged between 0.01 and 0.51 % of the ingested amount, corresponding to 5.8 and 896 mg in absolute amounts, respectively. Mean PEG excretion in patients with impaired mucosa such as inflammation or ulceration of the intestine (0.24 % +/- 0.19, n = 11) was not significantly higher (p = 0.173) compared to that in subjects with macroscopically normal intestinal mucosa (0.13 % +/- 0.13, n = 13). The results indicate that intestinal absorption of PEG 3350 is higher than previously assumed and underlies a strong inter-individual variation. Inflammatory changes of the intestine do not necessarily lead to a significantly higher permeability of PEG.

Supersaturation-nucleation behavior of poorly soluble drugs and its impact on the oral absorption of drugs in thermodynamically high-energy forms.

PubMed

Ozaki, Shunsuke; Minamisono, Takuma; Yamashita, Taro; Kato, Takashi; Kushida, Ikuo

2012-01-01

In order to better understand the oral absorption behavior of poorly water-soluble drugs, their supersaturation-nucleation behavior was characterized in fasted state simulated intestinal fluid. The induction time (t(ind)) for nucleation was measured for four model drugs: itraconazole, erlotinib, troglitazone, and PLX4032. Supersaturated solutions were prepared by solvent shift method, and nucleation initiation was monitored by ultraviolet detection. The relationship between t(ind) and degree of supersaturation was analyzed in terms of classical nucleation theory. The defined supersaturation stability proved to be compound specific. Clinical data on oral absorption were investigated for drugs in thermodynamically high-energy forms such as amorphous forms and salts and was compared with in vitro supersaturation-nucleation characteristics. Solubility-limited maximum absorbable dose was proportionate to intestinal effective drug concentrations, which are related to supersaturation stability and thermodynamic solubility. Supersaturation stability was shown to be an important factor in determining the effect of high-energy forms. The characterization of supersaturation-nucleation behavior by the presented method is, therefore, valuable for assessing the potential absorbability of poorly water-soluble drugs. Copyright © 2011 Wiley-Liss, Inc.

Enhanced solubility and intestinal absorption of candesartan cilexetil solid dispersions using everted rat intestinal sacs.

PubMed

Gurunath, S; Nanjwade, Baswaraj K; Patila, P A

2014-07-01

Candesartan cilexetil (CAN) is a poor aqueous soluble compound and a P-glycoprotein (P-gp) efflux pump substrate. These key factors are responsible for its incomplete intestinal absorption. In this study, we investigated to enhance the absorption of CAN by improving its solubility and inhibiting intestinal P-gp activity. A phase solubility method was used to evaluate the aqueous solubility of CAN in PVP K30 (0.2-2%). Gibbs free energy [Formula: see text] values were all negative. Solubility was enhanced by the freeze drying technique. The in vitro dissolution was evaluated using the USP paddle method. The interaction between drug and carrier was evaluated by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and Differential scanning calorimetry (DSC) studies. Naringin was selected as P-gp inhibitor. Absorption studies were performed using the everted gut sac model from rat jejunum. The drug analysis was performed by HPLC. FTIR spectra revealed no interaction between drug and PVP K30. From XRD and DSC data, CAN was in the amorphous form, which explains the cumulative release of drug from its prepared systems. We noticed an enhancement of CAN absorption by improving its solubility and inhibiting the P-gp activity. The significant results (p < 0.05) were obtained for freeze dried solid dispersions in the presence of P-gp inhibitor than without naringin (15 mg/kg) with an absorption enhancement of 8-fold. Naringin, a natural flavonoid, has no undesirable side effects. Therefore, it could be employed as an excipient in the form of solid dispersions to increase CAN intestinal absorption and its oral bioavailability.

Enhanced solubility and intestinal absorption of candesartan cilexetil solid dispersions using everted rat intestinal sacs

PubMed Central

Gurunath, S.; Nanjwade, Baswaraj K.; Patila, P.A.

2013-01-01

Objective Candesartan cilexetil (CAN) is a poor aqueous soluble compound and a P-glycoprotein (P-gp) efflux pump substrate. These key factors are responsible for its incomplete intestinal absorption. Methods In this study, we investigated to enhance the absorption of CAN by improving its solubility and inhibiting intestinal P-gp activity. A phase solubility method was used to evaluate the aqueous solubility of CAN in PVP K30 (0.2–2%). Gibbs free energy (ΔGtro) values were all negative. Solubility was enhanced by the freeze drying technique. The in vitro dissolution was evaluated using the USP paddle method. The interaction between drug and carrier was evaluated by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and Differential scanning calorimetry (DSC) studies. Naringin was selected as P-gp inhibitor. Absorption studies were performed using the everted gut sac model from rat jejunum. The drug analysis was performed by HPLC. Results FTIR spectra revealed no interaction between drug and PVP K30. From XRD and DSC data, CAN was in the amorphous form, which explains the cumulative release of drug from its prepared systems. We noticed an enhancement of CAN absorption by improving its solubility and inhibiting the P-gp activity. The significant results (p < 0.05) were obtained for freeze dried solid dispersions in the presence of P-gp inhibitor than without naringin (15 mg/kg) with an absorption enhancement of 8-fold. Conclusion Naringin, a natural flavonoid, has no undesirable side effects. Therefore, it could be employed as an excipient in the form of solid dispersions to increase CAN intestinal absorption and its oral bioavailability. PMID:25067902

Role of Self-Association and Supersaturation in Oral Absorption of a Poorly Soluble Weakly Basic Drug.

PubMed

Narang, Ajit S; Badawy, Sherif; Ye, Qingmei; Patel, Dhaval; Vincent, Maria; Raghavan, Krishnaswamy; Huang, Yande; Yamniuk, Aaron; Vig, Balvinder; Crison, John; Derbin, George; Xu, Yan; Ramirez, Antonio; Galella, Michael; Rinaldi, Frank A

2015-08-01

Precipitation of weakly basic drugs in intestinal fluids can affect oral drug absorption. In this study, the implications of self-association of brivanib alaninate in acidic aqueous solution, leading to supersaturation at basic pH condition, on its solubility and oral absorption were investigated. Self-association of brivanib alaninate was investigated by proton NMR spectroscopy, surface tension measurement, dynamic light scattering, isothermal titration calorimetry, and molecular modeling. Drug solubility was determined in various pH media, and its tendency to supersaturate upon pH shift was investigated in buffered and biorelevant aqueous solutions. Pharmacokinetic modeling of human oral drug absorption was utilized for parameter sensitivity analyses of input variables. Brivanib alaninate exhibited continuous, and pH- and concentration-dependent self-association. This phenomenon resulted in positive deviation of drug solubility at acidic pH and the formation of a stable supersaturated drug solution in pH-shift assays. Consistent with the supersaturation phenomenon observed in vitro, oral absorption simulations necessitated invoking long precipitation time in the intestine to successfully predict in vivo data. Self-association of a weakly basic drug in acidic aqueous solution can increase its oral absorption by supersaturation and precipitation resistance at the intestinal pH. This consideration is important to the selection of parameters for oral absorption simulation.

Self-Assembled Core-Shell-Type Lipid-Polymer Hybrid Nanoparticles: Intracellular Trafficking and Relevance for Oral Absorption.

PubMed

Li, Qiuxia; Xia, Dengning; Tao, Jinsong; Shen, Aijun; He, Yuan; Gan, Yong; Wang, Chi

2017-10-01

Lipid-polymer hybrid nanoparticles (NPs) are advantageous for drug delivery. However, their intracellular trafficking mechanism and relevance for oral drug absorption are poorly understood. In this study, self-assembled core-shell lipid-polymer hybrid NPs made of poly(lactic-co-glycolic acid) (PLGA) and various lipids were developed to study their differing intracellular trafficking in intestinal epithelial cells and their relevance for oral absorption of a model drug saquinavir (SQV). Our results demonstrated that the endocytosis and exocytosis of hybrid NPs could be changed by varying the kind of lipid. A glyceride mixture (hybrid NPs-1) decreased endocytosis but increased exocytosis in Caco-2 cells, whereas the phospholipid (E200) (hybrid NPs-2) decreased endocytosis but exocytosis was unaffected as compared with PLGA nanoparticles. The transport of hybrid NPs-1 in cells involved various pathways, including caveolae/lipid raft-dependent endocytosis, and clathrin-mediated endocytosis and macropinocytosis, which was different from the other groups of NPs that involved only caveolae/lipid raft-dependent endocytosis. Compared with that of the reference formulation (nanoemulsion), the oral absorption of SQV-loaded hybrid NPs in rats was poor, probably due to the limited drug release and transcytosis of NPs across the intestinal epithelium. In conclusion, the intracellular processing of hybrid NPs in intestinal epithelia can be altered by adding lipids to the NP. However, it appears unfavorable to use PLGA-based NPs to improve oral absorption of SQV compared with nanoemulsion. Our findings will be essential in the development of polymer-based NPs for the oral delivery of drugs with the purpose of improving their oral absorption. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Pathophysiology of avian intestinal ion transport.

PubMed

Nighot, Meghali; Nighot, Prashant

2018-06-01

The gut has great importance for the commercial success of poultry production. Numerous ion transporters, exchangers, and channels are present on both the apical and the basolateral membrane of intestinal epithelial cells, and their differential expression along the crypt-villus axis within the various intestinal segments ensures efficient intestinal absorption and effective barrier function. Recent studies have shown that intensive production systems, microbial exposure, and nutritional management significantly affect intestinal physiology and intestinal ion transport. Dysregulation of normal intestinal ion transport is manifested as diarrhoea, malabsorption, and intestinal inflammation resulting into poor production efficiency. This review discusses the basic mechanisms involved in avian intestinal ion transport and the impact of development during growth, nutritional and environmental alterations, and intestinal microbial infections on it. The effect of intestinal microbial infections on avian intestinal ion transport depends on factors such as host immunity, pathogen virulence, and the mucosal organisation of the particular intestinal segment.

Assessment of Passive Intestinal Permeability Using an Artificial Membrane Insert System.

PubMed

Berben, Philippe; Brouwers, Joachim; Augustijns, Patrick

2018-01-01

Despite reasonable predictive power of current cell-based and cell-free absorption models for the assessment of intestinal drug permeability, high costs and lengthy preparation steps hamper their use. The use of a simple artificial membrane (without any lipids present) as intestinal barrier substitute would overcome these hurdles. In the present study, a set of 14 poorly water-soluble drugs, dissolved in 2 different media (fasted state simulated/human intestinal fluids [FaSSIF/FaHIF]), were applied to the donor compartment of an artificial membrane insert system (AMI-system) containing a regenerated cellulose membrane. Furthermore, to investigate the predictive capacity of the AMI-system as substitute for the well-established Caco-2 system to assess intestinal permeability, the same set of 14 drugs dissolved in FaHIF were applied to the donor compartment of a Caco-2 system. For 14 drugs, covering a broad range of physicochemical parameters, a reasonable correlation between both absorption systems was observed, characterized by a Pearson correlation coefficient r of 0.95 (FaHIF). Using the AMI-system, an excellent predictive capacity of FaSSIF as surrogate medium for FaHIF was demonstrated (r = 0.96). Based on the acquired data, the AMI-system appears to be a time- and cost-effective tool for the early-stage estimation of passive intestinal permeability for poorly water-soluble drugs. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

The intestine is a blender

NASA Astrophysics Data System (ADS)

Yang, Patricia; Lamarca, Morgan; Kravets, Victoria; Hu, David

According to the U.S. Department of Health and Human Services, digestive disease affects 60 to 70 million people and costs over 140 billion annually. Despite the significance of the gastrointestinal tract to human health, the physics of digestion remains poorly understood. In this study, we ask a simple question: what sets the frequency of intestinal contractions? We measure the frequency of intestinal contractions in rats, as a function of distance down the intestine. We find that intestines Contract radially ten times faster than longitudinally. This motion promotes mixing and, in turn, absorption of food products by the intestinal wall. We calculate viscous dissipation in the intestinal fluid to rationalize the relationship between frequency of intestinal contraction and the viscosity of the intestinal contents. Our findings may help to understand the evolution of the intestine as an ideal mixer.

The intestine is a blender

NASA Astrophysics Data System (ADS)

Yang, Patricia; Lamarca, Morgan; Hu, David

2015-11-01

According to the U.S. Department of Health and Human Services, digestive disease affects 60 to 70 million people and costs over 140 billion annually. Despite the significance of the gastrointestinal tract to human health, the physics of digestion remains poorly understood. In this study, we ask a simple question: what sets the frequency of intestinal contractions? We measure the frequency of intestinal contractions in rats, as a function of distance down the intestine. We find that intestines contract radially ten times faster than longitudinally. This motion promotes mixing and, in turn, absorption of food products by the intestinal wall. We calculate viscous dissipation in the intestinal fluid to rationalize the relationship between frequency of intestinal contraction and the viscosity of the intestinal contents. Our findings may help to understand the evolution of the intestine as an ideal mixer.

Absorption of Manganese and Iron in a Mouse Model of Hemochromatosis

PubMed Central

Kim, Jonghan; Buckett, Peter D.; Wessling-Resnick, Marianne

2013-01-01

Hereditary hemochromatosis, an iron overload disease associated with excessive intestinal iron absorption, is commonly caused by loss of HFE gene function. Both iron and manganese absorption are regulated by iron status, but the relationships between the transport pathways of these metals and how they are affected by HFE-associated hemochromatosis remain poorly understood. Loss of HFE function is known to alter the intestinal expression of DMT1 (divalent metal transporter-1) and Fpn (ferroportin), transporters that have been implicated in absorption of both iron and manganese. Although the influence of HFE deficiency on dietary iron absorption has been characterized, potential effects on manganese metabolism have yet to be explored. To investigate the role of HFE in manganese absorption, we characterized the uptake and distribution of the metal in Hfe −/− knockout mice after intravenous, intragastric, and intranasal administration of 54Mn. These values were compared to intravenous and intragastric administration of 59Fe. Intestinal absorption of 59Fe was increased and clearance of injected 59Fe was also increased in Hfe−/− mice compared to controls. Hfe −/− mice displayed greater intestinal absorption of 54Mn compared to wild-type Hfe+/+ control mice. After intravenous injection, the distribution of 59Fe to heart and liver was greater in Hfe −/− mice but no remarkable differences were observed for 54Mn. Although olfactory absorption of 54Mn into blood was unchanged in Hfe −/− mice, higher levels of intranasally-instilled 54Mn were associated with Hfe−/− brain compared to controls. These results show that manganese transport and metabolism can be modified by HFE deficiency. PMID:23705020

Intestinal Permeability of β-Lapachone and Its Cyclodextrin Complexes and Physical Mixtures.

PubMed

Mangas-Sanjuan, Victor; Gutiérrez-Nieto, Jorge; Echezarreta-López, Magdalena; González-Álvarez, Isabel; González-Álvarez, Marta; Casabó, Vicente-Germán; Bermejo, Marival; Landin, Mariana

2016-12-01

β-Lapachone (βLAP) is a promising, poorly soluble, antitumoral drug. βLAP combination with cyclodextrins (CDs) improves its solubility and dissolution but there is not enough information about the impact of cyclodextrins on βLAP intestinal permeability. The objectives of this work were to characterize βLAP intestinal permeability and to elucidate cyclodextrins effect on the dissolution properties and on the intestinal permeability. The final goal was to evaluate CDs influence on the oral absorption of βLAP. Binary systems (physical mixtures and inclusion complexes) including βLAP and CDs (β-cyclodextrin: βCD, random-methyl-β-cyclodextrin: RMβCD and sulfobutylether-β-cyclodextrin: SBEβCD) have been prepared and analysed by differential scanning calorimetry. βLAP (and its combinations with CDs) absorption rate coefficients and effective permeability values have been determined in vitro in MDCK or MDCK-Mdr1 monolayers and in situ in rat by a closed loop perfusion technique. DSC results confirmed the formation of the inclusion complexes. βLAP-CDs inclusion complexes improve drug solubility and dissolution rate in comparison with physical mixtures. βLAP presented a high permeability value which can provide complete oral absorption. Its oral absorption is limited by its low solubility and dissolution rate. Cyclodextrin (both as physical mixtures and inclusion complexes) showed a positive effect on the intestinal permeability of βLAP. Complexation with CDs does not reduce βLAP intestinal permeability in spite of the potential negative effect of the reduction in free fraction of the drug. The use of RMβCD or SBEβCD inclusion complexes could benefit βLAP oral absorption by enhancing its solubility, dissolution rate and permeability.

A comparison of absorption of glycerol tristearate and glycerol trioleate by rat small intestine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bergstedt, S.E.; Hayashi, H.; Kritchevsky, D.

1990-09-01

Generally, fats rich in saturated fatty acids raise serum cholesterol, whereas fats rich in polyunsaturated fatty acids lower it. There appear to be exceptions; e.g., stearic acid (18:0)-rich fats have little or no effect on serum cholesterol concentrations. This apparent lack of cholesterolemic effect of stearic acid-rich fat could be because intestinal absorption of fat is poor or subsequent plasma and/or tissue metabolism of fat is different. To investigate mechanisms involved, we compared intestinal digestion, uptake, and lymphatic transport of glycerol tristearate (TS) and glycerol trioleate (TO, 18:1). Two groups of rats bearing intestinal lymph fistulas were used. TO ratsmore » were fed intraduodenally for 8 h at a constant rate a lipid emulsion of 25 mumols/h of TO (labeled with glycerol tri(9,10 (n)-3H)oleate), 7.8 mumols of egg phosphatidylcholine, and 57 mumols of sodium taurocholate in 3 ml of phosphate-buffered saline. TS rats were fed the same lipid emulsion except that TS replaced TO and the emulsion was labeled with glyceryl (1,3-14C)tristearate. The lymph triglyceride and radioactivity were determined. After infusion, the luminal and mucosal radioactive lipid content was analyzed. The results showed that there was significantly less lipid transported in the lymph of TS rats compared with TO rats. The results also showed a significant decrease in the absorption of TS as compared with TO. This was due in part to poor lipolysis. In addition, the lipid absorbed by the intestine of the TS rats was transported into lymph less efficiently than in TO rats.« less

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

PubMed Central

Cho, Hyun-Jong; Park, Jin Woo; Yoon, In-Soo; Kim, Dae-Duk

2014-01-01

Docetaxel is a potent anticancer drug, but development of an oral formulation has been hindered mainly due to its poor oral bioavailability. In this study, solid lipid nanoparticles (SLNs) surface-modified by Tween 80 or D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS 1000) were prepared and evaluated in terms of their feasibility as oral delivery systems for docetaxel. Tween 80-emulsified and TPGS 1000-emulsified tristearin-based lipidic nanoparticles were prepared by a solvent-diffusion method, and their particle size distribution, zeta potential, drug loading, and particle morphology were characterized. An in vitro release study showed a sustained-release profile of docetaxel from the SLNs compared with an intravenous docetaxel formulation (Taxotere®). Tween 80-emulsified SLNs showed enhanced intestinal absorption, lymphatic uptake, and relative oral bioavailability of docetaxel compared with Taxotere in rats. These results may be attributable to the absorption-enhancing effects of the tristearin nanoparticle. Moreover, compared with Tween 80-emulsified SLNs, the intestinal absorption and relative oral bioavailability of docetaxel in rats were further improved in TPGS 1000-emulsified SLNs, probably due to better inhibition of drug efflux by TPGS 1000, along with intestinal lymphatic uptake. Taken together, it is worth noting that these surface-modified SLNs may serve as efficient oral delivery systems for docetaxel. PMID:24531717

Biopharmaceutics classification of puerarin and comparison of perfusion approaches in rats.

PubMed

Li, Hewei; Dong, Ling; Liu, Yang; Wang, Guopeng; Wang, Gang; Qiao, Yanjiang

2014-05-15

The present study was conducted to characterize the biopharmaceutics classification system (BCS) category of puerarin in terms of intrinsic dissolution rate (IDR) and rat intestinal permeability and to investigate the poor intestinal absorption probably related to the drug metabolism in the gut wall of rats. Equilibrium solubility of puerarin was determined in various phosphate buffers and water, and IDR was estimated by measuring the dissolution of a non-disintegrating compact. Intestinal permeability (Peff and Pblood) of puerarin was determined using the technology of in situ single-pass intestinal perfusion (SPIP) and intestinal perfusion with venous sampling (IPVS) in fasted rats. Metabolism of puerarin in intestinal tissue was tested by S9 incubation in vitro. The aqueous solubility of puerarin in phosphate buffers and water was good with a maximum solubility of 7.56 mg/mL at pH 7.4. Obtained IDR values of puerarin were in the range of 0.360-1.088 mg/min/cm(2), with maximum and minimum IDR value of pH 7.4 and pH 4.0, respectively. The Peff was 1.252 × 10(-5)cm/s determined by SPIP and the Pblood was 0.068×10(-5)cm/s by IPVS in jejunum at puerarin 80 μg/mL. The metabolism rate of puerarin determined by the intestinal S9 fraction indicated that the gut wall metabolism of puerarin is one cause of poor absorption. According to the proposed classification of drugs and the results obtained from equilibrium solubility, IDR, Peff and Pblood, it is concluded that puerarin could be categorized IV drug of the BCS based on its low solubility and low intestinal permeability values. Copyright © 2014 Elsevier B.V. All rights reserved.

Molecular mechanisms of the naringin low uptake by intestinal Caco-2 cells.

PubMed

Tourniaire, Franck; Hassan, Meryl; André, Marc; Ghiringhelli, Odette; Alquier, Christian; Amiot, Marie-Josèphe

2005-10-01

Naringin, the main flavanone of grapefruit, was reported to display numerous biological effects: antioxidant, hypocholesteremic, anti-atherogenic and favoring drug absorption. Naringin absorption mechanisms were studied in Caco-2 cells (TC7 clone). We investigated the possible involvement of several membrane transporters implicated in polyphenolic compounds intestinal transport (sodium-dependent glucose transporter 1, monocarboxylate transporter, multidrug-associated resistance proteins 1 and 2, and P-glycoprotein). Naringin was poorly absorbed by Caco-2 cells, according to its low value of apparent permeability coefficient (P(app) = 8.1 +/- 0.9 x 10(-8) cm/s). In the presence of verapamil, a specific inhibitor of P-glycoprotein, cellular uptake was increased by almost threefold after 5 min, and P(app) was doubled after 30 min. Our results indicated the involvement of P-glycoprotein, an ATP-driven efflux pump, capable of transporting naringin from the Caco-2 cell to the apical side. This phenomenon could explain, at least in part, the low absorption of this flavanone at the upper intestinal level.

Poor permeability and absorption affect the activity of four alkaloids from Coptis.

PubMed

Cui, Han-Ming; Zhang, Qiu-Yan; Wang, Jia-Long; Chen, Jian-Long; Zhang, Yu-Ling; Tong, Xiao-Lin

2015-11-01

Coptidis rhizoma (Coptis) and its alkaloids exert various pharmacological functions in cells and tissues; however, the oral absorption of these alkaloids requires further elucidation. The present study aimed to examine the mechanism underlying the poor absorption of alkaloids, including berberine (BER), coptisine (COP), palmatine (PAL) and jatrorrhizine (JAT). An ultra‑performance liquid chromatography (UPLC) method was validated for the determination of BER, COP, PAL and JAT in the above experimental medium. In addition, the apparent oil‑water partition coefficient (Po/w); apparent permeability coefficient (Papp), determined using a parallel artificial membrane permeability assay (PAMPA) plate; membrane retention coefficient (R %); and effect of P‑glycoprotein (P‑gp) inhibitor on the Papp of the four alkaloids were investigated. The intestinal absorption rate constant (Ka) and absorption percentage (A %) of the four alkaloids were also determined. The results of the present study demonstrated that the Po/w of the four alkaloids in 0.1 mol·l‑1 HCl medium was significantly higher (P<0.01), compared with those of the alkaloids in phosphate buffer (pH 7.4). The Papp of BER was 1.0‑1.2x10‑6 cm·s‑1, determined using a PAMPA plate, and the Papp of BER, COP, PAL and JAT decreased sequentially. The concentrations of the four alkaloids on the apical‑to‑basolateral (AP‑BL) surface and the basolateral‑to‑apical (BL‑AP) surface increased in a linear manner, with increasing concentrations between 10 and 100 µmol. In addition, the transportation of BER on the BL‑AP surface was significantly faster (P<0.01), compared with that on the AP‑BL surface and, following the addition of verpamil (a P‑gp inhibitor), the Papp (AP‑BL) of the four alkaloids increased, whereas the Papp (BL‑AP) was significantly decreased (P<0.01). The rat intestinal perfusion experiment demonstrated that the four alkaloids were poorly absorbed; however, the Ka of BER was significantly higher, compared with the three other alkaloids. Furthermore, the A % and Ka provided evidence that the absorption of BER was increased in the jejunum, compared with in the ileum. In conclusion, the four alkaloids from Coptis appeared to be poorly absorbed, determined using a shake flask, pre‑coated PAMPA plates, a Caco‑2 cell monolayer model and intestinal perfusion; however, absorption was higher in the jejunum than in the ileum. Among the four alkaloids, the permeability of BER was markedly higher than the others, and P‑gp efflux had a significant effect on the absorption of those alkaloids.

Unique insights into the intestinal absorption, transit, and subsequent biodistribution of polymer-derived microspheres

PubMed Central

Reineke, Joshua J.; Cho, Daniel Y.; Dingle, Yu-Ting; Morello, A. Peter; Jacob, Jules; Thanos, Christopher G.; Mathiowitz, Edith

2013-01-01

Polymeric microspheres (MSs) have received attention for their potential to improve the delivery of drugs with poor oral bioavailability. Although MSs can be absorbed into the absorptive epithelium of the small intestine, little is known about the physiologic mechanisms that are responsible for their cellular trafficking. In these experiments, nonbiodegradable polystyrene MSs (diameter range: 500 nm to 5 µm) were delivered locally to the jejunum or ileum or by oral administration to young male rats. Following administration, MSs were taken up rapidly (≤5 min) by the small intestine and were detected by transmission electron microscopy and confocal laser scanning microscopy. Gel permeation chromatography confirmed that polymer was present in all tissue samples, including the brain. These results confirm that MSs (diameter range: 500 nm to 5 µm) were absorbed by the small intestine and distributed throughout the rat. After delivering MSs to the jejunum or ileum, high concentrations of polystyrene were detected in the liver, kidneys, and lungs. The pharmacologic inhibitors chlorpromazine, phorbol 12-myristate 13-acetate, and cytochalasin D caused a reduction in the total number of MSs absorbed in the jejunum and ileum, demonstrating that nonphagocytic processes (including endocytosis) direct the uptake of MSs in the small intestine. These results challenge the convention that phagocytic cells such as the microfold cells solely facilitate MS absorption in the small intestine. PMID:23922388

Delphinidin Reduces Glucose Uptake in Mice Jejunal Tissue and Human Intestinal Cells Lines through FFA1/GPR40.

PubMed

Hidalgo, Jorge; Teuber, Stefanie; Morera, Francisco J; Ojeda, Camila; Flores, Carlos A; Hidalgo, María A; Núñez, Lucía; Villalobos, Carlos; Burgos, Rafael A

2017-04-05

Anthocyanins are pigments with antihyperglycemic properties, and they are potential candidates for developing functional foods for the therapy or prevention of Diabetes mellitus type 2 (DM2). The mechanism of these beneficial effects of anthocyanins are, however, hard to explain, given their very low bioavailability due to poor intestinal absorption. We propose that free fatty acid receptor 1 (FFA1, also named GPR40), is involved in an inhibitory effect of the anthocyanidin delphinidin over intestinal glucose absorption. We show the direct effects of delphinidin on the intestine using jejunum samples from RF/J mice, and the human intestinal cell lines HT-29, Caco-2, and NCM460. By the use of specific pharmacological antagonists, we determined that delphinidin inhibits glucose absorption in both mouse jejunum and a human enterocytic cell line in a FFA1-dependent manner. Delphinidin also affects the function of sodium-glucose cotransporter 1 (SGLT1). Intracellular signaling after FFA1 activation involved cAMP increase and cytosolic Ca 2+ oscillations originated from intracellular Ca 2+ stores and were followed by store-operated Ca 2+ entry. Taken together, our results suggest a new GPR-40 mediated local mechanism of action for delphinidin over intestinal cells that may in part explain its antidiabetic effect. These findings are promising for the search for new prevention and pharmacological treatment strategies for DM2 management.

The effect of P-glycoprotein on methadone hydrochloride flux in equine intestinal mucosa.

PubMed

Linardi, R L; Stokes, A M; Andrews, F M

2013-02-01

Methadone is an effective analgesic opioid that may have a place for the treatment of pain in horses. However, its absorption seems to be impaired by the presence of a transmembrane protein, P-glycoprotein, present in different tissues including the small intestine in other species. This study aims to determine the effect of the P-glycoprotein on methadone flux in the equine intestinal mucosa, as an indicator of in vivo drug absorption. Jejunum tissues from five horses were placed into the Ussing chambers and exposed to methadone solution in the presence or absence of Rhodamine 123 or verapamil. Electrical measurements demonstrated tissue viability for 120 min, and the flux of methadone across the jejunal membrane (mucosal to submucosal direction) was calculated based on the relative drug concentration measured by ELISA. The flux of methadone was significantly higher only in the presence of verapamil. P-glycoprotein was immunolocalized in the apical membrane of the jejunal epithelial cells (enterocytes), mainly located in the tip of the villi compared to cells of the crypts. P-glycoprotein is present in the equine jejunum and may possibly mediate the intestinal transport of methadone. This study suggests that P-glycoprotein may play a role in the poor intestinal absorption of methadone in vivo. © 2012 Blackwell Publishing Ltd.

Nonlinear intestinal absorption kinetics of cefuroxime axetil in rats.

PubMed Central

Ruiz-Balaguer, N; Nacher, A; Casabo, V G; Merino, M

1997-01-01

Cefuroxime is commercially available for parenteral administration as a sodium salt and for oral administration as cefuroxime axetil, the 1-(acetoxy)ethyl ester of the drug. Cefuroxime axetil is a prodrug of cefuroxime and has little, if any, antibacterial activity until hydrolyzed in vivo to cefuroxime. In this study, the absorption of cefuroxime axetil in the small intestines of anesthetized rats was investigated in situ, by perfusion at four concentrations (11.8, 5, 118 and 200 microM). Oral absorption of cefuroxime axetil can apparently be described as a specialized transport mechanism which obeys Michaelis-Menten kinetics. Parameters characterizing absorption of prodrug in free solution were obtained: maximum rate of absorption (Vmax) = 289.08 +/- 46.26 microM h-1, and Km = 162.77 +/- 31.17 microM. Cefuroxime axetil transport was significantly reduced in the presence of the enzymatic inhibitor sodium azide. On the other hand, the prodrug was metabolized in the gut wall through contact with membrane-bound enzymes in the brush border membrane before absorption occurred. This process reduces the prodrug fraction directly available for absorption. From a bioavailability point of view, therefore, the effects mentioned above can explain the variable and poor bioavailability following oral administration of cefuroxime axetil. Thus, future strategies in oral cefuroxime axetil absorption should focus on increasing the stability of the prodrug in the intestine by modifying the prodrug structure and/or targeting the compound to the absorption site. PMID:9021205

[Causes of iron deficiency in children].

PubMed

Olives, J-P

2017-05-01

Iron deficiency and iron deficiency anemia are common conditions worldwide affecting especially children. In developing countries, iron deficiency is caused by poor iron intake and parasitic infection. Poor iron intake linked to inadequate diets, low iron intestinal absorption, chronic blood losses and increased requirements are common causes in high-income countries. © 2017 Elsevier Masson SAS. Tous droits réservés.

Effect of composition of simulated intestinal media on the solubility of poorly soluble compounds investigated by design of experiments.

PubMed

Madsen, Cecilie Maria; Feng, Kung-I; Leithead, Andrew; Canfield, Nicole; Jørgensen, Søren Astrup; Müllertz, Anette; Rades, Thomas

2018-01-01

The composition of the human intestinal fluids varies both intra- and inter-individually. This will influence the solubility of orally administered drug compounds, and hence, the absorption and efficacy of compounds displaying solubility limited absorption. The purpose of this study was to assess the influence of simulated intestinal fluid (SIF) composition on the solubility of poorly soluble compounds. Using a Design of Experiments (DoE) approach, a set of 24 SIF was defined within the known compositions of human fasted state intestinal fluid. The SIF were composed of phospholipid, bile salt, and different pH, buffer capacities and osmolarities. On a small scale semi-robotic system, the solubility of 6 compounds (aprepitant, carvedilol, felodipine, fenofibrate, probucol, and zafirlukast) was determined in the 24 SIF. Compound specific models, describing key factors influencing the solubility of each compound, were identified. Although all models were different, the level of phospholipid and bile salt, the pH, and the interactions between these, had the biggest influences on solubility overall. Thus, a reduction of the DoE from five to three factors was possible (11-13 media), making DoE solubility studies feasible compared to single SIF solubility studies. Applying this DoE approach will lead to a better understanding of the impact of intestinal fluid composition on the solubility of a given drug compound. Copyright © 2017 Elsevier B.V. All rights reserved.

A novel core-shell lipid nanoparticle for improving oral administration of water soluble chemotherapeutic agents: inhibited intestinal hydrolysis and enhanced lymphatic absorption.

PubMed

Wang, Tao; Shen, Liao; Zhang, Zhen; Li, Haiyan; Huang, Ri; Zhang, Yadan; Quan, Dongqin

2017-11-01

The oral administration of water-soluble chemotherapeutical agents is limited by their serious gastrointestinal side effects, instability at intestinal pH, and poor absorption. Aiming to solve these problems, we chose topotecan (TPT) as a model drug and developed a novel lipid formulation containing core-shell lipid nanoparticle (CLN) that makes the water-soluble drug to 'dissolve' in oil. TPT molecules can be encapsulated into nanoparticles surrounded by oil barrier while avoiding the direct contact with intestinal environment, thus easing the intestinal hydrolytic degradation and gastrointestinal (GI) irritation. Microstructure and mean particle size of TPT-CLN were characterized by Transmission Electron Microscope (TEM) and Dynamic Light Scattering (DLS), respectively. The average size of nanoparticles was approximately 60 nm with a homogeneous distribution in shapes of spheres or ellipsoid. According to in vitro stability studies, more initial form of TPT was observed in presence of lipid nanoparticle compared with free topotecan solution in artificial intestinal juice (pH 6.5). After oral administration of TPT-CLN in rats, AUC and C max of TPT were all increased compared with free TPT, indicating significant enhancement of oral absorption. Intestinal lymphatic transport was confirmed as the major way for CLN to enhance oral absorption of TPT by the treatment of blocking chylomicron flow. Lower GI irritation of TPT-CLN was observed in the gastrointestinal damage studies. The in vivo antitumor activity of TPT-CLN showed an improved antitumor efficacy by oral treatment of TPT-CLN compared to free TPT. From the obtained data, the systems appear an attractive progress in oral administration of topotecan.

Intestinal transport of HDND-7, a novel hesperetin derivative, in in vitro MDCK cell and in situ single-pass intestinal perfusion models.

PubMed

Chen, Ruonan; Li, Lan; Shen, Chenlin; Huang, Cheng; Ma, Taotao; Meng, Xiaoming; Qian, Zhengyue; Li, Yangyang; Li, Jun

2017-08-01

1. Hesperetin (HDND) possesses extensive bioactivities, however, its poor solubility and low bioavailability limit its application. HDND-7, a derivative of HDND, has better solubility and high bioavailability. In this study, we investigated the intestinal absorption mechanisms of HDND-7. 2. MDCK cells were used to examine the transport mechanisms of HDND-7 in vitro, and a rat in situ intestinal perfusion model was used to characterize the absorption of HDND-7. The concentration of HDND-7 was determined by HPLC. 3. In MDCK cells, HDND-7 was effectively absorbed in a concentration-dependent manner in both directions. Moreover, HDND-7 showed pH-dependent and TEER-independent transport in both directions. The transport of HDND-7 was significantly reduced at 4 °C or in the presence of NaN3. Furthermore, the efflux of HDND-7 was apparently reduced in the presence of MRP2 inhibitors MK-571 or probenecid. However, P-gp inhibitor verapamil had no effect on the transport of HDND-7. The in situ intestinal perfusion study indicated HDND-7 was well-absorbed in four intestinal segments. Furthermore, MRP2 inhibitors may slightly increase the absorption of HDND-7 in jejunum. 4. In summary, all results indicated that HDND-7 might be absorbed mainly by passive diffusion via transcellular pathway, MRP2 but P-gp may participate in the efflux of HDND-7.

In Silico Prediction for Intestinal Absorption and Brain Penetration of Chemical Pesticides in Humans.

PubMed

Chedik, Lisa; Mias-Lucquin, Dominique; Bruyere, Arnaud; Fardel, Olivier

2017-06-30

Intestinal absorption and brain permeation constitute key parameters of toxicokinetics for pesticides, conditioning their toxicity, including neurotoxicity. However, they remain poorly characterized in humans. The present study was therefore designed to evaluate human intestine and brain permeation for a large set of pesticides ( n = 338) belonging to various chemical classes, using an in silico graphical BOILED-Egg/SwissADME online method based on lipophilicity and polarity that was initially developed for drugs. A high percentage of the pesticides (81.4%) was predicted to exhibit high intestinal absorption, with a high accuracy (96%), whereas a lower, but substantial, percentage (38.5%) displayed brain permeation. Among the pesticide classes, organochlorines ( n = 30) constitute the class with the lowest percentage of intestine-permeant members (40%), whereas that of the organophosphorus compounds ( n = 99) has the lowest percentage of brain-permeant chemicals (9%). The predictions of the permeations for the pesticides were additionally shown to be significantly associated with various molecular descriptors well-known to discriminate between permeant and non-permeant drugs. Overall, our in silico data suggest that human exposure to pesticides through the oral way is likely to result in an intake of these dietary contaminants for most of them and brain permeation for some of them, thus supporting the idea that they have toxic effects on human health, including neurotoxic effects.

In Silico Prediction for Intestinal Absorption and Brain Penetration of Chemical Pesticides in Humans

PubMed Central

Chedik, Lisa; Mias-Lucquin, Dominique; Bruyere, Arnaud; Fardel, Olivier

2017-01-01

Intestinal absorption and brain permeation constitute key parameters of toxicokinetics for pesticides, conditioning their toxicity, including neurotoxicity. However, they remain poorly characterized in humans. The present study was therefore designed to evaluate human intestine and brain permeation for a large set of pesticides (n = 338) belonging to various chemical classes, using an in silico graphical BOILED-Egg/SwissADME online method based on lipophilicity and polarity that was initially developed for drugs. A high percentage of the pesticides (81.4%) was predicted to exhibit high intestinal absorption, with a high accuracy (96%), whereas a lower, but substantial, percentage (38.5%) displayed brain permeation. Among the pesticide classes, organochlorines (n = 30) constitute the class with the lowest percentage of intestine-permeant members (40%), whereas that of the organophosphorus compounds (n = 99) has the lowest percentage of brain-permeant chemicals (9%). The predictions of the permeations for the pesticides were additionally shown to be significantly associated with various molecular descriptors well-known to discriminate between permeant and non-permeant drugs. Overall, our in silico data suggest that human exposure to pesticides through the oral way is likely to result in an intake of these dietary contaminants for most of them and brain permeation for some of them, thus supporting the idea that they have toxic effects on human health, including neurotoxic effects. PMID:28665355

Lipids in the Stomach - Implications for the Evaluation of Food Effects on Oral Drug Absorption.

PubMed

Koziolek, Mirko; Carrière, Frédéric; Porter, Christopher J H

2018-02-08

Food effects on oral drug bioavailability can have significant impact on the provision of safe and reliable oral pharmacotherapy. A mechanistic understanding of the events that contribute to the occurrence of food effects is therefore critical. An increased oral bioavailability is often seen for poorly water-soluble drugs after co-administration with lipids, including lipids in food, and is commonly explained by the ability of lipids to enhance drug solubility in intestinal luminal fluids. In contrast, the impact of lipids on drug solubilisation in the stomach has received less attention. This is in spite of the fact that lipid digestion is initiated in the stomach by human gastric lipase and that gastric events also initiate emulsification of lipids in the gastrointestinal tract. The stomach therefore acts to 'pre-process' lipids for subsequent events in the intestine and may significantly affect downstream events at intestinal drug absorption sites. In this article, the mechanisms by which lipids are processed in the stomach are reviewed and the potential impact of these processes on drug absorption discussed. Attention is also focused on in vitro methods that are used to assess gastric processing of lipids and their application to better understand food effects on drug release and absorption.

[Study on intestinal absorption features of oligosaccharides in Morinda officinalis How. with sigle-pass perfusion].

PubMed

Deng, Shao-Dong; Zhang, Peng; Lin, Li; Xiao, Feng-Xia; Lin, Jing-Ran

2015-01-01

To study the in situ intestinal absorption of five oligosaccharides contained in Morinda officinalis How. (sucrose, kestose, nystose, 1F-Fructofuranosyinystose and Bajijiasu). The absorption of the five oligosaccharides in small intestine (duodenum, jejunum and ileum) and colon of rats and their contents were investigated by using in situ single-pass perfusion model and HPLC-ELSD. The effects of drug concentration, pH in perfusate and P-glycoprotein inhibitor on the intestinal absorption were investigated to define the intestinal absorption mechanism of the five oligosaccharides in rats. According to the results, all of the five oligosaccharides were absorbed in the whole intestine, and their absorption rates were affected by the pH of the perfusion solution, drug concentration and intestinal segments. Verapamil Hydrochloride could significantly increase the absorptive amount of sucrose and Bajijiasu, suggesting sucrose and Bajijiasu are P-gp's substrate. The five oligosaccharides are absorbed mainly through passive diffusion in the intestinal segments, without saturated absorption. They are absorbed well in all intestines and mainly in duodenum and jejunum.

Ex-vivo absorption study of lysine R-lipoate salt, a new pharmaceutical form of R-ALA.

PubMed

Amenta, Francesco; Buccioni, Michela; Ben, Diego Dal; Lambertucci, Catia; Navia, Aleix Martí; Ngouadjeu Ngnintedem, Michael A; Ricciutelli, Massimo; Spinaci, Andrea; Volpini, Rosaria; Marucci, Gabriella

2018-06-15

Alpha-lipoic acid (ALA) oral supplements were used in many pathologies associated with increased oxidative stress. Although only R-ALA is considered the biologically active form, R,S-ALA is used in therapeutic applications even showing poor water solubility. The aim of this work was to study the absorption and transport mechanism across the intestinal barrier of new R-ALA stable and water soluble form, consisting in the lysine R-ALA salt, in presence and absence of specific inhibitors of Na + /multivitamin (SMVT) and monocarboxylic acids (MCT). The absorption of a new ALA form was investigated at rat everted sacs in comparison with R-ALA, S-ALA, and R,S-ALA. Results showed that duodenum is the best portion of intestine for ALA forms absorption. The absorption percentage of R-ALA, S-ALA, R,S-ALA, and lysine R-ALA salt was 66%, 43%, 55%, and 70%, respectively. The modest effect of the SMVT inhibitor biotin demonstrated that this transporter system is not principally involved in the absorption of lysine R-lipoate salt across the rat intestinal barrier. On the contrary, the MCT inhibitor octanoic acid significantly reduced the transport of this salt, whit an absorption decrease of R-ALA and lysine R-lipoate salt of 28% and 24%, respectively. Since the highest concentration of these inhibitors did not completely inhibit the absorption of lysine R-lipoate salt, other transport mechanisms probably operate for its intracellular delivery. The new form of ALA, lysine R-lipoate salt, was the most absorbed respect to the other ALA forms demonstrating that this compound is more suitable for oral administration. This new salt could represent a promising candidate for ALA oral supplementation. Copyright © 2018 Elsevier B.V. All rights reserved.

[Trans-intestinal cholesterol excretion (TICE): a new route for cholesterol excretion].

PubMed

Blanchard, Claire; Moreau, François; Cariou, Bertrand; Le May, Cédric

2014-10-01

The small intestine plays a crucial role in dietary and biliary cholesterol absorption, as well as its lymphatic secretion as chylomicrons (lipoprotein exogenous way). Recently, a new metabolic pathway called TICE (trans-intestinal excretion of cholesterol) that plays a central role in cholesterol metabolism has emerged. TICE is an inducible way, complementary to the hepatobiliary pathway, allowing the elimination of the plasma cholesterol directly into the intestine lumen through the enterocytes. This pathway is poorly characterized but several molecular actors of TICE have been recently identified. Although it is a matter of debate, two independent studies suggest that TICE is involved in the anti-atherogenic reverse cholesterol transport pathway. Thus, TICE is an innovative drug target to reduce -cardiovascular diseases. © 2014 médecine/sciences – Inserm.

Improved intestinal absorption of a poorly water-soluble oral drug using mannitol microparticles containing a nanosolid drug dispersion.

PubMed

Nishino, Yukiko; Kubota, Aya; Kanazawa, Takanori; Takashima, Yuuki; Ozeki, Tetsuya; Okada, Hiroaki

2012-11-01

A nozzle for a spray dryer that can prepare microparticles of water-soluble carriers containing various nanoparticles in a single step was previously developed in our laboratory. To enhance the solubility and intestinal absorption of poorly water-soluble drugs, we used probucol (PBL) as a poorly water-soluble drug, mannitol (MAN) as a water-soluble carrier for the microparticles, and EUDRAGIT (EUD) as a polymer vehicle for the solid dispersion. PBL-EUD-acetone-methanol and aqueous MAN solutions were simultaneously supplied through different liquid passages of the spray nozzle and dried together. PBL-EUD solid dispersion was nanoprecipitated in the MAN solution using an antisolvent mechanism and rapidly dried by surrounding it with MAN. PBL in the dispersion vehicle was amorphous and had higher physical stability according to powder X-ray diffraction and differential scanning calorimetry analysis. The bioavailability of PBL in PBL-EUD S-100-MAN microparticles after oral administration in rats was markedly higher (14- and 6.2-fold, respectively) than that of the original PBL powder and PBL-MAN microparticles. These results demonstrate that the composite microparticles containing a nanosized solid dispersion of a poorly water-soluble drug prepared using the spray nozzle developed by us should be useful to increase the solubility and bioavailability of drugs after oral administration. Copyright © 2012 Wiley Periodicals, Inc.

[Study on intestinal absorption of formononetin in Millettia nitita var. hirsutissima in rats].

PubMed

Liu, Ya-Li; Xiong, Xian-Bing; Su, Dan; Song, Yong-Gui; Zhang, Ling; Yang, Shi-Lin

2013-10-01

To use the single-pass intestine perfusion (SPIP) model and HPLC to determine the concentration of formononetin, the effect of quality concentrations of formononetin, different intestinal segments and P-glycoprotein inhibitor on intestinal absorption of formononetin, in order to observe the intestinal absorption mechanism of formononetin from Millettia nitita var. hirsutissima in rats. The experimental results showed that the qulaity concentration of formononetin in the perfusate had no significant effect on the absorption rate constant (K(a)) and the apparent absorption coefficient (P(app)); K(a) and P(app) of formononetin in duodenum, jejunum and ileum showed no significant difference. However, K(a) was significantly higher than that in colon (P < 0.05), with significant difference between that in intestinum tenue and colon. P-glycoprotein inhibitor verapamil showed significant difference in K(a) and P(app) in intestinal segments (P < 0.05). This indicated that the absorption mechanism of formononein in rat intestinal tracts passive diffusion, without any saturated absorption. Formononein is absorbed well in all intestines. Their absorption windows were mainly concentrated in the intestinum tenue, without specific absorption sites. Formononein may be the substrate of P-glycoprotein.

Evaluation of intestinal metabolism and absorption using the Ussing chamber system equipped with intestinal tissue from rats and dogs.

PubMed

Miyake, Masateru; Kondo, Satoshi; Koga, Toshihisa; Yoda, Noriaki; Nakazato, Satoru; Emoto, Chie; Mukai, Tadashi; Toguchi, Hajime

2018-01-01

The purpose of this study was to evaluate the intestinal metabolism and absorption in a mini-Ussing chamber equipped with animal intestinal tissues, based on the transport index (TI). TI value was defined as the sum of drug amounts transported to the basal-side component (X corr ) and drug amounts accumulated in the tissue (T corr ), which are normalized by AUC of a drug in the apical compartment, as an index for drug absorption. Midazolam was used as a test compound for the evaluation of intestinal metabolism and absorption. The metabolite formulation of midazolam was observed in both rats and dogs. Ketoconazole inhibited the intestinal metabolism of midazolam in rats and improved its intestinal absorption to a statistically significant extent. Therefore, the mini-Ussing chamber, equipped with animal intestinal tissues, showed potential to use the evaluation of the intestinal metabolism and absorption, including the assessment of species differences. Copyright © 2017. Published by Elsevier B.V.

Intestinal and Hepatic Expression of Cytochrome P450s and mdr1a in Rats with Indomethacin-Induced Small Intestinal Ulcers

PubMed Central

Kawauchi, Shoji; Nakamura, Tsutomu; Yasui, Hiroyuki; Nishikawa, Chikako; Miki, Ikuya; Inoue, Jun; Horibe, Sayo; Hamaguchi, Tsuneo; Tanahashi, Toshihito; Mizuno, Shigeto

2014-01-01

Background: Non-steroidal anti-inflammatory drugs induce the serious side effect of small intestinal ulcerations (SIUs), but little information is available regarding the consequences to drug metabolism and absorption. Aim: We examined the existence of secondary hepatic inflammation in rats with indomethacin (INM)-induced SIUs and assessed its relationship to the cytochrome P450 (CYP) and P-glycoprotein (mdr1a), the major drug-metabolizing factors in the small intestine and the liver. Methods: Gene expression of the CYP family of enzymes and mdr1a was measured with quantitative real-time polymerase chain reaction (qPCR). Vancomycin (VCM), a poorly absorbed drug, was administered intraduodenally to rats with SIUs. Results: INM induced SIUs predominantly in the lower region of the small intestine with high expression of inflammatory markers. Liver dysfunction was also observed, which suggested a secondary inflammatory response in rats with SIUs. In the liver of rats with SIUs, the expression of CYP2C11, CYP2E1, and CYP3A1 was significantly decreased, and loss of CYP3A protein was observed. Although previous studies have shown a direct effect of INM on CYP3A activity, we could not confirm any change in hepatic CY3A4 expression (major isoform of human CYP3A) in vitro. The plasma VCM concentration was increased in rats with SIUs due to partial absorption from the mucosal injury, but not in normal mucosa. Conclusions: INM-induced SIUs had a subtle effect on intestinal CYP expression, but had an apparent action on hepatic CYP, which was influenced, at least in part, by the secondary inflammation. Furthermore, drug absorption was increased in rats with SIUs. PMID:25317066

The effect of gastric inhibitory polypeptide on intestinal glucose absorption and intestinal motility in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ogawa, Eiichi; Hosokawa, Masaya; Faculty of Human Sciences, Tezukayama Gakuin University, Osaka

2011-01-07

Research highlights: {yields} Exogenous GIP inhibits intestinal motility through a somatostatin-mediated pathway. {yields} Exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility. {yields} The GIP-receptor-mediated action in intestine does not involve in GLP-1-mediated pathway. -- Abstract: Gastric inhibitory polypeptide (GIP) is released from the small intestine upon meal ingestion and increases insulin secretion from pancreatic {beta} cells. Although the GIP receptor is known to be expressed in small intestine, the effects of GIP in small intestine are not fully understood. This study was designed to clarify the effect of GIP on intestinal glucose absorption and intestinal motility. Intestinal glucosemore » absorption in vivo was measured by single-pass perfusion method. Incorporation of [{sup 14}C]-glucose into everted jejunal rings in vitro was used to evaluate the effect of GIP on sodium-glucose co-transporter (SGLT). Motility of small intestine was measured by intestinal transit after oral administration of a non-absorbed marker. Intraperitoneal administration of GIP inhibited glucose absorption in wild-type mice in a concentration-dependent manner, showing maximum decrease at the dosage of 50 nmol/kg body weight. In glucagon-like-peptide-1 (GLP-1) receptor-deficient mice, GIP inhibited glucose absorption as in wild-type mice. In vitro examination of [{sup 14}C]-glucose uptake revealed that 100 nM GIP did not change SGLT-dependent glucose uptake in wild-type mice. After intraperitoneal administration of GIP (50 nmol/kg body weight), small intestinal transit was inhibited to 40% in both wild-type and GLP-1 receptor-deficient mice. Furthermore, a somatostatin receptor antagonist, cyclosomatostatin, reduced the inhibitory effect of GIP on both intestinal transit and glucose absorption in wild-type mice. These results demonstrate that exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility through a somatostatin-mediated pathway rather than through a GLP-1-mediated pathway.« less

Segmental transport of Ca²⁺ and Mg²⁺ along the gastrointestinal tract.

PubMed

Lameris, Anke L; Nevalainen, Pasi I; Reijnen, Daphne; Simons, Ellen; Eygensteyn, Jelle; Monnens, Leo; Bindels, René J M; Hoenderop, Joost G J

2015-02-01

Calcium (Ca(2+)) and magnesium (Mg(2+)) ions are involved in many vital physiological functions. Since dietary intake is the only source of minerals for the body, intestinal absorption is essential for normal homeostatic levels. The aim of this study was to characterize the absorption of Ca(2+) as well as Mg(2+) along the gastrointestinal tract at a molecular and functional level. In both humans and mice the Ca(2+) channel transient receptor potential vanilloid subtype 6 (TRPV6) is expressed in the proximal intestinal segments, whereas Mg(2+) channel transient receptor potential melastatin subtype 6 (TRPM6) is expressed in the distal parts of the intestine. A method was established to measure the rate of Mg(2+) absorption from the intestine in a time-dependent manner by use of (25)Mg(2+). In addition, local absorption of Ca(2+) and Mg(2+) in different segments of the intestine of mice was determined by using surgically implanted intestinal cannulas. By these methods, it was demonstrated that intestinal absorption of Mg(2+) is regulated by dietary needs in a vitamin D-independent manner. Also, it was shown that at low luminal concentrations, favoring transcellular absorption, Ca(2+) transport mainly takes place in the proximal segments of the intestine, whereas Mg(2+) absorption predominantly occurs in the distal part of the gastrointestinal tract. Vitamin D treatment of mice increased serum Mg(2+) levels and 24-h urinary Mg(2+) excretion, but not intestinal absorption of (25)Mg(2+). Segmental cannulation of the intestine and time-dependent absorption studies using (25)Mg(2+) provide new ways to study intestinal Mg(2+) absorption. Copyright © 2015 the American Physiological Society.

Ex Vivo and In Situ Evaluation of 'Dispelling-Wind' Chinese Medicine Herb-Drugs on Intestinal Absorption of Chlorogenic Acid.

PubMed

Zhai, Lixiang; Shi, Jun; Xu, Weitong; Heinrich, Michael; Wang, Jianying; Deng, Wenji

2015-12-01

This study aims to investigate the additive or synergistic effects and mechanism of intestinal absorption of extracts from two commonly used 'dispelling-wind' TCM botanical drugs [roots of Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav. (RAD) and Saposhnikovia divaricata (Turcz.) Schischk. (RSD)] using chlorogenic acid as a marker substance. Ex vivo everted intestinal sac and in situ single pass perfusion methods using rats were employed to investigate the effects of two TCM botanical drugs extracts on the intestinal absorption of chlorogenic acid. Both the extracts of RAD and RSD showed synergistic properties on the intestinal absorption of chlorogenic acid. The verapamil (a P-gp inhibitor) and intestinal dysbacteriosis model induced by norfloxacin increased the P(app) and K(a) of intestinal absorption of chlorogenic acid. These synergistic effects on intestinal absorption in a rat model can be correlated with the inhibition of P-gp and regulation of gut microbiota. This experimental approach has helped to better understand changes in the absorption of chlorogenic acid under different conditions. Copyright © 2015 John Wiley & Sons, Ltd.

Transmembrane transport of peptide type compounds: prospects for oral delivery

NASA Technical Reports Server (NTRS)

Lipka, E.; Crison, J.; Amidon, G. L.

1996-01-01

Synthesis and delivery of potential therapeutic peptides and peptidomimetic compounds has been the focus of intense research over the last 10 years. While it is widely recognized that numerous limitations apply to oral delivery of peptides, some of the limiting factors have been addressed and their mechanisms elucidated, which has lead to promising strategies. This article will briefly summarize the challenges, results and current approaches of oral peptide delivery and give some insight on future strategies. The barriers determining peptide bioavailability after oral administration are intestinal membrane permability, size limitations, intestinal and hepatic metabolism and in some cases solubility limitations. Poor membrane permeabilities of hydrophilic peptides might be overcome by structurally modifying the compounds, thus increasing their membrane partition characteristics and/or their affinity to carrier proteins. Another approach is the site-specific delivery of the peptide to the most permeable parts of the intestine. The current view on size limitation for oral drug delivery has neglected partition considerations. Recent studies suggest that compounds with a molecular weight up to 4000 might be significantly absorbed, assuming appropriate partition behavior and stability. Metabolism, probably the most significant factor in the absorption fate of peptides, might be controlled by coadministration of competitive enzyme inhibitors, structural modifications and administration of the compound as a well absorbed prodrug that is converted into the therapeutically active agent after its absorption. For some peptides poor solubility might present a limitation to oral absorption, an issue that has been addressed by mechanistically defining and therefore improving formulation parameters. Effective oral peptide delivery requires further development in understanding these complex mechanisms in order to maximize the therapeutic potential of this class of compounds.

Ursodeoxycholic and deoxycholic acids: A good and a bad bile acid for intestinal calcium absorption.

PubMed

Rodríguez, Valeria; Rivoira, María; Marchionatti, Ana; Pérez, Adriana; Tolosa de Talamoni, Nori

2013-12-01

The aim of this study was to investigate the effect of ursodeoxycholic acid (UDCA) on intestinal Ca(2+) absorption and to find out whether the inhibition of this process caused by NaDOC could be prevented by UDCA. Chicks were employed and divided into four groups: (a) controls, (b) treated with 10mM NaDOC, (c) treated with 60 μg UDCA/100g of b.w., and (d) treated with 10mM NaDOC and 60 μg UDCA/100g of b.w. UDCA enhanced intestinal Ca(2+) absorption, which was time and dose-dependent. UDCA avoided the inhibition of intestinal Ca(2+) absorption caused by NaDOC. Both bile acids altered protein and gene expression of molecules involved in the transcellular pathway of intestinal Ca(2+) absorption, but in the opposite way. UDCA aborted the oxidative stress produced by NaDOC in the intestine. UDCA and UDCA plus NaDOC increased vitamin D receptor protein expression. In conclusion, UDCA is a beneficial bile acid for intestinal Ca(2+) absorption. Contrarily, NaDOC inhibits the intestinal cation absorption through triggering oxidative stress. The use of UDCA in patients with cholestasis would be benefited because of the protective effect on the intestinal Ca(2+) absorption, avoiding the inhibition caused by hydrophobic bile acids and neutralizing the oxidative stress. Copyright © 2013 Elsevier Inc. All rights reserved.

Improving intestinal absorption and oral bioavailability of curcumin via taurocholic acid-modified nanostructured lipid carriers.

PubMed

Tian, Cihui; Asghar, Sajid; Wu, Yifan; Chen, Zhipeng; Jin, Xin; Yin, Lining; Huang, Lin; Ping, Qineng; Xiao, Yanyu

2017-01-01

The expression of multiple receptors on intestinal epithelial cells enables an actively targeted carrier to significantly enhance the oral delivery of payloads. Conjugating the receptors' ligands on the surfaces of a particulate-delivery system allows site-specific targeting. Here, we used taurocholic acid (TCA) as a ligand for uptake of nanostructured lipid carriers (NLCs) mediated by a bile-acid transporter to improve oral bioavailability of curcumin (Cur). First, synthesis of TCA-polyethylene glycol 100-monostearate (S100-TCA) was carried out. Then, the physical and chemical properties of S100-TCA-modified Cur-loaded NLCs (Cur-TCA NLCs) with varying levels of S100-TCA modifications were investigated. Small particle size (<150 nm), high drug encapsulation (>90%), drug loading (about 3%), negative ζ-potential (-7 to -3 mV), and sustained release were obtained. In situ intestinal perfusion studies demonstrated improved absorption rate and permeability coefficient of Cur-TCA NLCs. Depending on the degree of modification, Cur-TCA NLCs displayed about a five- to 15-fold higher area under the curve in rats after oral administration than unmodified Cur NLCs, which established that the addition of S100-TCA to the NLCs boosted absorption of Cur. Further investigations of TCA NLCs might reveal a bright future for effective oral delivery of poorly bioavailable drugs.

Pharmacological evaluation of mangiferin herbosomes for antioxidant and hepatoprotection potential against ethanol induced hepatic damage.

PubMed

Jain, Pushpendra Kumar; Kharya, Murlidhar; Gajbhiye, Asmita

2013-11-01

Fatty liver is the first stage of alcoholic damage which is reversible with abstinence from alcohol. Mangiferin (MF) showed potent scavenging activity on diphenyl-1-picrylhydrazyl radicals which stimulate liver regeneration in various liver injuries. Although, MF shows hepatoprotection against various liver disorders but due to rapid clearance and limited solubility in lipoid environment, there is problem of its poor absorption from intestine hence poor bioavailability. Owing to which there is a need to develop MF herbosomes to resolve the problem of poor bioavailability to enhance the therapeutic potential. Successfully prepared MF herbosomes through complexation with phospholipids were characterized by physicochemical, chromatography, spectroscopy (differential scanning calorimetry (DSC), infrared (IR), and nuclear magnetic resonance (NMR)), ex vivo absorption using everted small intestine sac technique and in vivo studies using ethanol inducing hepatotoxicity in albino rats and comparing the results against plain MF. Ex vivo study showed significant increased absorption of MF from prepared MF herbosomes as compared to plain MF. The hepatoprotective potential of MF herbosomes evaluated by in vivo study revealed significantly decreased levels of serum glutamate oxaloacetate transminase (SGOT), serum glutamate pyruvate transminase (SGPT), total bilirubin, and alkaline phosphatase (ALP) in MF herbosomes as compared to plain MF. MF herbosomes also showed significantly decreased level of malonyl dehydrogenase along with increased levels of reduced glutathione, superoxide dismutase (SOD) and catalase as compared to plain MF which was also comparable to the standard drug, silymarin (SL). The above mentioned results showed that hepatoprotective and antioxidant potency of MF enhanced due to the preparation of its herbosomes.

Developments in Methods for Measuring the Intestinal Absorption of Nanoparticle-Bound Drugs

PubMed Central

Liu, Wei; Pan, Hao; Zhang, Caiyun; Zhao, Liling; Zhao, Ruixia; Zhu, Yongtao; Pan, Weisan

2016-01-01

With the rapid development of nanotechnology, novel drug delivery systems comprising orally administered nanoparticles (NPs) have been paid increasing attention in recent years. The bioavailability of orally administered drugs has significant influence on drug efficacy and therapeutic dosage, and it is therefore imperative that the intestinal absorption of oral NPs be investigated. This review examines the various literature on the oral absorption of polymeric NPs, and provides an overview of the intestinal absorption models that have been developed for the study of oral nanoparticles. Three major categories of models including a total of eight measurement methods are described in detail (in vitro: dialysis bag, rat gut sac, Ussing chamber, cell culture model; in situ: intestinal perfusion, intestinal loops, intestinal vascular cannulation; in vivo: the blood/urine drug concentration method), and the advantages and disadvantages of each method are contrasted and elucidated. In general, in vitro and in situ methods are relatively convenient but lack accuracy, while the in vivo method is troublesome but can provide a true reflection of drug absorption in vivo. This review summarizes the development of intestinal absorption experiments in recent years and provides a reference for the systematic study of the intestinal absorption of nanoparticle-bound drugs. PMID:27455239

Quantitative analysis of the effect of supersaturation on in vivo drug absorption.

PubMed

Takano, Ryusuke; Takata, Noriyuki; Saito, Ryoichi; Furumoto, Kentaro; Higo, Shoichi; Hayashi, Yoshiki; Machida, Minoru; Aso, Yoshinori; Yamashita, Shinji

2010-10-04

The purpose of this study is to clarify the effects of intestinal drug supersaturation on solubility-limited nonlinear absorption. Oral absorption of a novel farnesyltransferase inhibitor (FTI-2600) from its crystalline free base and its HCl salt was determined in dogs. To clarify the contribution of supersaturation on improving drug absorption, in vivo intraluminal concentration of FTI-2600 after oral administration was estimated from the pharmacokinetics data using a physiologically based model. Dissolution and precipitation characteristics of FTI-2600 in a biorelevant media were investigated in vitro using a miniscale dissolution test and powder X-ray diffraction analysis. In the in vitro study, the HCl salt immediately dissolved but precipitated rapidly. The metastable amorphous free base precipitant, which did not convert into the stable crystalline free base in the simulated intestinal fluids for several hours, generated a 5-fold increase in dissolved concentration compared to the equilibrium solubility of the crystalline free base. By computer simulation, the intraluminal drug concentration after administration of the free base was estimated to reach the saturated solubility, indicating solubility-limited absorption. On the other hand, administration of the HCl salt resulted in an increased intraluminal concentration and the plasma concentration was 400% greater than that after administration of the free base. This in vivo/in vitro correlation of the increased drug concentrations in the small intestine provide clear evidence that not only the increase in the dissolution rate, but also the supersaturation phenomenon, improved the solubility-limited absorption of FTI-2600. These results indicate that formulation technologies that can induce supersaturation may be of great assistance to the successful development of poorly water-soluble drugs.

Physicochemical characteristics and gastrointestinal absorption behaviors of S-propargyl-cysteine, a potential new drug candidate for cardiovascular protection and antitumor treatment.

PubMed

Ma, Guo; Zhang, Lin; Zhang, Peng; Bao, Xingfei; Zhou, Ning; Shi, Qingling; Zheng, Yuanting; Liu, Hongrui; Bu, Fengjiao; Zhang, Ying; Huang, Wenjie; Wang, Fen; Zhu, Yizhun; Cai, Weimin

2015-04-01

1. As a potential new drug candidate for cardiovascular protection and antitumor treatment, the physicochemical properties, gastrointestinal (GI) absorption behaviors and mechanisms of S-propargyl-cysteine (SPRC) were investigated in this study. 2. SPRC exhibited favorable solubility in aqueous media. The log P and log D values were low (≤1.93 ± 0.08). The pKa in the acidic and basic regions was 2.08 ± 0.02 and 8.72 ± 0.03, respectively. The isoelectric point was 5.40 ± 0.02. SPRC was stable in the rat GI fluids, and showed no obvious adsorption and metabolism in the rat GI tract. 3. SPRC displayed poor gastric absorption and favorable intestinal absorption in the rat in situ GI perfusion model. Absorption rate constants (ka), hourly absorption percentage (P) and apparent permeability coefficient (Papp) of SPRC in the small intestine were ≥0.77 ± 0.06 h(-1), 59.25 ± 4.02% and (7.99 ± 0.88) × 10(-5 )cm/s, respectively. Absorption of SPRC exhibited a certain dependence on physiological pH and absorption region. Absorption of SPRC was not inhibited by l-methionine and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid. 4. SPRC showed favorable oral absorption. It can be categorized as a BCS class I drug. The membrane pore transport appeared to be one of the predominant absorption modes for SPRC.

Intestinal Water Absorption Varies with Expected Dietary Water Load among Bats but Does Not Drive Paracellular Nutrient Absorption.

PubMed

Price, Edwin R; Brun, Antonio; Gontero-Fourcade, Manuel; Fernández-Marinone, Guido; Cruz-Neto, Ariovaldo P; Karasov, William H; Caviedes-Vidal, Enrique

2015-01-01

Rapid absorption and elimination of dietary water should be particularly important to flying species and were predicted to vary with the water content of the natural diet. Additionally, high water absorption capacity was predicted to be associated with high paracellular nutrient absorption due to solvent drag. We compared the water absorption rates of sanguivorous, nectarivorous, frugivorous, and insectivorous bats in intestinal luminal perfusions. High water absorption rates were associated with high expected dietary water load but were not highly correlated with previously measured rates of (paracellular) arabinose clearance. In conjunction with these tests, we measured water absorption and the paracellular absorption of nutrients in the intestine and stomach of vampire bats using luminal perfusions to test the hypothesis that the unique elongated vampire stomach is a critical site of water absorption. Vampire bats' gastric water absorption was high compared to mice but not compared to their intestines. We therefore conclude that (1) dietary water content has influenced the evolution of intestinal water absorption capacity in bats, (2) solvent drag is not the only driver of paracellular nutrient absorption, and (3) the vampire stomach is a capable but not critical location for water absorption.

The Use of Low Molecular Weight Protamine Chemical Chimera to Enhance Monomeric Insulin Intestinal Absorption

PubMed Central

He, Huining; Sheng, Jianyong; David, Allan E.; Kwon, Young Min; Zhang, Jian; Huang, Yongzhuo; Wang, Jianxin; Yang, Victor C.

2013-01-01

Although oral delivery of insulin offers a number of unmatched advantages, it nevertheless is beset by the poor permeability of insulin molecules through the epithelial cell membranes of the intestinal mucosal layer. We previously reported the development of low molecular weight protamine (LMWP) as a nontoxic yet potent cell penetrating peptide, of which via covalent linkage was capable of translocating protein cargos through the membranes of almost all cell types. It is therefore hypothesized that LMWP could be practically employed as a safe and effective tool to deliver insulin across the intestinal mucosal membrane, thereby augmenting its absorption through the GI tract. However, formulating 1:1 monomeric insulin/LMWP conjugate presents a tall order of challenge, as the acidic insulin and basic LMWP would automatically form tight aggregates through electrostatic interactions. In this paper, we developed an innovative conjugation strategy to solve this problem, by using succinimidyl-[(N-maleimidopropionamido)-polyethyleneglycol] ester (NHS-PEG-MAL) as an intermediate cross-linker during the coupling process. Both SDS-PAGE and MALDI-TOF mass spectroscopy confirmed the formation of a homogeneous, monomeric (1:1 ratio) insulin/LMWP conjugate without encountering the conventional problem of substrate aggregation. Cell culture studies demonstrated that transport of the Insulin-PEG-LMWP conjugate across the intestinal mucosal monolayer was augmented by almost five folds compared to native insulin. Furthermore, results from the in situ loop absorption tests in rats showed that systemic pharmacological bioavailability of insulin was significantly enhanced after its conjugation with LMWP. Overall, the presented chemical conjugation with LMWP could offer a reliable and safe means to improve the intestinal permeability of therapeutic peptides/proteins, shedding light of the possibility for their effective oral delivery. PMID:23863452

Absorption of thiamine and nicotinic acid in the rat intestine during fasting and immobilization stress

NASA Technical Reports Server (NTRS)

Kirilyuk, O. G.; Khmelevskiy, Y. V.

1980-01-01

By perfusion of isolated sections of intestine with a solution containing thiamine at a concentration of 3.1 micromole, it was established that thiamine absorption in animals fasted for 72 hours decreased by 28 percent, whereas absorption increased by 12 percent in rats after 24 hour immobilization. After immobilization, absorption of label in the intestinal mucosa increased. Na K ATPase activity in the intestinal mucosa decreased by 10 percent during fasting, and it increased with immobilization of the animals. Activity of Na K ATPase in the intestinal mucosa cells determined the absorption rate of thiamine and nicotinic acid at the level of vitamin transport through the plasma membranes of the enterocytes.

Intestinal absorption differences of major bioactive compounds of Gegenqinlian Decoction between normal and bacterial diarrheal mini-pigs in vitro and in situ.

PubMed

Ling, Xiao; Xiang, Yuqiang; Chen, Feilong; Tang, Qingfa; Zhang, Wei; Tan, Xiaomei

2018-04-15

Intestinal condition plays an important role in drug absorption and metabolism, thus the effects of varied gastrointestinal diseases such as infectious diarrhea on the intestinal function are crucial for drug absorption. However, due to the lack of suitable models, the differences of absorption and metabolism of drugs between the diarrheal and normal intestines are rarely reported. Thus, in this study, Escherichia coli diarrhea model was induced in mini-pigs and single-pass intestinal perfusion and intestinal mucosal enzyme metabolism experiments were conducted. A simple and rapid ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed to determine the concentrations of 9 major components in Gegen Qinlian decoction (GQD). Samples were pretreated by protein precipitation with methanol and naringin and prednisolone were used as internal standards. The validated method demonstrated adequate sensitivity, selectivity, and process efficiency for the bioanalysis of 9 compounds. Results of intestinal perfusion showed that puerarin, daidzein, daidzin and baicalin and berberine were absorbed faster in diarrheal jejunum than in normal intestines (p < 0.05). However, puerarin, daidzin and liquiritin were metabolized more slowly in diarrheal intestine after incubation compared with the normal group (p < 0.05). The concentrations of daidzein in both perfusion and metabolism and wogonin in metabolism were significantly increased (p < 0.05). In conclusion, absorption and metabolism of GQD were significantly different between the diarrheal and normal intestines, which suggest that bacterial diarrheal mini-pigs model can be used in the intestinal absorption study and is worthy to be applied in the other intestinal absorption study of anti- diarrheal drugs. Copyright © 2018 Elsevier B.V. All rights reserved.

Abnormal passive chloride absorption in cystic fibrosis jejunum functionally opposes the classic chloride secretory defect

PubMed Central

Russo, Michael A.; Högenauer, Christoph; Coates, Stephen W.; Santa Ana, Carol A.; Porter, Jack L.; Rosenblatt, Randall L.; Emmett, Michael; Fordtran, John S.

2003-01-01

Due to genetic defects in apical membrane chloride channels, the cystic fibrosis (CF) intestine does not secrete chloride normally. Depressed chloride secretion leaves CF intestinal absorptive processes unopposed, which results in net fluid hyperabsorption, dehydration of intestinal contents, and a propensity to inspissated intestinal obstruction. This theory is based primarily on in vitro studies of jejunal mucosa. To determine if CF patients actually hyperabsorb fluid in vivo, we measured electrolyte and water absorption during steady-state perfusion of the jejunum. As expected, chloride secretion was abnormally low in CF, but surprisingly, there was no net hyperabsorption of sodium or water during perfusion of a balanced electrolyte solution. This suggested that fluid absorption processes are reduced in CF jejunum, and further studies revealed that this was due to a marked depression of passive chloride absorption. Although Na+-glucose cotransport was normal in the CF jejunum, absence of passive chloride absorption completely blocked glucose-stimulated net sodium absorption and reduced glucose-stimulated water absorption 66%. This chloride absorptive abnormality acts in physiological opposition to the classic chloride secretory defect in the CF intestine. By increasing the fluidity of intraluminal contents, absence of passive chloride absorption may reduce the incidence and severity of intestinal disease in patients with CF. PMID:12840066

Iron Absorption in Drosophila melanogaster

PubMed Central

Mandilaras, Konstantinos; Pathmanathan, Tharse; Missirlis, Fanis

2013-01-01

The way in which Drosophila melanogaster acquires iron from the diet remains poorly understood despite iron absorption being of vital significance for larval growth. To describe the process of organismal iron absorption, consideration needs to be given to cellular iron import, storage, export and how intestinal epithelial cells sense and respond to iron availability. Here we review studies on the Divalent Metal Transporter-1 homolog Malvolio (iron import), the recent discovery that Multicopper Oxidase-1 has ferroxidase activity (iron export) and the role of ferritin in the process of iron acquisition (iron storage). We also describe what is known about iron regulation in insect cells. We then draw upon knowledge from mammalian iron homeostasis to identify candidate genes in flies. Questions arise from the lack of conservation in Drosophila for key mammalian players, such as ferroportin, hepcidin and all the components of the hemochromatosis-related pathway. Drosophila and other insects also lack erythropoiesis. Thus, systemic iron regulation is likely to be conveyed by different signaling pathways and tissue requirements. The significance of regulating intestinal iron uptake is inferred from reports linking Drosophila developmental, immune, heat-shock and behavioral responses to iron sequestration. PMID:23686013

Absorption sites of orally administered drugs in the small intestine.

PubMed

Murakami, Teruo

2017-12-01

In pharmacotherapy, drugs are mostly taken orally to be absorbed systemically from the small intestine, and some drugs are known to have preferential absorption sites in the small intestine. It would therefore be valuable to know the absorption sites of orally administered drugs and the influencing factors. Areas covered:In this review, the author summarizes the reported absorption sites of orally administered drugs, as well as, influencing factors and experimental techniques. Information on the main absorption sites and influencing factors can help to develop ideal drug delivery systems and more effective pharmacotherapies. Expert opinion: Various factors including: the solubility, lipophilicity, luminal concentration, pKa value, transporter substrate specificity, transporter expression, luminal fluid pH, gastrointestinal transit time, and intestinal metabolism determine the site-dependent intestinal absorption. However, most of the dissolved fraction of orally administered drugs including substrates for ABC and SLC transporters, except for some weakly basic drugs with higher pKa values, are considered to be absorbed sequentially from the proximal small intestine. Securing the solubility and stability of drugs prior to reaching to the main absorption sites and appropriate delivery rates of drugs at absorption sites are important goals for achieving effective pharmacotherapy.

Improving permeability and oral absorption of mangiferin by phospholipid complexation.

PubMed

Ma, Hequn; Chen, Hongming; Sun, Le; Tong, Lijin; Zhang, Tianhong

2014-03-01

Mangiferin is an active ingredient of medicinal plant with poor hydrophilicity and lipophilicity. Many reports focused on improving aqueous solubility, but oral bioavailability of mangiferin was still limited. In this study, we intended to increase not only solubility, but also membrane permeability of mangiferin by a phospholipid complexation technique. The new complex's physicochemical properties were characterized in terms of scanning electron microscopy (SEM), differential scanning calorimetry (DSC), infrared absorption spectroscopy (IR), aqueous solubility, oil-water partition coefficient and in vitro dissolution. The intestinal absorption of the complex was studied by the rat in situ intestinal perfusion model. After oral administration of mangiferin-phospholipid complex and crude mangiferin in rats, the concentrations of mangiferin were determined by a validated RP-HPLC method. Results showed that the solubility of the complex in water and in n-octanol was enhanced and the oil-water partition coefficient was improved by 6.2 times and the intestinal permeability in rats was enhanced significantly. Peak plasma concentration and AUC of mangiferin from the complex (Cmax: 377.66 μg/L, AUC: 1039.94 μg/L*h) were higher than crude mangiferin (Cmax: 180 μg/L, AUC: 2355.63 μg/L*h). In view of improved solubility and enhanced permeability, phospholipid complexation technique can increase bioavailability of mangiferin by 2.3 times in comparison to the crude mangiferin. Copyright © 2013 Elsevier B.V. All rights reserved.

Optimization of the Ussing chamber setup with excised rat intestinal segments for dissolution/permeation experiments of poorly soluble drugs.

PubMed

Forner, Kristin; Roos, Carl; Dahlgren, David; Kesisoglou, Filippos; Konerding, Moritz A; Mazur, Johanna; Lennernäs, Hans; Langguth, Peter

2017-02-01

Prediction of the in vivo absorption of poorly soluble drugs may require simultaneous dissolution/permeation experiments. In vivo predictive media have been modified for permeation experiments with Caco-2 cells, but not for excised rat intestinal segments. The present study aimed at improving the setup of dissolution/permeation experiments with excised rat intestinal segments by assessing suitable donor and receiver media. The regional compatibility of rat intestine in Ussing chambers with modified Fasted and Fed State Simulated Intestinal Fluids (Fa/FeSSIF mod ) as donor media was evaluated via several parameters that reflect the viability of the excised intestinal segments. Receiver media that establish sink conditions were investigated for their foaming potential and toxicity. Dissolution/permeation experiments with the optimized conditions were then tested for two particle sizes of the BCS class II drug aprepitant. Fa/FeSSIF mod were toxic for excised rat ileal sheets but not duodenal sheets, the compatibility with jejunal segments depended on the bile salt concentration. A non-foaming receiver medium containing bovine serum albumin (BSA) and Antifoam B was nontoxic. With these conditions, the permeation of nanosized aprepitant was higher than of the unmilled drug formulations. The compatibility of Fa/FeSSIF mod depends on the excised intestinal region. The chosen conditions enable dissolution/permeation experiments with excised rat duodenal segments. The experiments correctly predicted the superior permeation of nanosized over unmilled aprepitant that is observed in vivo. The optimized setup uses FaSSIF mod as donor medium, excised rat duodenal sheets as permeation membrane and a receiver medium containing BSA and Antifoam B.

Limited interaction between tacrolimus and P-glycoprotein in the rat small intestine.

PubMed

Saitoh, Hiroshi; Saikachi, Yuko; Kobayashi, Mikako; Yamaguchi, Michiko; Oda, Masako; Yuhki, Yoshimitsu; Achiwa, Kazuhito; Tadano, Koji; Takahashi, Yasushi; Aungst, Bruce J

2006-05-01

The significance of intestinal P-glycoprotein (P-gp) in determining the oral bioavailability of tacrolimus has been still controversial. In this study, we reevaluated the interaction of tacrolimus with P-gp in the rat small intestine, by evaluating its absorption from the rat small intestine and its modulating effect on the absorption of known P-gp substrates (digoxin, methylprednisolone, and vinblastine). Intestinal absorption of tacrolimus itself was as extensive as other P-gp modulators such as cyclosporine and verapamil. While cyclosporine and verapamil significantly increased the absorption of methylprednisolone and vinblastine through potent inhibition of intestinal P-gp, tacrolimus failed to achieve this. When cyclosporine and tacrolimus were intravenously administered to rats, digoxin absorption was significantly increased by cyclosporine but not by tacrolimus. When tacrolimus was coadministered with clotrimazole, a specific CYP3A inhibitor, into the rat small intestine, the area under the curve of tacrolimus blood concentrations increased more than seven-fold compared with that of tacrolimus alone. Our present results strongly suggest that the interaction between tacrolimus and P-gp is limited in the rat small intestine and that extensive metabolism by CYP3A enzymes is more responsible for the low oral bioavailability of tacrolimus. It was considered that the extensive absorption of cyclosporine and verapamil was closely associated with their potent ability to inhibit intestinal P-gp.

Lipid Absorption Defects in Intestine-specific Microsomal Triglyceride Transfer Protein and ATP-binding Cassette Transporter A1-deficient Mice*

PubMed Central

Iqbal, Jahangir; Parks, John S.; Hussain, M. Mahmood

2013-01-01

We have previously described apolipoprotein B (apoB)-dependent and -independent cholesterol absorption pathways and the role of microsomal triglyceride transfer protein (MTP) and ATP-binding cassette transporter A1 (ABCA1) in these pathways. To assess the contribution of these pathways to cholesterol absorption and to determine whether there are other pathways, we generated mice that lack MTP and ABCA1, individually and in combination, in the intestine. Intestinal deletions of Mttp and Abca1 decreased plasma cholesterol concentrations by 45 and 24%, respectively, whereas their combined deletion reduced it by 59%. Acute cholesterol absorption was reduced by 28% in the absence of ABCA1, and it was reduced by 92–95% when MTP was deleted in the intestine alone or together with ABCA1. MTP deficiency significantly reduced triglyceride absorption, although ABCA1 deficiency had no effect. ABCA1 deficiency did not affect cellular lipids, but Mttp deficiency significantly increased intestinal levels of triglycerides and free fatty acids. Accumulation of intestinal free fatty acids, but not triglycerides, in Mttp-deficient intestines was prevented when mice were also deficient in intestinal ABCA1. Combined deficiency of these genes increased intestinal fatty acid oxidation as a consequence of increased expression of peroxisome proliferator-activated receptor-γ (PPARγ) and carnitine palmitoyltransferase 1α (CPT1α). These studies show that intestinal MTP and ABCA1 are critical for lipid absorption and are the main determinants of plasma and intestinal lipid levels. Reducing their activities might lower plasma lipid concentrations. PMID:24019513

Absorption of Orally Administered Hyaluronan.

PubMed

Kimura, Mamoru; Maeshima, Takuya; Kubota, Takumi; Kurihara, Hitoshi; Masuda, Yasunobu; Nomura, Yoshihiro

2016-12-01

Hyaluronan (HA) has been utilized as a supplement. However, the absorption of orally administrated HA remains controversial. The degradation and absorption of HA in the intestine were investigated in this study. HA excretion into the feces, degradation in the intestinal tract, absorption through the large intestine, and translocation to the blood and skin were examined. HA administered orally was not detected in rat feces. HA was degraded by cecal content, but not by artificial gastric juice and intestinal juice. Oligosaccharide HA passed through excised large intestine sacs. Furthermore, disaccharides, tetrasaccharides, and polysaccharides HA were distributed to the skin of rats following oral administration of high molecular weight HA (300 kDa). The results of the study suggest that orally administered HA is degraded to oligosaccharides by intestinal bacteria, and oligosaccharide HA is absorbed in the large intestine and is subsequently distributed throughout the tissues, including the skin.

Effects of xylitol on carbohydrate digesting enzymes activity, intestinal glucose absorption and muscle glucose uptake: a multi-mode study.

PubMed

Chukwuma, Chika Ifeanyi; Islam, Md Shahidul

2015-03-01

The present study investigated the possible mechanism(s) behind the effects of xylitol on carbohydrate digesting enzymes activity, muscle glucose uptake and intestinal glucose absorption using in vitro, ex vivo and in vivo experimental models. The effects of increasing concentrations of xylitol (2.5%-40% or 164.31 mM-2628.99 mM) on alpha amylase and alpha glucosidase activity in vitro and intestinal glucose absorption and muscle glucose uptake were investigated under ex vivo conditions. Additionally, the effects of an oral bolus dose of xylitol (1 g per kg BW) on gastric emptying and intestinal glucose absorption and digesta transit in the different segments of the intestinal tract were investigated in normal and type 2 diabetic rats at 1 hour after dose administration, when phenol red was used as a recovery marker. Xylitol exhibited concentration-dependent inhibition of alpha amylase (IC₅₀ = 1364.04 mM) and alpha glucosidase (IC₅₀ = 1127.52 mM) activity in vitro and small intestinal glucose absorption under ex vivo condition. Xylitol also increased dose dependent muscle glucose uptake with and without insulin, although the uptake was not significantly affected by the addition of insulin. Oral single bolus dose of xylitol significantly delayed gastric emptying, inhibited intestinal glucose absorption but increased the intestinal digesta transit rate in both normal and diabetic rats compared to their respective controls. The data of this study suggest that xylitol reduces intestinal glucose absorption via inhibiting major carbohydrate digesting enzymes, slowing gastric emptying and fastening the intestinal transit rate, but increases muscle glucose uptake in normal and type 2 diabetic rats.

Intestinal Lymphatic Transport: an Overlooked Pathway for Understanding Absorption of Plant Secondary Compounds in Vertebrate Herbivores.

PubMed

Kohl, Kevin D; Dearing, M Denise

2017-03-01

Herbivores employ numerous strategies to reduce their exposure to toxic plant secondary chemicals (PSCs). However, the physiological mechanisms of PSC absorption have not been extensively explored. In particular, the absorption of PSCs via intestinal lymphatic absorption has been largely overlooked in herbivores, even though this pathway is well recognized for pharmaceutical uptake. Here, we investigated for the first time whether PSCs might be absorbed by lymphatic transport. We fed woodrats (Neotoma albigula) diets with increasing concentrations of terpene-rich juniper (Juniperus monosperma) either with or without a compound that blocks intestinal lymphatic absorption (Pluronic L-81). Woodrats consuming diets that contained the intestinal lymphatic absorption blocker exhibited increased food intakes and maintained higher body masses on juniper diets. Our study represents the first demonstration that PSCs may be absorbed by intestinal lymphatic absorption. This absorption pathway has numerous implications for the metabolism and distribution of PSCs in the systemic circulation, given that compounds absorbed via lymphatic transport bypass first-pass hepatic metabolism. The area of lymphatic transport of PSCs represents an understudied physiological pathway in plant-herbivore interactions.

Intestinal permeability of forskolin by in situ single pass perfusion in rats.

PubMed

Liu, Zhen-Jun; Jiang, Dong-bo; Tian, Lu-Lu; Yin, Jia-Jun; Huang, Jian-Ming; Weng, Wei-Yu

2012-05-01

The intestinal permeability of forskolin was investigated using a single pass intestinal perfusion (SPIP) technique in rats. SPIP was performed in different intestinal segments (duodenum, jejunum, ileum, and colon) with three concentrations of forskolin (11.90, 29.75, and 59.90 µg/mL). The investigations of adsorption and stability were performed to ensure that the disappearance of forskolin from the perfusate was due to intestinal absorption. The results of the SPIP study indicated that forskolin could be absorbed in all segments of the intestine. The effective permeability (P (eff)) of forskolin was in the range of drugs with high intestinal permeability. The P (eff) was highest in the duodenum as compared to other intestinal segments. The decreases of P (eff) in the duodenum and ileum at the highest forskolin concentration suggested a saturable transport process. The addition of verapamil, a P-glycoprotein inhibitor, significantly enhanced the permeability of forskolin across the rat jejunum. The absorbed fraction of dissolved forskolin after oral administration in humans was estimated to be 100 % calculated from rat P (eff). In conclusion, dissolved forskolin can be absorbed readily in the intestine. The low aqueous solubility of forskolin might be a crucial factor for its poor oral bioavailability. © Georg Thieme Verlag KG Stuttgart · New York.

Effect of raw legume diets on intestinal absorption of D-galactose by chick.

PubMed

Lasheras, B; Bolufer, J; Cenarruzabeitia, M N; Lluch, M; Larralde, J

1980-03-01

The effect of four raw legume diets on the intestinal absorption of D-galactose and oxygen consumption were studied in chick. Field beans (Vicia faba), soybeans (Glycine soja), bitter vetch (Vicia ervilia), and navy beans (Phaseolus vulgaris), were used. The intestinal absorption was determined by both in vivo and in vitro techniques. In vivo, only navy beans and soybeans inhibit intestinal transport of D-galactose, while in vitro all the diets do. Oxygen consumption by intestinal rings increases in chicks fed on bitter vetch diet.

Water and solute absorption from carbohydrate-electrolyte solutions in the human proximal small intestine: a review and statistical analysis.

PubMed

Shi, Xiaocai; Passe, Dennis H

2010-10-01

The purpose of this study is to summarize water, carbohydrate (CHO), and electrolyte absorption from carbohydrate-electrolyte (CHO-E) solutions based on all of the triple-lumen-perfusion studies in humans since the early 1960s. The current statistical analysis included 30 reports from which were obtained information on water absorption, CHO absorption, total solute absorption, CHO concentration, CHO type, osmolality, sodium concentration, and sodium absorption in the different gut segments during exercise and at rest. Mean differences were assessed using independent-samples t tests. Exploratory multiple-regression analyses were conducted to create prediction models for intestinal water absorption. The factors influencing water and solute absorption are carefully evaluated and extensively discussed. The authors suggest that in the human proximal small intestine, water absorption is related to both total solute and CHO absorption; osmolality exerts various impacts on water absorption in the different segments; the multiple types of CHO in the ingested CHO-E solutions play a critical role in stimulating CHO, sodium, total solute, and water absorption; CHO concentration is negatively related to water absorption; and exercise may result in greater water absorption than rest. A potential regression model for predicting water absorption is also proposed for future research and practical application. In conclusion, water absorption in the human small intestine is influenced by osmolality, solute absorption, and the anatomical structures of gut segments. Multiple types of CHO in a CHO-E solution facilitate water absorption by stimulating CHO and solute absorption and lowering osmolality in the intestinal lumen.

A rule of unity for human intestinal absorption 3: Application to pharmaceuticals.

PubMed

Patel, Raj B; Yalkowsky, Samuel H

2018-02-01

The rule of unity is based on a simple absorption parameter, Π, that can accurately predict whether or not an orally administered drug will be well absorbed or poorly absorbed. The intrinsic aqueous solubility and octanol-water partition coefficient, along with the drug dose are used to calculate Π. We show that a single delineator value for Π exist that can distinguish whether a drug is likely to be well absorbed (FA ≥ 0.5) or poorly absorbed (FA < 0.5) at any specified dose. The model is shown to give 82.5% correct predictions for over 938 pharmaceuticals. The maximum well-absorbed dose (i.e. the maximum dose that will be more than 50% absorbed) calculated using this model can be utilized as a guideline for drug design and synthesis. Copyright © 2017 John Wiley & Sons, Ltd.

Dietary Plant Sterol Esters Must Be Hydrolyzed to Reduce Intestinal Cholesterol Absorption in Hamsters123

PubMed Central

Carden, Trevor J; Hang, Jiliang; Dussault, Patrick H; Carr, Timothy P

2015-01-01

Background: Elevated concentrations of LDL cholesterol are associated with the development of atherosclerosis and therefore are considered an important target for intervention to prevent cardiovascular diseases. The inhibition of cholesterol absorption in the small intestine is an attractive approach to lowering plasma cholesterol, one that is addressed by drug therapy as well as dietary supplementation with plant sterols and plant sterol esters (PSEs). Objective: This study was conducted to test the hypothesis that the cholesterol-lowering effects of PSE require hydrolysis to free sterols (FSs). Methods: Male Syrian hamsters were fed atherogenic diets (AIN-93M purified diet containing 0.12% cholesterol and 8% coconut oil) to which one of the following was added: no PSEs or ethers (control), 5% sterol stearate esters, 5% sterol palmitate esters (PEs), 5% sterol oleate esters (OEs), 5% sterol stearate ethers (STs; to mimic nonhydrolyzable PSE), or 3% FSs plus 2% sunflower oil. The treatments effectively created a spectrum of PSE hydrolysis across which cholesterol metabolism could be compared. Metabolic measurements included cholesterol absorption, plasma and liver lipid concentration, and fecal neutral sterol and bile acid excretion. Results: The STs and the PEs and SEs were poorly hydrolyzed (1.69–4.12%). In contrast, OEs were 88.3% hydrolyzed. The percent hydrolysis was negatively correlated with cholesterol absorption (r = −0.85; P < 0.0001) and positively correlated with fecal cholesterol excretion (r = 0.92; P < 0.0001), suggesting that PSE hydrolysis plays a central role in the cholesterol-lowering properties of PSE. Conclusions: Our data on hamsters suggest that PSE hydrolysis and the presence of FSs is necessary to induce an optimum cholesterol-lowering effect and that poorly hydrolyzed PSEs may lower cholesterol through an alternative mechanism than that of competition with cholesterol for micelle incorporation. PMID:25972524

Dietary Plant Sterol Esters Must Be Hydrolyzed to Reduce Intestinal Cholesterol Absorption in Hamsters.

PubMed

Carden, Trevor J; Hang, Jiliang; Dussault, Patrick H; Carr, Timothy P

2015-07-01

Elevated concentrations of LDL cholesterol are associated with the development of atherosclerosis and therefore are considered an important target for intervention to prevent cardiovascular diseases. The inhibition of cholesterol absorption in the small intestine is an attractive approach to lowering plasma cholesterol, one that is addressed by drug therapy as well as dietary supplementation with plant sterols and plant sterol esters (PSEs). This study was conducted to test the hypothesis that the cholesterol-lowering effects of PSE require hydrolysis to free sterols (FSs). Male Syrian hamsters were fed atherogenic diets (AIN-93M purified diet containing 0.12% cholesterol and 8% coconut oil) to which one of the following was added: no PSEs or ethers (control), 5% sterol stearate esters, 5% sterol palmitate esters (PEs), 5% sterol oleate esters (OEs), 5% sterol stearate ethers (STs; to mimic nonhydrolyzable PSE), or 3% FSs plus 2% sunflower oil. The treatments effectively created a spectrum of PSE hydrolysis across which cholesterol metabolism could be compared. Metabolic measurements included cholesterol absorption, plasma and liver lipid concentration, and fecal neutral sterol and bile acid excretion. The STs and the PEs and SEs were poorly hydrolyzed (1.69-4.12%). In contrast, OEs were 88.3% hydrolyzed. The percent hydrolysis was negatively correlated with cholesterol absorption (r = -0.85; P < 0.0001) and positively correlated with fecal cholesterol excretion (r = 0.92; P < 0.0001), suggesting that PSE hydrolysis plays a central role in the cholesterol-lowering properties of PSE. Our data on hamsters suggest that PSE hydrolysis and the presence of FSs is necessary to induce an optimum cholesterol-lowering effect and that poorly hydrolyzed PSEs may lower cholesterol through an alternative mechanism than that of competition with cholesterol for micelle incorporation. © 2015 American Society for Nutrition.

Bioavailability enhancement of curcumin by complexation with phosphatidyl choline.

PubMed

Gupta, Nishant Kumar; Dixit, Vinod Kumar

2011-05-01

Curcumin is a major constituent of rhizomes of Curcuma longa. Pharmacokinetic studies of curcumin reveal its poor absorption through intestine. Objective of the present study was to enhance bioavailability of curcumin by its complexation with phosphatidyl choline (PC). Complex of curcumin was prepared with PC and characterized on the basis of solubility, melting point, differential scanning calorimetry, thin layer chromatography, and infrared spectroscopic analysis. Everted intestine sac technique was used to study ex vivo drug absorption of curcumin-PC (CU-PC) complex and plain curcumin. Pharmacokinetic studies were performed in rats, and hepatoprotective activity of CU-PC complex was also compared with curcumin and CU-PC physical mixture in isolated rat hepatocytes. Analytical reports along with spectroscopic data revealed the formation of complex. The results of ex vivo study show that CU-PC complex has significantly increased absorption compared with curcumin, when given in equimolar doses. Complex showed enhanced bioavailability, improved pharmacokinetics, and increased hepatoprotective activity as compared with curcumin or CU-PC physical mixture. Enhanced bioavailability of CU-PC complex may be due to the amphiphilic nature of the complex, which greatly enhance the water and lipid solubility of the curcumin. The present study clearly indicates the superiority of complex over curcumin, in terms of better absorption, enhanced bioavailability, and improved pharmacokinetics. Copyright © 2010 Wiley-Liss, Inc.

The digestive adaptation of flying vertebrates: high intestinal paracellular absorption compensates for smaller guts.

PubMed

Caviedes-Vidal, Enrique; McWhorter, Todd J; Lavin, Shana R; Chediack, Juan G; Tracy, Christopher R; Karasov, William H

2007-11-27

Anecdotal evidence suggests that birds have smaller intestines than mammals. In the present analysis, we show that small birds and bats have significantly shorter small intestines and less small intestine nominal (smooth bore tube) surface area than similarly sized nonflying mammals. The corresponding >50% reduction in intestinal volume and hence mass of digesta carried is advantageous because the energetic costs of flight increase with load carried. But, a central dilemma is how birds and bats satisfy relatively high energy needs with less absorptive surface area. Here, we further show that an enhanced paracellular pathway for intestinal absorption of water-soluble nutrients such as glucose and amino acids may compensate for reduced small intestines in volant vertebrates. The evidence is that l-rhamnose and other similarly sized, metabolically inert, nonactively transported monosaccharides are absorbed significantly more in small birds and bats than in nonflying mammals. To broaden our comparison and test the veracity of our finding we surveyed the literature for other similar studies of paracellular absorption. The patterns found in our focal species held up when we included other species surveyed in our analysis. Significantly greater amplification of digestive surface area by villi in small birds, also uncovered by our analysis, may provide one mechanistic explanation for the observation of higher paracellular absorption relative to nonflying mammals. It appears that reduced intestinal size and relatively enhanced intestinal paracellular absorption can be added to the suite of adaptations that have evolved in actively flying vertebrates.

New insights into the molecular mechanism of intestinal fatty acid absorption

PubMed Central

Wang, Tony Y.; Liu, Min; Portincasa, Piero; Wang, David Q.-H.

2013-01-01

Background Dietary fat is the most important energy source of all the nutrients. Fatty acids, stored as triacylglycerols in the body, are an important reservoir of stored energy and derive primarily from animal fats and vegetable oils. Design Although the molecular mechanisms for the transport of water-insoluble amphipathic fatty acids across cell membranes have been debated for many years, it is now believed that the dominant means for intestinal fatty acid uptake is via membrane-associated fatty acid-binding proteins, i.e., fatty acid transporters on the apical membrane of enterocytes. Results These findings indicate that intestinal fatty acid absorption is a multistep process that is regulated by multiple genes at the enterocyte level, and intestinal fatty acid absorption efficiency could be determined by factors influencing intraluminal fatty acid molecules across the brush border membrane of enterocytes. To facilitate research on intestinal, hepatic and plasma triacylglycerol metabolism, it is imperative to establish standard protocols for precisely and accurately measuring the efficiency of intestinal fatty acid absorption in humans and animal models. In this review, we will discuss the chemical structure and nomenclature of fatty acids and summarize recent progress in investigating the molecular mechanisms underlying the intestinal absorption of fatty acids, with a particular emphasis on the physical-chemistry of intestinal lipids and the molecular physiology of intestinal fatty acid transporters. Conclusions A better understanding of the molecular mechanism of intestinal fatty acid absorption should lead to novel approaches to the treatment and the prevention of fatty acid-related metabolic diseases that are prevalent worldwide. PMID:24102389

Development and application of bio-sample quantification to evaluate stability and pharmacokinetics of inulin-type fructo-oligosaccharides from Morinda Officinalis.

PubMed

Chi, Liandi; Chen, Lingxiao; Zhang, Jiwen; Zhao, Jing; Li, Shaoping; Zheng, Ying

2018-07-15

Inulin-type fructooligosaccharides (FOS) purified from Morinda Officinalis, with degrees of polymerization (DP) from 3 to 9, have been approved in China as an oral prescribed drug for mild and moderate depression episode, while the stability and oral absorption of this FOS mixtures are largely unknown. As the main active component and quality control marker for above FOS, DP5 was selected as the representative FOS in this study. Desalting method by ion exchange resin was developed to treat bio-sample, followed by separation and quantification by high performance liquid chromatography-charged aerosol detector. Results showed that the DP5 was stepwisely hydrolyzed in simulated gastric fluid and gut microbiota, while maintained stable in intestinal fluid. DP5 has poor permeability across Caco-2 monolayer with P app of 5.22 × 10 -7  cm/s, and very poor oral absorption with bioavailability of (0.50 ± 0.12)% in rat. In conclusion, FOS in Morinda Officinalis demonstrated poor chemical stability in simulated gastric fluid and human gut microbiota, and low oral absorption in rats. Copyright © 2018 Elsevier B.V. All rights reserved.

Development of a novel microemulsion for oral absorption enhancement of all-trans retinoic acid

PubMed Central

Subongkot, Thirapit; Ngawhirunpat, Tanasait

2017-01-01

This study was aimed to develop a novel microemulsion that contained oleth-5 as a surfactant to enhance the oral absorption of all-trans retinoic acid (ATRA). The prepared microemulsion was evaluated for its particle size, shape, zeta potential, in vitro release, in vitro intestinal absorption, intestinal membrane cytotoxicity and stability. The obtained microemulsion was spherical in shape with a particle size of <200 nm and a negative surface charge. The in vitro release of the ATRA-loaded microemulsion was best fit with the zero-order model. This microemulsion significantly improved the intestinal absorption of ATRA. Confocal laser scanning microscopy analysis using a fluorescent dye-loaded microemulsion also confirmed the intestinal absorption result. The intestinal membrane cytotoxicity of the ATRA-loaded microemulsion did not differ from an edible oil (fish oil). Stability testing showed that the ATRA-loaded microemulsion was more stable at 25°C than 40°C. PMID:28831254

Development of a novel microemulsion for oral absorption enhancement of all-trans retinoic acid.

PubMed

Subongkot, Thirapit; Ngawhirunpat, Tanasait

2017-01-01

This study was aimed to develop a novel microemulsion that contained oleth-5 as a surfactant to enhance the oral absorption of all-trans retinoic acid (ATRA). The prepared microemulsion was evaluated for its particle size, shape, zeta potential, in vitro release, in vitro intestinal absorption, intestinal membrane cytotoxicity and stability. The obtained microemulsion was spherical in shape with a particle size of <200 nm and a negative surface charge. The in vitro release of the ATRA-loaded microemulsion was best fit with the zero-order model. This microemulsion significantly improved the intestinal absorption of ATRA. Confocal laser scanning microscopy analysis using a fluorescent dye-loaded microemulsion also confirmed the intestinal absorption result. The intestinal membrane cytotoxicity of the ATRA-loaded microemulsion did not differ from an edible oil (fish oil). Stability testing showed that the ATRA-loaded microemulsion was more stable at 25°C than 40°C.

Metabolic fate of poly-(lactic-co-glycolic acid)-based curcumin nanoparticles following oral administration.

PubMed

Harigae, Takahiro; Nakagawa, Kiyotaka; Miyazawa, Taiki; Inoue, Nao; Kimura, Fumiko; Ikeda, Ikuo; Miyazawa, Teruo

2016-01-01

Curcumin (CUR), the main polyphenol in turmeric, is poorly absorbed and rapidly metabolized following oral administration, which severely curtails its bioavailability. Poly-(lactic-co-glycolic acid)-based CUR nanoparticles (CUR-NP) have recently been suggested to improve CUR bioavailability, but this has not been fully verified. Specifically, no data are available about curcumin glucuronide (CURG), the major metabolite of CUR found in the plasma following oral administration of CUR-NP. Herein, we investigated the absorption and metabolism of CUR-NP and evaluated whether CUR-NP improves CUR bioavailability. Following oral administration of CUR-NP in rats, we analyzed the plasma and organ distribution of CUR and its metabolites using high-performance liquid chromatography-tandem mass spectrometry. To elucidate the mechanism of increased intestinal absorption of CUR-NP, we prepared mixed micelles comprised of phosphatidylcholine and bile salts and examined the micellar solubility of CUR-NP. Additionally, we investigated the cellular incorporation of the resultant micelles into differentiated Caco-2 human intestinal cells. Following in vivo administration of CUR-NP, CUR was effectively absorbed and present mainly as CURG in the plasma which contained significant amounts of the metabolite compared with other organs. Thus, CUR-NP increased intestinal absorption of CUR rather than decreasing metabolic degradation and conversion to other metabolites. In vitro, CUR encapsulated in CUR-NP was solubilized in mixed micelles; however, whether the micelles contained CUR or CUR-NP had little influence on cellular uptake efficiency. Therefore, we suggest that the high solubilization capacity of CUR-NP in mixed micelles, rather than cellular uptake efficiency, explains the high intestinal absorption of CUR-NP in vivo. These findings provide a better understanding of the bioavailability of CUR and CUR-NP following oral administration. To improve the bioavailability of CUR, future studies should focus on enhancing the resistance to metabolic degradation and conversion of CUR to other metabolites, which may lead to novel discoveries regarding food function and disease prevention.

A modified physiological BCS for prediction of intestinal absorption in drug discovery.

PubMed

Zaki, Noha M; Artursson, Per; Bergström, Christel A S

2010-10-04

In this study, the influence of physiologically relevant media on the compound position in a biopharmaceutical classification system (BCS) which resembled the intestinal absorption was investigated. Both solubility and permeability limited compounds (n = 22) were included to analyze the importance of each of these on the final absorption. Solubility was determined in three different dissolution media, phosphate buffer pH 6.5 (PhB 6.5), fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF) at 37 °C, and permeability values were determined using the 2/4/A1 cell line. The solubility data and membrane permeability values were used for sorting the compounds into a BCS modified to reflect the fasted and fed state. Three of the seven compounds sorted as BCS II in PhB 6.5 (high permeability, low solubility) changed their position to BCS I when dissolved in FaSSIF and/or FeSSIF (high permeability, high solubility). These were low dosed (20 mg or less) lipophilic molecules displaying solvation limited solubility. In contrast, compounds having solid-state limited solubility had a minor increase in solubility when dissolved in FaSSIF and/or FeSSIF. Although further studies are needed to enable general cutoff values, our study indicates that low dosed BCS Class II compounds which have solubility normally restricted by poor solvation may behave as BCS Class I compounds in vivo. The large series of compounds investigated herein reveals the importance of investigating solubility and dissolution under physiologically relevant conditions in all stages of the drug discovery process to push suitable compounds forward, to select proper formulations, and to reduce the risk of food effects.

Paracetamol absorption from different sites in the human small intestine.

PubMed Central

Gramatté, T; Richter, K

1994-01-01

Site-specificity in the small intestinal absorption of paracetamol was investigated using a segmental intestinal steady state perfusion technique (triple-lumen tubing system) combined with simultaneous measurements of serum drug concentrations. Dissolved paracetamol was perfused over 160 min into different parts of the small intestine (65-210 cm beyond the teeth). Each of the four healthy subjects was studied twice with a proximal and a more distal site of perfusion. Serum drug concentrations were similar after proximal and distal perfusions. Mean drug absorption rates calculated from intestinal aspirate concentrations were similar in both parts of the intestine--proximal: 869 micrograms 30 cm-1 min-1 (95% CI: 659-1079) vs distal: 941 micrograms 30 cm-1 min-1 (794-1088). The absorption rate was related directly to the amount of paracetamol perfused per unit time as well as to the rate of transmucosal water fluxes. PMID:7917782

Modulating effect of polyethylene glycol on the intestinal transport and absorption of prednisolone, methylprednisolone and quinidine in rats by in-vitro and in-situ absorption studies.

PubMed

Shen, Qi; Li, Wenji; Lin, Yulian; Katsumi, Hidemasa; Okada, Naoki; Sakane, Toshiyasu; Fujita, Takuya; Yamamoto, Akira

2008-12-01

The effects of polyethylene glycol 20000 (PEG 20000) on the intestinal absorption of prednisolone, methylprednisolone and quinidine, three P-glycoprotein (P-gp) substrates, across the isolated rat intestinal membranes were examined by an in-vitro diffusion chamber system. The serosal-to-mucosal (secretory) transport of these P-gp substrates was greater than their mucosal-to-serosal (absorptive) transport, indicating that their net movement across the intestinal membranes was preferentially in the secretory direction. The polarized secretory transport of these drugs was remarkably diminished and their efflux ratios decreased in the presence of PEG 20000. In addition, PEG 20000 did not affect the transport of Lucifer yellow, a non-P-gp substrate. The intestinal membrane toxicity of PEG 20000 was evaluated by measuring the release of alkaline phosphatase (ALP) and protein from the intestinal membranes. The release of ALP and protein was enhanced in the presence of 20 mM sodium deoxycholate (NaDC), a positive control, while these biological parameters did not change in the presence of 0.1-5% (w/v) PEG 20000. These findings indicated that the intestinal membrane damage caused by PEG 20000 was not a main reason for the enhanced absorptive transport of these P-gp substrates in the presence of PEG 20000. Furthermore, the transepithelial electrical resistance (TEER) of rat jejunal membranes in the presence or absence of PEG 20000 was measured by a diffusion chamber method. PEG 20000 (0.1-5.0 % w/v) did not change the TEER values of the rat jejunal membranes, indicating that the increase in the absorptive transport of these P-gp substrates might not be due to the increased transport of these P-gp substrates via a paracellular pathway caused by PEG 20000. Finally, the effect of PEG 20000 on the intestinal absorption of quinidine was examined by an in-situ closed-loop method. The intestinal absorption of quinidine was significantly enhanced in the presence of 0.1-1.0% (w/v) PEG 20000. These findings suggest that PEG 20000 might be a useful excipient to improve the intestinal absorption of quinidine, which is mainly secreted by a P-gp-mediated efflux system in the intestine.

New insights into the molecular mechanism of intestinal fatty acid absorption.

PubMed

Wang, Tony Y; Liu, Min; Portincasa, Piero; Wang, David Q-H

2013-11-01

Dietary fat is one of the most important energy sources of all the nutrients. Fatty acids, stored as triacylglycerols (also called triglycerides) in the body, are an important reservoir of stored energy and derived primarily from animal fats and vegetable oils. Although the molecular mechanisms for the transport of water-insoluble amphipathic fatty acids across cell membranes have been debated for many years, it is now believed that the dominant means for intestinal fatty acid uptake is via membrane-associated fatty acid-binding proteins, that is, fatty acid transporters on the apical membrane of enterocytes. These findings indicate that intestinal fatty acid absorption is a multistep process that is regulated by multiple genes at the enterocyte level, and intestinal fatty acid absorption efficiency could be determined by factors influencing intraluminal fatty acid molecules across the brush border membrane of enterocytes. To facilitate research on intestinal, hepatic and plasma triacylglycerol metabolism, it is imperative to establish standard protocols for precisely and accurately measuring the efficiency of intestinal fatty acid absorption in humans and animal models. In this review, we will discuss the chemical structure and nomenclature of fatty acids and summarize recent progress in investigating the molecular mechanisms underlying the intestinal absorption of fatty acids, with a particular emphasis on the physical chemistry of intestinal lipids and the molecular physiology of intestinal fatty acid transporters. A better understanding of the molecular mechanism of intestinal fatty acid absorption should lead to novel approaches to the treatment and the prevention of fatty acid-related metabolic diseases that are prevalent worldwide. © 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.

Rifaximin for the treatment of diarrhoea-predominant irritable bowel syndrome.

PubMed

Laterza, Lucrezia; Ianiro, Gianluca; Scoleri, Iolanda; Landi, Rosario; Bruno, Giovanni; Scaldaferri, Franco; Gaetani, Eleonora; Campanale, Mariachiara; Gasbarrini, Antonio

2015-03-01

Rifaximin is a non-absorbable, semisynthetic antibiotic that acts as an inhibitor of bacterial RNA synthesis, with a broad spectrum of antibacterial activity. Due to its poor absorption, rifaximin has an increased exposure to the intestine, thus it is suitable for the treatment of many gastrointestinal (GI) diseases. In irritable bowel syndrome (IBS) pathogenesis, gut microbiota impairment may play a major role. The possibility of modulating intestinal bacteria using antibiotics, in particular, rifaximin, has been demonstrated to improve IBS symptoms in non-constipation subtypes of IBS. We reviewed the use of rifaximin in diarrhoea-predominant IBS, focusing on its pharmacokinetic characteristics, its absorption in GI disease, its lack of interaction with other drugs and its new extended release formulation. Rifaximin, with its low systemic absorption and no clinically significant interactions with other drugs, may represent a treatment of choice for IBS, mainly due to its ability to act on IBS pathogenesis, through the modulation of gut microbiota. Further studies to analyse the effect of rifaximin treatment on the composition of faecal microbiota are warranted. In particular, they need to evaluate whether resistant bacterial strains are selected and whether they are still present in the faecal sample even a long time after therapy.

Effects of dietary glucose and sodium chloride on intestinal glucose absorption of common carp (Cyprinus carpio L.).

PubMed

Qin, Chaobin; Yang, Liping; Zheng, Wenjia; Yan, Xiao; Lu, Ronghua; Xie, Dizhi; Nie, Guoxing

2018-01-08

The co-transport of sodium and glucose is the first step for intestinal glucose absorption. Dietary glucose and sodium chloride (NaCl) may facilitate this physiological process in common carp (Cyprinus carpio L.). To test this hypothesis, we first investigated the feeding rhythm of intestinal glucose absorption. Carps were fed to satiety once a day (09:00 a.m.) for 1 month. Intestinal samples were collected at 01:00, 05:00, 09:00, 13:00, 17:00 and 21:00. Result showed that food intake greatly enhanced sodium/glucose cotransporter 1 (SGLT1) and glucose transporter type 2 (GLUT2) expressions, and improved glucose absorption, with highest levels at 09:00 a.m.. Then we designed iso-nitrogenous and iso-energetic diets with graded levels of glucose (10%, 20%, 30%, 40% and 50%) and NaCl (0%, 1%, 3% and 5%), and submitted to feeding trial for 10 weeks. The expressions of SGLT1 and GLUT2, brush border membrane vesicles (BBMVs) glucose transport and intestinal villus height were determined after the feeding trial. Increasing levels of dietary glucose and NaCl up-regulated mRNA and protein levels of SGLT1 and GLUT2, enhanced BBMVs glucose transport in the proximal, mid and distal intestine. As for histological adaptive response, however, high-glucose diet prolonged while high-NaCl diet shrank intestinal villus height. Furthermore, we also found that higher mRNA levels of SGLT1 and GLUT2, higher glucose transport capacity of BBMVs, and higher intestinal villus were detected in the proximal and mid intestine, compared to the distal part. Taken together, our study indicated that intestinal glucose absorption in carp was primarily occurred in the proximal and mid intestine, and increasing levels of dietary glucose and NaCl enhanced intestinal glucose absorption in carp. Copyright © 2017 Elsevier Inc. All rights reserved.

Interaction of Food Additives with Intestinal Efflux Transporters.

PubMed

Sjöstedt, Noora; Deng, Feng; Rauvala, Oskari; Tepponen, Tuomas; Kidron, Heidi

2017-11-06

Breast cancer resistance protein (BCRP), multidrug resistance associated protein 2 (MRP2) and P-glycoprotein (P-gp) are ABC transporters that are expressed in the intestine, where they are involved in the efflux of many drugs from enterocytes back into the intestinal lumen. The inhibition of BCRP, MRP2, and P-gp can result in enhanced absorption and exposure of substrate drugs. Food additives are widely used by the food industry to improve the stability, flavor, and consistency of food products. Although they are considered safe for consumption, their interactions with intestinal transporters are poorly characterized. Therefore, in this study, selected food additives, including preservatives, colorants, and sweeteners, were studied in vitro for their inhibitory effects on intestinal ABC transporters. Among the studied compounds, several colorants were able to inhibit BCRP and MRP2, whereas P-gp was fairly insensitive to inhibition. Additionally, one sweetener was identified as a potent inhibitor of BCRP. Dose-response studies revealed that the IC 50 values of the inhibitors were lower than the estimated intestinal concentrations after the consumption of beverages containing food colorants. This suggests that there is potential for previously unrecognized transporter-mediated food additive-drug interactions.

Bovine colostrum to children with short bowel syndrome: a randomized, double-blind, crossover pilot study.

PubMed

Aunsholt, Lise; Jeppesen, Palle Bekker; Lund, Pernille; Sangild, Per Torp; Ifaoui, Inge Bøtker Rasmussen; Qvist, Niels; Husby, Steffen

2014-01-01

Management of short bowel syndrome (SBS) aims to achieve intestinal autonomy to prevent fluid, electrolyte, and nutrient deficiencies and maintain adequate development. Remnant intestinal adaptation is required to obtain autonomy. In the newborn pig, colostrum has been shown to support intestinal development and hence adaptive processes. The efficacy of bovine colostrum to improve intestinal function in children with SBS was evaluated by metabolic balance studies. Nine children with SBS were included in a randomized, double-blind, crossover study. Twenty percent of enteral fluid intake was replaced with bovine colostrum or a mixed milk diet for 4 weeks, separated by a 4-week washout period. Intestinal absorption of energy and wet weight was used to assess intestinal function and the efficacy of colostrum. Colostrum did not improve energy or wet weight absorption compared with the mixed milk diet (P = 1.00 and P = .93, respectively). Growth as measured by weight and knemometry did not differ between diets (P = .93 and P = .28). In these patients, <150% enteral energy absorption of basal metabolic rate and 50% enteral fluid absorption of basal fluid requirement suggested intestinal failure and a need for parenteral nutrition (PN). Inclusion of bovine colostrum to the diet did not improve intestinal function. Metabolic nutrient and wet weight balance studies successfully assessed intestinal function, and this method may distinguish between intestinal insufficiency (non-PN-dependent) and intestinal failure (PN-dependent) patients.

Increased intracellular calcium level and impaired nutrient absorption are important pathogenicity traits in the chicken intestinal epithelium during Campylobacter jejuni colonization.

PubMed

Awad, Wageha A; Smorodchenko, Alina; Hess, Claudia; Aschenbach, Jörg R; Molnár, Andor; Dublecz, Károly; Khayal, Basel; Pohl, Elena E; Hess, Michael

2015-08-01

Although a high number of chickens carry Campylobacter jejuni, the mechanistic action of colonization in the intestine is still poorly understood. The current study was therefore designed to investigate the effects of C. jejuni on glucose uptake, amino acids availability in digesta, and intracellular calcium [Ca(2+)]i signaling in the intestines of broiler chickens. For this, we compared: control birds (n = 60) and C. jejuni-infected birds (n = 60; infected orally with 1 × 10(8) CFU of C. jejuni NCTC 12744 at 14 days of age). Our results showed that glucose uptake was reduced due to C. jejuni infection in isolated jejunal, but not in cecal mucosa at 14 days postinfection (dpi). The decrease in intestinal glucose absorption coincided with a decrease in body weight gain during the 2-week post-infectious period. A reduction in the amount of the amino acids (serine, proline, valine, leucine, phenylalanine, arginine, histidine, and lysine) in ileal digesta of the infected birds at 2 and/or 7 dpi was found, indicating that Campylobacter utilizes amino acids as a carbon source for their multiplication. Applying the cell-permeable Ca(2+) indicator Fluo-4 and two-photon microscopy, we revealed that [Ca(2+)]i was increased in the jejunal and cecal mucosa of infected birds. The muscarinic agonist carbachol induced an increase in [Ca(2+)]i in jejunum and cecum mucosa of control chickens, a response absent in the mucosa of infected chickens, demonstrating that the modulation of [Ca(2+)]i by Campylobacter might be involved in facilitating the necessary cytoskeletal rearrangements that occur during the bacterial invasion of epithelial cells. In conclusion, this study demonstrates the multifaceted interactions of C. jejuni with the gastrointestinal mucosa of broiler chickens. For the first time, it could be shown that a Campylobacter infection could interfere with intracellular Ca(2+) signaling and nutrient absorption in the small intestine with consequences on intestinal function, performance, and Campylobacter colonization. Altogether, these findings indicate that Campylobacter is not entirely a commensal and can be recognized as an important factor contributing to an impaired chicken gut health.

Molecular imaging analysis of intestinal insulin absorption boosted by cell-penetrating peptides by using positron emission tomography.

PubMed

Kamei, Noriyasu; Morishita, Mariko; Kanayama, Yousuke; Hasegawa, Koki; Nishimura, Mie; Hayashinaka, Emi; Wada, Yasuhiro; Watanabe, Yasuyoshi; Takayama, Kozo

2010-08-17

Molecular imaging technique by use of positron emission tomography (PET) is a noninvasive tool that allows one to quantitatively analyze the function of endogenous molecules and the pharmacokinetics of therapeutic agents in vivo. This technique is expected to be useful for evaluating the effectiveness of diverse drug delivery systems. We demonstrated previously that intestinal insulin absorption is increased significantly by coadministration of cell-penetrating peptides (CPPs), which are taken up effectively by several cells. However, the distribution behavior of insulin whose absorption is increased by CPPs is not clear. We used PET imaging and quantitatively analyzed the intestinal absorption and subsequent distribution of insulin and the effect of CPPs on its absorption and distribution. An unlabeled insulin solution containing tracer insulin, (68)Ga-DOTA-insulin, was administered with or without CPPs into a rat ileal closed loop. PET imaging showed that the CPPs, particularly D-R8 and L-penetratin, significantly increased the (68)Ga-DOTA-insulin level in the liver, kidney, and circulation. After absorption from the intestine, the (68)Ga-DOTA-insulin passed rapidly through the liver and accumulated in the kidney. The increase in the hepatic and renal distribution of (68)Ga-DOTA-insulin by each CPP coadministration was similar manner as that in intestinal absorption, suggesting that the increased accumulation of insulin in the liver and kidney induced by coadministration of CPPs was associated with the increased intestinal absorption of insulin. This is the first study to show that PET imaging enables one to quantitatively analyze the distribution behavior of intestinally absorbed insulin in several organs. This imaging methodology is likely to be useful for developing effective drug delivery systems targeted to specific organs. Copyright 2010 Elsevier B.V. All rights reserved.

In situ absorption and relative bioavailability studies of zaleplon loaded self-nanoemulsifying powders.

PubMed

Janga, Karthik Y; Jukanti, Raju; Sunkavalli, Sharath; Velpula, Ashok; Bandari, Suresh; Kandadi, Prabhakar; Veerareddy, Prabhakar Reddy

2013-01-01

Self-nanoemulsifying drug delivery systems (SNEDDSs) offer potential as suitable carriers for improved oral delivery of poorly soluble and low bioavailable drugs. To derive self-nanoemulsifying powders (SNEPs), the optimized Z-SNEDDS formulation was adsorbed onto different carriers and based on micromeritics the formulation loaded onto neusilin US2 (SNEP-N) was selected for further characterization. The solid-state characterization (scanning electron microscopy, differential scanning calorimetry and powder X-ray diffraction) studies unravel the transformation of native crystalline state to amorphous and/or molecular state. The higher predictive effective permeability coefficient and fraction absorbed in humans extrapolated from in situ single-pass intestinal absorption study data in rats provide an insight on the potential of SNEPs for augment in absorption across gastrointestinal barrier. Overall a 3.5-fold enhancement in the extent of absorption of zaleplon from SNEP-N formulation proves the feasibility of SNEPs formulation for improved oral delivery of zaleplon.

Update: The Digestion and Absorption of Carbohydrate and Protein: Role of the Small Intestine.

ERIC Educational Resources Information Center

Leese, H. J.

1984-01-01

Discusses the role of the small intestine in the digestion and absorption of carbohydrates and proteins. Indicates as outdated the view that these materials must be broken down to monomeric units before absorption and that the gut secretes a mixture of digestive juices which brings about absorption. (JN)

Intestinal absorption of D-galactose and L-leucine and intestinal disaccharidase activities in growing chickens fed different raw legume diets.

PubMed

Santidrian, S; Lasheras, B; Cenarruzabeitia, M N; Bolufer, J; Larralde, J

1981-04-01

A significant (P less than .01) impairment in the rate of growth, along with a significant (P less than .01) inhibition in the rate of in vivo intestinal absorption of D-galactose and L-leucine, and in the in vitro intestinal absorption of D-galactose, was found in growing chickens fed ad libitum over a 60-day period, diets containing the raw legumes Vicia faba, Glycine soja, Vicia ervilia, and Phaseolus vulgaris as the main source of protein. Furthermore, a significant (P less than .01) reduction in the intestinal disaccharidase activity was found in the legume-fed chickens. The possible nature of these effects was discussed.

Inhibitory effect and mechanism of acarbose combined with gymnemic acid on maltose absorption in rat intestine

PubMed Central

Luo, Hong; Wang, Le Feng; Imoto, Toshiaki; Hiji, Yasutake

2001-01-01

AIM: To compare the combinative and individual effect of acarbose and gymnemic acid (GA) on maltose absorption and hydrolysis in small intestine to determine whether nutrient control in diabetic care can be improved by combination of them. METHODS: The absorption and hydrolysis of maltose were studied by cyclic perfusion of intestinal loops in situ and motility of the intestine was recorded with the intestinal ring in vitro using Wistar rats. RESULTS: The total inhibitory rate of maltose absorption was improved by the combination of GA (0.1 g/L-1.0 g/L) and acarbose (0.1 mmol/L-2.0 mmol/L) throughout their effective duration (P < 0.05, U test of Mann-Whitney), although the improvement only could be seen at a low dosage during the first hour. With the combination, inhibitory duration of acarbose on maltose absorption was prolonged to 3 h and the inhibitory effect onset of GA was fastened to 15 min. GA suppressed the intestinal mobility with a good correlation (r = 0.98) to the inhibitory effect of GA on maltose absorption and the inhibitory effect of 2 mmol/L (high dose) acarbose on maltose hydrolysis was dual modulated by 1 g/L GA in vivo indicating that the combined effects involved the functional alteration of intestinal barriers. CONCLUSION: There are augmented effects of acarbose and GA, which involve pre-cellular and paracellular barriers. Diabetic care can be improved by employing the combination. PMID:11819725

Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D–induced inhibition of bone mineralization

PubMed Central

Lieben, Liesbet; Masuyama, Ritsuko; Torrekens, Sophie; Van Looveren, Riet; Schrooten, Jan; Baatsen, Pieter; Lafage-Proust, Marie-Hélène; Dresselaers, Tom; Feng, Jian Q.; Bonewald, Lynda F.; Meyer, Mark B.; Pike, J. Wesley; Bouillon, Roger; Carmeliet, Geert

2012-01-01

Serum calcium levels are tightly controlled by an integrated hormone-controlled system that involves active vitamin D [1,25(OH)2D], which can elicit calcium mobilization from bone when intestinal calcium absorption is decreased. The skeletal adaptations, however, are still poorly characterized. To gain insight into these issues, we analyzed the consequences of specific vitamin D receptor (Vdr) inactivation in the intestine and in mature osteoblasts on calcium and bone homeostasis. We report here that decreased intestinal calcium absorption in intestine-specific Vdr knockout mice resulted in severely reduced skeletal calcium levels so as to ensure normal levels of calcium in the serum. Furthermore, increased 1,25(OH)2D levels not only stimulated bone turnover, leading to osteopenia, but also suppressed bone matrix mineralization. This resulted in extensive hyperosteoidosis, also surrounding the osteocytes, and hypomineralization of the entire bone cortex, which may have contributed to the increase in bone fractures. Mechanistically, osteoblastic VDR signaling suppressed calcium incorporation in bone by directly stimulating the transcription of genes encoding mineralization inhibitors. Ablation of skeletal Vdr signaling precluded this calcium transfer from bone to serum, leading to better preservation of bone mass and mineralization. These findings indicate that in mice, maintaining normocalcemia has priority over skeletal integrity, and that to minimize skeletal calcium storage, 1,25(OH)2D not only increases calcium release from bone, but also inhibits calcium incorporation in bone. PMID:22523068

Intestinal fluid absorption in spontaneously hypertensive rats.

PubMed Central

Dorey, P G; King, J; Munday, K A; Parsons, B J; Poat, J A

1983-01-01

A comparison has been made of intestinal fluid absorption between male Okamoto spontaneously hypertensive rats (s.h.r.) and normotensive male Wistar controls. S.h.r. show enhanced fluid absorption both in hypertensive adults and in young s.h.r. before hypertension has developed. Several potential causes for increased fluid transport in s.h.r. were tested using pharmacological antagonists. It is unlikely that enhanced fluid absorption is due to high sympathetic nervous activity, the renin-angiotensin system or is secondary to hypertension. Intestine from s.h.r. have a high short-circuit current indicating a change in ion pump activity. These results are discussed in relation to the possible causes of increased fluid (ion) transport by the intestine of s.h.r. PMID:6361232

Sorbitol increases muscle glucose uptake ex vivo and inhibits intestinal glucose absorption ex vivo and in normal and type 2 diabetic rats.

PubMed

Chukwuma, Chika Ifeanyi; Islam, Md Shahidul

2017-04-01

Previous studies have suggested that sorbitol, a known polyol sweetener, possesses glycemic control potentials. However, the effect of sorbitol on intestinal glucose absorption and muscle glucose uptake still remains elusive. The present study investigated the effects of sorbitol on intestinal glucose absorption and muscle glucose uptake as possible anti-hyperglycemic or glycemic control potentials using ex vivo and in vivo experimental models. Sorbitol (2.5% to 20%) inhibited glucose absorption in isolated rat jejuna (IC 50 = 14.6% ± 4.6%) and increased glucose uptake in isolated rat psoas muscle with (GU 50 = 3.5% ± 1.6%) or without insulin (GU 50 = 7.0% ± 0.5%) in a concentration-dependent manner. Furthermore, sorbitol significantly delayed gastric emptying, accelerated digesta transit, inhibited intestinal glucose absorption, and reduced blood glucose increase in both normoglycemic and type 2 diabetic rats after 1 h of coingestion with glucose. Data of this study suggest that sorbitol exhibited anti-hyperglycemic potentials, possibly via increasing muscle glucose uptake ex vivo and reducing intestinal glucose absorption in normal and type 2 diabetic rats. Hence, sorbitol may be further investigated as a possible anti-hyperglycemic sweetener.

Intestinal absorption of hawthorn flavonoids--in vitro, in situ and in vivo correlations.

PubMed

Zuo, Zhong; Zhang, Li; Zhou, Limin; Chang, Qi; Chow, Moses

2006-11-25

Our previous studies identified hyperoside (HP), isoquercitrin (IQ) and epicatechin (EC) to be the major active flavonoid components of the hawthorn phenolic extract from hawthorn fruits demonstrating inhibitory effect on in vitro Cu(+2)-mediated low density lipoproteins oxidation. Among these three hawthorn flavonoids, EC was the only one detectable in plasma after the oral administration of hawthorn phenolic extract to rats. The present study aims to investigate the intestinal absorption mechanisms of these three hawthorn flavonoids by in vitro Caco-2 monolayer model, rat in situ intestinal perfusion model and in vivo pharmacokinetics studies in rats. In addition, in order to investigate the effect of the co-occurring components in hawthorn phenolic extract on the intestinal absorption of these three major hawthorn flavonoids, intestinal absorption transport profiles of HP, IQ and EC in forms of individual pure compound, mixture of pure compounds and hawthorn phenolic extract were studied and compared. The observations from in vitro Caco-2 monolayer model and in situ intestinal perfusion model indicated that all three studied hawthorn flavonoids have quite limited permeabilities. EC and IQ demonstrated more extensive metabolism in the rat in situ intestinal perfusion model and in vivo study than in Caco-2 monolayer model. Moreover, results from the Caco-2 monolayer model, rat in situ intestinal perfusion model as well as the in vivo pharmacokinetics studies in rats consistently showed that the co-occurring components in hawthorn phenolic extract might not have significant effect on the intestinal absorption of the three major hawthorn flavonoids studied.

The transit of dosage forms through the small intestine.

PubMed

Yuen, Kah-Hay

2010-08-16

The human small intestine, with its enormous absorptive surface area, is invariably the principal site of drug absorption. Hence, the residence time of a dosage form in this part of the gut can have a great influence on the absorption of the contained drug. Various methods have been employed to monitor the gastrointestinal transit of pharmaceutical dosage forms, but the use of gamma-scintigraphy has superceded all the other methods. However, careful consideration of the time interval for image acquisition and proper analysis of the scintigraphic data are important for obtaining reliable results. Most studies reported the mean small intestinal transit time of various dosage forms to be about 3-4h, being closely similar to that of food and water. The value does not appear to be influenced by their physical state nor the presence of food, but the timing of food intake following administration of the dosage forms can influence the small intestinal transit time. While the mean small intestinal transit time is quite consistent among dosage forms and studies, individual values can vary widely. There are differing opinions regarding the effect of density and size of dosage forms on their small intestinal transit properties. Some common excipients employed in pharmaceutical formulations can affect the small intestinal transit and drug absorption. There is currently a lack of studies regarding the effects of excipients, as well as the timing of food intake on the small intestinal transit of dosage forms and drug absorption. Copyright (c) 2010 Elsevier B.V. All rights reserved.

The role of the rectum in osmoregulation and the potential effect of renoguanylin on SLC26a6 transport activity in the Gulf toadfish (Opsanus beta)

PubMed Central

Takei, Yoshio; Grosell, Martin

2016-01-01

Teleosts living in seawater continually absorb water across the intestine to compensate for branchial water loss to the environment. The present study reveals that the Gulf toadfish (Opsanus beta) rectum plays a comparable role to the posterior intestine in ion and water absorption. However, the posterior intestine appears to rely more on SLC26a6 (a HCO3−/Cl− antiporter) and the rectum appears to rely on NKCC2 (SLC12a1) for the purposes of solute-coupled water absorption. The present study also demonstrates that the rectum responds to renoguanylin (RGN), a member of the guanylin family of peptides that alters the normal osmoregulatory processes of the distal intestine, by inhibited water absorption. RGN decreases rectal water absorption more greatly than in the posterior intestine and leads to net Na+ and Cl− secretion, and a reversal of the absorptive short-circuit current (ISC). It is hypothesized that maintaining a larger fluid volume within the distal segments of intestinal tract facilitates the removal of CaCO3 precipitates and other solids from the intestine. Indeed, the expression of the components of the Cl−-secretory response, apical CFTR, and basolateral NKCC1 (SLC12a2), are upregulated in the rectum of the Gulf toadfish after 96 h in 60 ppt, an exposure that increases CaCO3 precipitate formation relative to 35 ppt. Moreover, the downstream intracellular effects of RGN appear to directly inhibit ion absorption by NKCC2 and anion exchange by SLC26a6. Overall, the present findings elucidate key electrophysiological differences between the posterior intestine and rectum of Gulf toadfish and the potent regulatory role renoguanylin plays in osmoregulation. PMID:27030664

Naringin prevents the inhibition of intestinal Ca2+ absorption induced by a fructose rich diet.

PubMed

Rodríguez, V; Rivoira, M; Guizzardi, S; Tolosa de Talamoni, N

2017-12-15

This study tries to elucidate the mechanisms by which fructose rich diets (FRD) inhibit the rat intestinal Ca 2+ absorption, and determine if any or all underlying alterations are prevented by naringin (NAR). Male rats were divided into: 1) controls, 2) treated with FRD, 3) treated with FRD and NAR. The intestinal Ca 2+ absorption and proteins of the transcellular and paracellular Ca 2+ pathways were measured. Oxidative/nitrosative stress and inflammation parameters were evaluated. FRD rats showed inhibition of the intestinal Ca 2+ absorption and decrease in the protein expression of molecules of both Ca 2+ pathways, which were blocked by NAR. FRD rats showed an increase in the superoxide anion, a decrease in the glutathione and in the enzymatic activities of the antioxidant system, as well as an increase in the NO content and in the nitrotyrosine content of proteins. They also exhibited an increase in both IL-6 and nuclear NF-κB. All these changes were prevented by NAR. In conclusion, FRD inhibit both pathways of the intestinal Ca 2+ absorption due to the oxidative/nitrosative stress and inflammation. Since NAR prevents the oxidative/nitrosative stress and inflammation, it might be a drug to avoid alteration in the intestinal Ca 2+ absorption caused by FRD. Copyright © 2017 Elsevier Inc. All rights reserved.

An assessment of the intestinal lumen as a site for intervention in reducing body burdens of organochlorine compounds.

PubMed

Jandacek, Ronald J; Genuis, Stephen J

2013-01-01

Many individuals maintain a persistent body burden of organochlorine compounds (OCs) as well as other lipophilic compounds, largely as a result of airborne and dietary exposures. Ingested OCs are typically absorbed from the small intestine along with dietary lipids. Once in the body, stored OCs can mobilize from adipose tissue storage sites and, along with circulating OCs, are delivered into the small intestine via hepatic processing and biliary transport. Retained OCs are also transported into both the large and small intestinal lumen via non-biliary mechanisms involving both secretion and desquamation from enterocytes. OCs and some other toxicants can be reabsorbed from the intestine, however, they take part in enterohepatic circulation(EHC). While dietary fat facilitates the absorption of OCs from the small intestine, it has little effect on OCs within the large intestine. Non-absorbable dietary fats and fat absorption inhibitors, however, can reduce the re-absorption of OCs and other lipophiles involved in EHC and may enhance the secretion of these compounds into the large intestine--thereby hastening their elimination. Clinical studies are currently underway to determine the efficacy of using non-absorbable fats and inhibitors of fat absorption in facilitating the elimination of persistent body burdens of OCs and other lipophilic human contaminants.

Clostridium perfringens epsilon toxin is absorbed from different intestinal segments of mice.

PubMed

Losada-Eaton, D M; Uzal, F A; Fernández Miyakawa, M E

2008-06-01

Clostridium perfringens epsilon toxin is a potent toxin responsible for a rapidly fatal enterotoxaemia in several animal species. The pathogenesis of epsilon toxin includes toxicity to endothelial cells and neurons. Although epsilon toxin is absorbed from the gastrointestinal tract, the intestinal regions where the toxin is absorbed and the conditions favoring epsilon toxin absorption are unknown. The aim of this paper was to determine the toxicity of epsilon toxin absorbed from different gastrointestinal segments of mice and to evaluate the influence of the intestinal environment in the absorption of this toxin. Epsilon toxin diluted in one of several different saline solutions was surgically introduced into ligated stomach or intestinal segments of mice. Comparison of the toxicity of epsilon toxin injected in different sections of the gastrointestinal tract showed that this toxin can be absorbed from the small and the large intestine but not from the stomach of mice. The lethality of epsilon toxin was higher when this toxin was injected in the colon than in the small intestine. Low pH, and Na(+) and glucose added to the saline solution increased the toxicity of epsilon toxin injected into the small intestine. This study shows that absorption of epsilon toxin can occur in any intestinal segment of mice and that the physicochemical characteristics of the intestinal content can affect the absorption of this toxin.

Effects of gastric pH on oral drug absorption: In vitro assessment using a dissolution/permeation system reflecting the gastric dissolution process.

PubMed

Kataoka, Makoto; Fukahori, Miho; Ikemura, Atsumi; Kubota, Ayaka; Higashino, Haruki; Sakuma, Shinji; Yamashita, Shinji

2016-04-01

The aim of the present study was to evaluate the effects of gastric pH on the oral absorption of poorly water-soluble drugs using an in vitro system. A dissolution/permeation system (D/P system) equipped with a Caco-2 cell monolayer was used as the in vitro system to evaluate oral drug absorption, while a small vessel filled with simulated gastric fluid (SGF) was used to reflect the gastric dissolution phase. After applying drugs in their solid forms to SGF, SGF solution containing a 1/100 clinical dose of each drug was mixed with the apical solution of the D/P system, which was changed to fasted state-simulated intestinal fluid. Dissolved and permeated amounts on applied amount of drugs were then monitored for 2h. Similar experiments were performed using the same drugs, but without the gastric phase. Oral absorption with or without the gastric phase was predicted in humans based on the amount of the drug that permeated in the D/P system, assuming that the system without the gastric phase reflected human absorption with an elevated gastric pH. The dissolved amounts of basic drugs with poor water solubility, namely albendazole, dipyridamole, and ketoconazole, in the apical solution and their permeation across a Caco-2 cell monolayer were significantly enhanced when the gastric dissolution process was reflected due to the physicochemical properties of basic drugs. These amounts resulted in the prediction of higher oral absorption with normal gastric pH than with high gastric pH. On the other hand, when diclofenac sodium, the salt form of an acidic drug, was applied to the D/P system with the gastric phase, its dissolved and permeated amounts were significantly lower than those without the gastric phase. However, the oral absorption of diclofenac was predicted to be complete (96-98%) irrespective of gastric pH because the permeated amounts of diclofenac under both conditions were sufficiently high to achieve complete absorption. These estimations of the effects of gastric pH on the oral absorption of poorly water-soluble drugs were consistent with observations in humans. In conclusion, the D/P system with the gastric phase may be a useful tool for better predicting the oral absorption of poorly water-soluble basic drugs. In addition, the effects of gastric pH on the oral absorption of poorly water-soluble drugs may be evaluated by the D/P system with and without the gastric phase. Copyright © 2016 Elsevier B.V. All rights reserved.

Functional characterization of folic acid transport in the intestine of the laying hen using the everted intestinal sac model.

PubMed

Tactacan, G B; Rodriguez-Lecompte, J C; Karmin, O; House, J D

2011-01-01

Absorption at the level of the intestine is likely a primary regulatory mechanism for the deposition of dietary supplemented folic acid into the chicken egg. Therefore, factors affecting the intestinal transport of folic acid in the laying hen may influence the level of egg folate concentrations. To this end, a series of experiments using intestinal everted sacs were conducted to characterize intestinal folic acid absorption processes in laying hens. Effects of naturally occurring folate derivatives (5-methyl and 10-formyltetrahydrofolate) as well as heme on folic acid absorption were also investigated. Folic acid absorption was measured based on the rate of uptake of (3)H-labeled folic acid in the everted sac from various segments of the small and large intestines. Folic acid concentration, incubation length, and pH condition were optimized before the performance of uptake experiments. The distribution profile of folic acid transport along the intestine was highest in the upper half of the small intestine. Maximum uptake rate (nmol·100 g tissue(-1)·min(-1)) was observed in the duodenum (20.6 ± 1.9) and jejunum (22.3 ± 2.0) and decreased significantly in the ileum (15.3 ± 1.1) and cecum (9.3 ± 0.9). Transport increased proportionately (P < 0.05) between 0.0001 and 0.1 µM folic acid. Above 0.1 µM, the slope of the regression line was not significantly different from zero (P < 0.137). Folic acid uptake in the jejunum showed a maximum rate of transport at pH 6.0, but was lowest at pH 7.5. The presence of 5-methyl and 10-formyltetrahydrofolate as well as heme impeded folic acid uptake, reducing intestinal folic acid absorption when added at concentrations ranging from 0 to 100 µM. Overall, these data indicated the presence of a folic acid transport system in the entire intestine of the laying hen. Uptake of folic acid in the cecum raises the likelihood of absorption of bacterial-derived folate.

Role of the Small Intestine in Developmental Programming: Impact of Maternal Nutrition on the Dam and Offspring123

PubMed Central

Meyer, Allison M; Caton, Joel S

2016-01-01

Small-intestinal growth and function are critical for optimal animal growth and health and play a major role in nutrient digestion and absorption, energy and nutrient expenditure, and immunological competence. During fetal and perinatal development, the small intestine is affected by the maternal environment and nutrient intake. In ruminants, altered small-intestinal mass, villi morphology, hypertrophy, hyperplasia, vascularity, and gene expression have been observed as a result of poor gestational nutrition or intrauterine growth restriction. Although many of these data come from fetal stages, data have also demonstrated that nutrition during mid- and late gestation affects lamb small-intestinal growth, vascularity, digestive enzyme activity, and gene expression at 20 and 180 d of age as well. The small intestine is known to be a highly plastic tissue, changing with nutrient intake and physiological state even in adulthood, and the maternal small intestine adapts to pregnancy and advancing gestation. In ruminants, the growth, vascularity, and gene expression of the maternal small intestine also adapt to the nutritional plane and specific nutrient intake such as high selenium during pregnancy. These changes likely alter both pre- and postnatal nutrient delivery to offspring. More research is necessary to better understand the role of the offspring and maternal small intestines in whole-animal responses to developmental programming, but programming of this plastic tissue seems to play a dynamic role in gestational nutrition impacts on the whole animal. PMID:27180380

Food Chain Mycotoxin Exposure, Gut Health, and Impaired Growth: A Conceptual Framework1

PubMed Central

Smith, Laura E.; Stoltzfus, Rebecca J.; Prendergast, Andrew

2012-01-01

Childhood stunting is an important and intractable public health problem that underlies ∼20% of deaths among children aged <5 y in developing countries. Environmental enteropathy (EE), a subclinical condition of the small intestine characterized by reduced absorptive capacity and increased intestinal permeability, is almost universal among children in developing countries and may mediate stunting. However, the etiology of EE is poorly understood. Mycotoxins are metabolites of fungi that frequently contaminate the staple foods of children living in developing countries. We review evidence from human and animal studies that exposure to mycotoxins, particularly aflatoxin (AF), fumonisin (FUM), and deoxynivaenol (DON), may impair child growth. Although these toxins have distinct actions, they all mediate intestinal damage through: 1) inhibition of protein synthesis (AF, DON); 2) an increase in systemic proinflammatory cytokines (DON); and 3) inhibition of ceramide synthase (FUM). The intestinal pathology that arises from mycotoxin exposure is very similar to that of EE. We propose that future studies should address the role of mycotoxins in the pathogenesis of EE and evaluate interventions to limit mycotoxin exposure and reduce childhood stunting. PMID:22797988

ISX is a retinoic acid-sensitive gatekeeper that controls intestinal β,β-carotene absorption and vitamin A production

PubMed Central

Lobo, Glenn P.; Hessel, Susanne; Eichinger, Anne; Noy, Noa; Moise, Alexander R.; Wyss, Adrian; Palczewski, Krzysztof; von Lintig, Johannes

2010-01-01

The uptake of dietary lipids from the small intestine is a complex process that depends on the activities of specific membrane receptors with yet unknown regulatory mechanisms. Using both mouse models and human cell lines, we show here that intestinal lipid absorption by the scavenger receptor class B type 1 (SR-BI) is subject to control by retinoid signaling. Retinoic acid via retinoic acid receptors induced expression of the intestinal transcription factor ISX. ISX then repressed the expression of SR-B1 and the carotenoid-15,15′-oxygenase Bcmo1. BCMO1 acts downstream of SR-BI and converts absorbed β,β-carotene to the retinoic acid precursor, retinaldehyde. Using BCMO1-knockout mice, we demonstrated increased intestinal SR-BI expression and systemic β,β-carotene accumulation. SR-BI-dependent accumulation of β,β-carotene was prevented by dietary retinoids that induced ISX expression. Thus, our study revealed a diet-responsive regulatory network that controls β,β-carotene absorption and vitamin A production by negative feedback regulation. The role of SR-BI in the intestinal absorption of other dietary lipids, including cholesterol, fatty acids, and tocopherols, implicates retinoid signaling in the regulation of lipid absorption more generally and has clinical implications for diseases associated with dyslipidemia.—Lobo, G. P., Hessel, S., Eichinger, A., Noy, N., Moise, A. R., Wyss, A., Palczewski, K., von Lintig, J. ISX is a retinoic acid-sensitive gatekeeper that controls intestinal β,β-carotene absorption and vitamin A production. PMID:20061533

Effect of Vilon and Epithalon on glucose and glycine absorption in various regions of small intestine in aged rats.

PubMed

Khavinson, V Kh; Egorova, V V; Timofeeva, N M; Malinin, V V; Gordova, L A; Gromova, L V

2002-05-01

Vilon (Lys-Glu) and Epithalon (Ala-Glu-Asp-Gly) administered orally for 1 month improved transport characteristics of the small intestine in aged rats. Vilon enhanced passive glucose accumulation in the serous fluid in inverted sac made from the distal region of the small intestine, while Epithalon enhanced this process in the medial region. Vilon stimulated active glucose accumulation in the serous sac of the medial small intestine, Epithalon - in the proximal and distal small intestinal segments. Glycine absorption increased only in the proximal intestinal segment under the effect of Epithalon.

Absorption of calcium and magnesium in patients with intestinal resections treated with medium chain fatty acids

PubMed Central

Haderslev, K; Jeppesen, P; Mortensen, P; Staun, M

2000-01-01

BACKGROUND—Steatorrhoea is associated with increased faecal loss of calcium and magnesium. Medium chain C8-C10 triglycerides (MCTs) improve fat absorption in patients with small bowel resections but the effects on intestinal absorption of divalent cations are not clear.
AIM—To assess the effect of dietary replacement of long chain triglycerides (LCTs) with MCTs on calcium and magnesium absorption in patients with small bowel resections.
PATIENTS—Nineteen adult patients with a remaining small intestine averaging 171 cm (range 50-300).
METHODS—In a crossover design, patients were randomised to two high fat diets (10 MJ/day, 50% as fat) for four days each separated by one day of washout. Diets were prepared in duplicate and were based on either LCT (LCT period) or equal quantities of LCT and MCT (L/MCT period). Metabolic balances were calculated during the last three days of each period.
RESULTS—Mean stool volume increased significantly with the L/MCT diet and was 336 ml more than that with the LCT diet (95% confidence interval of mean difference, 26-649 ml). There was no significant change in the net absorption of calcium and magnesium between the two diets. On average, percentage calcium absorption was 8.6% with the LCT diet and 12.5% with the L/MCT diet. Mean percentage magnesium absorption was 5.4% with the LCT diet and 2.9% with the L/MCT diet.
CONCLUSIONS—Dietary replacement of 50% long chain triglycerides with medium chain triglycerides in small bowel resected patients increased faecal volume significantly. No changes in the intestinal net absorption of calcium and magnesium were demonstrated.


Keywords: medium chain triglycerides; calcium absorption; magnesium absorption; intestinal resections; fat absorption PMID:10807894

Intestinal absorption of water-soluble vitamins in health and disease.

PubMed

Said, Hamid M

2011-08-01

Our knowledge of the mechanisms and regulation of intestinal absorption of water-soluble vitamins under normal physiological conditions, and of the factors/conditions that affect and interfere with theses processes has been significantly expanded in recent years as a result of the availability of a host of valuable molecular/cellular tools. Although structurally and functionally unrelated, the water-soluble vitamins share the feature of being essential for normal cellular functions, growth and development, and that their deficiency leads to a variety of clinical abnormalities that range from anaemia to growth retardation and neurological disorders. Humans cannot synthesize water-soluble vitamins (with the exception of some endogenous synthesis of niacin) and must obtain these micronutrients from exogenous sources. Thus body homoeostasis of these micronutrients depends on their normal absorption in the intestine. Interference with absorption, which occurs in a variety of conditions (e.g. congenital defects in the digestive or absorptive system, intestinal disease/resection, drug interaction and chronic alcohol use), leads to the development of deficiency (and sub-optimal status) and results in clinical abnormalities. It is well established now that intestinal absorption of the water-soluble vitamins ascorbate, biotin, folate, niacin, pantothenic acid, pyridoxine, riboflavin and thiamin is via specific carrier-mediated processes. These processes are regulated by a variety of factors and conditions, and the regulation involves transcriptional and/or post-transcriptional mechanisms. Also well recognized now is the fact that the large intestine possesses specific and efficient uptake systems to absorb a number of water-soluble vitamins that are synthesized by the normal microflora. This source may contribute to total body vitamin nutrition, and especially towards the cellular nutrition and health of the local colonocytes. The present review aims to outline our current understanding of the mechanisms involved in intestinal absorption of water-soluble vitamins, their regulation, the cell biology of the carriers involved and the factors that negatively affect these absorptive events. © The Authors Journal compilation © 2011 Biochemical Society

Intestinal absorption of water-soluble vitamins in health and disease

PubMed Central

Said, Hamid M.

2014-01-01

Our knowledge of the mechanisms and regulation of intestinal absorption of water-soluble vitamins under normal physiological conditions, and of the factors/conditions that affect and interfere with theses processes has been significantly expanded in recent years as a result of the availability of a host of valuable molecular/cellular tools. Although structurally and functionally unrelated, the water-soluble vitamins share the feature of being essential for normal cellular functions, growth and development, and that their deficiency leads to a variety of clinical abnormalities that range from anaemia to growth retardation and neurological disorders. Humans cannot synthesize water-soluble vitamins (with the exception of some endogenous synthesis of niacin) and must obtain these micronutrients from exogenous sources. Thus body homoeostasis of these micronutrients depends on their normal absorption in the intestine. Interference with absorption, which occurs in a variety of conditions (e.g. congenital defects in the digestive or absorptive system, intestinal disease/resection, drug interaction and chronic alcohol use), leads to the development of deficiency (and sub-optimal status) and results in clinical abnormalities. It is well established now that intestinal absorption of the water-soluble vitamins ascorbate, biotin, folate, niacin, pantothenic acid, pyridoxine, riboflavin and thiamin is via specific carrier-mediated processes. These processes are regulated by a variety of factors and conditions, and the regulation involves transcriptional and/or post-transcriptional mechanisms. Also well recognized now is the fact that the large intestine possesses specific and efficient uptake systems to absorb a number of water-soluble vitamins that are synthesized by the normal microflora. This source may contribute to total body vitamin nutrition, and especially towards the cellular nutrition and health of the local colonocytes. The present review aims to outline our current understanding of the mechanisms involved in intestinal absorption of water-soluble vitamins, their regulation, the cell biology of the carriers involved and the factors that negatively affect these absorptive events. PMID:21749321

Mitochondrial dysfunction is responsible for the intestinal calcium absorption inhibition induced by menadione.

PubMed

Marchionatti, Ana M; Perez, Adriana V; Diaz de Barboza, Gabriela E; Pereira, Beatriz M; Tolosa de Talamoni, Nori G

2008-02-01

Menadione (MEN) inhibits intestinal calcium absorption by a mechanism not completely understood. The aim of this work was to find out the role of mitochondria in this inhibitory mechanism. Hence, normal chicks treated with one i.p. dose of MEN were studied in comparison with controls. Intestinal calcium absorption was measured by the in situ ligated intestinal segment technique. GSH, oxidoreductase activities from the Krebs cycle and enzymes of the antioxidant system were measured in isolated mitochondria. Mitochondrial membrane potential was measured by a flow cytometer technique. DNA fragmentation and cytochrome c localization were determined by immunocytochemistry. Data indicate that in 30 min, MEN decreases intestinal Ca(2+) absorption, which returns to the control values after 10 h. GSH was only decreased for half an hour, while the activity of malate dehydrogenase and alpha-ketoglutarate dehydrogenase was diminished for 48 h. Mn(2+)-superoxide dismutase activity was increased in 30 min, whereas the activity of catalase and glutathione peroxidase remained unaltered. DNA fragmentation and cytochrome c release were maximal in 30 min, but were recovered after 15 h. In conclusion, MEN inhibits intestinal Ca(2+) absorption by mitochondrial dysfunction as revealed by GSH depletion and alteration of the permeability triggering the release of cytochrome c and DNA fragmentation.

Prediction of drug intestinal absorption in human using the Ussing chamber system: A comparison of intestinal tissues from animals and humans.

PubMed

Miyake, Masateru; Koga, Toshihisa; Kondo, Satoshi; Yoda, Noriaki; Emoto, Chie; Mukai, Tadashi; Toguchi, Hajime

2017-01-01

An adequate evaluation system for drug intestinal absorption is essential in the pharmaceutical industry. Previously, we established a novel prediction system of drug intestinal absorption in humans, using the mini-Ussing chamber equipped with human intestinal tissues. In this system, the TI value was defined as the sum of drug amounts transported to the basal-side component (X corr ) and drug amounts accumulated in the tissue (T corr ), which are normalized by AUC of a drug in the apical compartment, as an index for drug absorption. In order to apply this system to the screening assay, it is important to understand the differences between animal and human tissues in the intestinal absorption of drugs. In this study, the transport index (TI) values of three drugs, with different levels of membrane permeability, were determined to evaluate the rank order of drug absorbability in intestinal tissues from rats, dogs, and monkeys. The TI values in small intestinal tissues in rats and dogs showed a good correlation with those in humans. On the other hand, the correlation of TI values in monkeys was lower compared to rats and dogs. The rank order of the correlation coefficient between human and investigated animal tissues was as follows: dog (r 2 =0.978), rat (r 2 =0.955), and monkey (r 2 =0.620). TI values in large intestinal tissues from rats (r 2 =0.929) and dogs (r 2 =0.808) also showed a good correlation. The obtained TI values in small intestinal tissues in rats and dogs were well correlated with the fraction of drug absorbed (F a ) in humans. From these results, the mini-Ussing chamber, equipped with intestinal tissues in rats and dogs, would be useful as a screening tool in the drug discovery stage. In addition, the obtained TI values can be used for the prediction of the F a in humans. Copyright © 2016 Elsevier B.V. All rights reserved.

Synergistic role of solid lipid and porous silica in improving the oral delivery of weakly basic poorly water soluble drugs.

PubMed

Yasmin, Rokhsana; Rao, Shasha; Bremmell, Kristen; Prestidge, Clive

2017-01-01

Oral absorption of weakly basic drugs (e.g. cinnarizine (CIN)) is limited by their pH dependent precipitation in intestinal conditions. To overcome this challenge, a novel drug delivery system composed of solid lipid and porous silica, namely silica encapsulated solid lipid (SESL) particles, was developed via hot homogenization of melted lipid dispersion, followed by ultra-sonication of the silica stabilized homogenized melted lipid dispersion. Scanning electron microscope (SEM) images of the SESL formulation revealed non-spherical and aggregated hybrid particles, with rough exterior and structured nanoparticles visible on the surface. A 1.5, 2.2 and 7-fold improvement in the dissolution of CIN was observed for the SESL particles, under simulated intestinal non-digesting conditions, in comparison to the drug loaded in solid lipid (CIN-SL) matrix, drug loaded in porous silica (CIN-PS) and pure drug powder. Under simulated intestinal digestive condition, significant improvement in the drug solubilization was reported for the SESL formulation in compared to the individual drug loaded systems i.e. CIN-PS and CIN-SL. Thereby, silica encapsulated solid lipid system provides a promising oral delivery approach for poorly water soluble weakly basic drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

A New Type of Liquid Silymarin Proliposome Containing Bile Salts: Its Preparation and Improved Hepatoprotective Effects.

PubMed

Wang, Mei; Xie, Tingting; Chang, Zhanying; Wang, Ling; Xie, Xiangyun; Kou, Yaohong; Xu, Hongxia; Gao, Xiaoli

2015-01-01

Silymarin, a known extract, is used in the treatment of liver diseases with various origins, but its current administration form cannot target the liver because of its poor oral bioavailability. A new type of oral silymarin proliposome aimed at improving silymarin's poor bioavailability and hepatoprotective effects, is introduced in this work. Silymarin-loaded liquid proliposome were prepared using a simple dissolving process. The morphology, particle size, zeta potential, and entrapment efficiency of the silymarin liposomes were analysed. The everted gut sac transport model was used to measure the intestinal transport of liposomes. The liposomal hepatoprotective activity was evaluated in three types of experimental hepatitis animal models. After staining with haematoxylin and eosin, the livers were microscopically examined to analyse any pathological changes. The prepared silymarin proliposome formed silymarin liposomes with a multilayer liposome structure and improved intestinal transport. In an injured liver, the silymarin liposomes produced a stronger hepatoprotective effect through a significant decrease in both the aminotransferase and MDA levels and a significant increase in the SOD and GSH-PX levels compared to orally administered silymarin tablets. This effect was also confirmed histopathologically. In a word, incorporation of silymarin into a liposomal carrier system increased intestinal absorption and showed better hepatoprotective effects compared to silymarin tablets.

A New Type of Liquid Silymarin Proliposome Containing Bile Salts: Its Preparation and Improved Hepatoprotective Effects

PubMed Central

Chang, Zhanying; Wang, Ling; Xie, Xiangyun; Kou, Yaohong; Xu, Hongxia; Gao, Xiaoli

2015-01-01

Silymarin, a known extract, is used in the treatment of liver diseases with various origins, but its current administration form cannot target the liver because of its poor oral bioavailability. A new type of oral silymarin proliposome aimed at improving silymarin’s poor bioavailability and hepatoprotective effects, is introduced in this work. Silymarin-loaded liquid proliposome were prepared using a simple dissolving process. The morphology, particle size, zeta potential, and entrapment efficiency of the silymarin liposomes were analysed. The everted gut sac transport model was used to measure the intestinal transport of liposomes. The liposomal hepatoprotective activity was evaluated in three types of experimental hepatitis animal models. After staining with haematoxylin and eosin, the livers were microscopically examined to analyse any pathological changes. The prepared silymarin proliposome formed silymarin liposomes with a multilayer liposome structure and improved intestinal transport. In an injured liver, the silymarin liposomes produced a stronger hepatoprotective effect through a significant decrease in both the aminotransferase and MDA levels and a significant increase in the SOD and GSH-PX levels compared to orally administered silymarin tablets. This effect was also confirmed histopathologically. In a word, incorporation of silymarin into a liposomal carrier system increased intestinal absorption and showed better hepatoprotective effects compared to silymarin tablets. PMID:26674103

A review of advanced oral drug delivery technologies facilitating the protection and absorption of protein and peptide molecules.

PubMed

Choonara, Bibi F; Choonara, Yahya E; Kumar, Pradeep; Bijukumar, Divya; du Toit, Lisa C; Pillay, Viness

2014-11-15

The oral delivery of proteins and peptides is a dynamic research field despite the numerous challenges limiting their effective delivery. Successful oral delivery of proteins and peptides requires the accomplishment of three key tasks: protection of the macromolecules from degradation in the gastrointestinal tract (GIT), permeation through the intestinal barrier and absorption of molecules into the systemic circulation. Currently, no clinically useful oral formulations have been developed but several attempts have been made to overcome the challenges of low oral bioavailability resulting from poor absorption, poor permeation and enzymatic degradation of the proteins and peptides in the GIT. Present strategies attempt to provide structural protection of the proteins and peptides and improved absorption through the use of enzyme inhibitors, absorption enhancers, novel polymeric delivery systems and chemical modification. However, each of these technologies has their limitations despite showing positive results. This review attempts to discuss the physical and chemical barriers of the GIT with particular emphasis on the current approaches employed to overcome these barriers, including the evaluation of other non-parenteral routes of protein and peptide delivery. In addition, this review assimilates oral formulation strategies under development and within the clinical trial stage in relation to their benefits and drawbacks with regard to facilitating optimal protection and absorption of proteins and peptides, as well as pertinent future challenges and opportunities governing oral drug delivery. Copyright © 2014 Elsevier Inc. All rights reserved.

Lactobacillus gasseri in the Upper Small Intestine Impacts an ACSL3-Dependent Fatty Acid-Sensing Pathway Regulating Whole-Body Glucose Homeostasis.

PubMed

Bauer, Paige V; Duca, Frank A; Waise, T M Zaved; Dranse, Helen J; Rasmussen, Brittany A; Puri, Akshita; Rasti, Mozhgan; O'Brien, Catherine A; Lam, Tony K T

2018-03-06

Long-chain acyl-CoA synthetase (ACSL)-dependent upper small intestinal lipid metabolism activates pre-absorptive pathways to regulate metabolic homeostasis, but whether changes in the upper small intestinal microbiota alter specific fatty acid-dependent pathways to impact glucose homeostasis remains unknown. We here first find that upper small intestinal infusion of Intralipid, oleic acid, or linoleic acid pre-absorptively increases glucose tolerance and lowers glucose production in rodents. High-fat feeding impairs pre-absorptive fatty acid sensing and reduces upper small intestinal Lactobacillus gasseri levels and ACSL3 expression. Transplantation of healthy upper small intestinal microbiota to high-fat-fed rodents restores L. gasseri levels and fatty acid sensing via increased ACSL3 expression, while L. gasseri probiotic administration to non-transplanted high-fat-fed rodents is sufficient to restore upper small intestinal ACSL3 expression and fatty acid sensing. In summary, we unveil a glucoregulatory role of upper small intestinal L. gasseri that impacts an ACSL3-dependent glucoregulatory fatty acid-sensing pathway. Copyright © 2018 Elsevier Inc. All rights reserved.

Stimulation of Intestinal Cl- Secretion Through CFTR by Caffeine Intake in Salt-Sensitive Hypertensive Rats.

PubMed

Wei, Xiao; Lu, Zongshi; Yang, Tao; Gao, Peng; Chen, Sijiao; Liu, Daoyan; Zhu, Zhiming

2018-03-16

High salt consumption is a major risk factor for hypertension, and sodium homeostasis is regulated by both intestinal sodium absorption and urinary sodium excretion. Chronic caffeine intake has been reported to attenuate salt-sensitive hypertension by promoting urinary sodium excretion; however, its exact role in intestinal sodium absorption remains unknown. Here, we investigated whether and how chronic caffeine consumption antagonizes salt-sensitive hypertension by inhibiting intestinal sodium absorption. Dahl salt-sensitive rats were fed 8% NaCl chow and 0.1% caffeine in their drinking water for 15 days. The blood pressure and fecal sodium content were measured. The effect of caffeine on the movement of Cl- in enterocyte cells was determined with the Ussing chamber assay. Rats that were treated with caffeine displayed significantly lower mean blood pressure and higher fecal sodium content than the controls. Consistent with these findings, caffeine intake decreased fluid absorption by the intestine in the fluid perfusion experiment. Further, the results from the Ussing chamber assay indicated that caffeine promoted Cl- secretion through enterocyte apical cystic fibrosis transmembrane conductance regulator (CFTR), and thus inhibited sodium absorption. Moreover, depletion of cAMP or inhibition of CFTR completely abolished the effect of caffeine on Cl- secretion. The results indicate that chronic caffeine consumption reduces sodium absorption by promoting CFTR-mediated Cl- secretion in the intestine, which contributes to the anti-hypertensive effect of caffeine in salt-sensitive rats. © 2018 The Author(s). Published by S. Karger AG, Basel.

Impact of Calcium Intake and Intestinal Calcium Absorption on Kidney Stones in Older Women: The Study of Osteoporotic Fractures (SOF)

PubMed Central

Sorensen, Mathew D.; Eisner, Brian H.; Stone, Katie L.; Kahn, Arnold J.; Lui, Li-Yung; Sadetsky, Natalia; Stoller, Marshall L.

2013-01-01

Purpose Intestinal calcium absorption is thought to play a critical role in nephrolithiasis; however, no study has directly assessed this association. The purpose of this study was to explore the relationship between intestinal fractional calcium absorption, calcium intake, and nephrolithiasis. Materials and Methods The Study of Osteoporotic Fractures is a prospective cohort of 9704 post-menopausal women recruited from population-based listings in 1986 and followed for more than 20 years. Secondary analyses were performed of 7982 women who reported their history of nephrolithiasis, of which 5452 (68%) underwent oral radioactive calcium assay (45Ca). The impact of dietary and supplemental calcium on intestinal fractional calcium absorption was evaluated and factors independently associated with nephrolithiasis were determined. Results Fractional calcium absorption decreased with increased calcium intake, with no difference between dietary and supplemental calcium. Fractional calcium absorption was higher in women with a nephrolithiasis history among all calcium intake groups. Increased dietary calcium intake reduced the likelihood of nephrolithiasis by 45–54% (p=0.03). Women with a history of nephrolithiasis were less likely to supplement calcium (p<0.001). In adjusted analyses, women who supplemented calcium were 21–38% less likely to have a nephrolithiasis history (p=0.007) and there was a 24% increased risk of kidney stones for each 10% increase in fractional calcium absorption (p=0.008). Conclusions Fractional calcium absorption is higher in women with a history of nephrolithiasis. Higher intestinal fractional calcium absorption is associated with a greater risk of historic nephrolithiasis. Dietary and supplemental calcium decrease fractional calcium absorption and may protect against nephrolithiasis. PMID:22341269

Impact of calcium intake and intestinal calcium absorption on kidney stones in older women: the study of osteoporotic fractures.

PubMed

Sorensen, Mathew D; Eisner, Brian H; Stone, Katie L; Kahn, Arnold J; Lui, Li-Yung; Sadetsky, Natalia; Stoller, Marshall L

2012-04-01

Intestinal calcium absorption is thought to have a critical role in nephrolithiasis. However, to our knowledge no study has directly assessed this association. Therefore, we explored the relationship among intestinal fractional calcium absorption, calcium intake and nephrolithiasis. The Study of Osteoporotic Fractures is a prospective cohort of 9,704 postmenopausal women recruited from population based listings in 1986 and followed for more than 20 years. Secondary analyses were performed of 7,982 women who reported their history of nephrolithiasis, of which 5,452 (68%) underwent an oral radioactive calcium assay (45Ca). The impact of dietary and supplemental calcium on intestinal fractional calcium absorption was evaluated, and factors independently associated with nephrolithiasis were determined. Fractional calcium absorption decreased with increased calcium intake, with no difference between dietary and supplemental calcium. Fractional calcium absorption was higher in women with a nephrolithiasis history among all calcium intake groups. Increased dietary calcium intake reduced the likelihood of nephrolithiasis by 45% to 54% (p=0.03). Women with a history of nephrolithiasis were less likely to supplement calcium (p<0.001). In adjusted analyses women who supplemented calcium were 21% to 38% less likely to have a nephrolithiasis history (p=0.007) and there was a 24% increased risk of kidney stones for each 10% increase in fractional calcium absorption (p=0.008). Fractional calcium absorption is higher in women with a history of nephrolithiasis. Higher intestinal fractional calcium absorption is associated with a greater risk of historical nephrolithiasis. Dietary and supplemental calcium decrease fractional calcium absorption, and may protect against nephrolithiasis. Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

An in vitro study of urea, water, ion and CO2/HCO3- transport in the gastrointestinal tract of the dogfish shark (Squalus acanthias): the influence of feeding.

PubMed

Liew, Hon Jung; De Boeck, Gudrun; Wood, Chris M

2013-06-01

In vitro gut sac preparations made from the cardiac stomach (stomach 1), pyloric stomach (stomach 2), intestine (spiral valve) and colon were used to examine the impact of feeding on transport processes in the gastrointestinal tract of the dogfish shark. Preparations were made from animals that were euthanized after 1-2 weeks of fasting, or at 24-48 h after voluntary feeding on a 3% ration of teleost fish (hake). Sacs were incubated under initially symmetrical conditions with dogfish saline on both surfaces. In comparison to an earlier in vivo study, the results confirmed that feeding caused increases in H(+) secretion in both stomach sections, but an increase in Cl(-) secretion only in stomach 2. Na(+) absorption, rather than Na(+) secretion, occurred in both stomach sections after feeding. All sections of the tract absorbed water and the intestine strongly absorbed Na(+) and Cl(-), regardless of feeding condition. The results also confirmed that feeding increased water absorption in the intestine (but not in the colon), and had little influence on the handling of Ca(2+) and Mg(2+), which exhibited negligible absorption across the tract. However, K(+) was secreted in the intestine in both fasted and fed preparations. Increased intestinal water absorption occurred despite net osmolyte secretion into the mucosal saline. The largest changes occurred in urea and CO2/HCO3(-) fluxes. In fasted preparations, urea was absorbed at a low rate in all sections except the intestine, where it was secreted. Instead of an increase in intestinal urea secretion predicted from in vivo data, feeding caused a marked switch to net urea absorption. This intestinal urea transport occurred at a rate comparable to urea reabsorption rates reported at gills and kidney, and was apparently active, establishing a large serosal-to-mucosal concentration gradient. Feeding also greatly increased intestinal CO2/HCO3(-) secretion; if interpreted as HCO3(-) transport, the rates were in the upper range of those reported in marine teleosts. Phloretin (0.25 mmol l(-1), applied mucosally) completely blocked the increases in intestinal urea absorption and CO2/HCO3(-) secretion caused by feeding, but had no effect on Na(+), Cl(-) or water absorption.

Lecithin inhibits fatty acid and bile salt absorption from rat small intestine in vivo.

PubMed

Saunders, D R; Sillery, J

1976-12-01

During digestion of a fatty meal, long chain free fatty acids (FFA) and lecithin are among the lipids solubilized in intestinal contents as mixed micelles with bile salts. We hypothesized that if lecithin were not hydrolyzed, the mixed micelles would be abnormal, and absorption of FFA and bile salts would be depressed. To test this hypothesis, isolated segments of rat small intestine were infused in vivo with micellar solutions of 2 mMolar linoleic acid and 10 mMolar taurocholate to which was added 3 mMolar 1-palmitoyl, 2-oleoyl lecithin (a common lecithin in bile and food), or 1-palmitoyl lysolecithin (the hydrolytic product of lecithin). Absorption of FFA and bile salt was measured under steady state conditions using a single-pass technique. Lecithin depressed the rate of FFA absorption by 40% (p less than 0.025) in jejunal and ileal segments whereas lysolecithin was associated with normal rates of FFA absorption. Lecithin also reduced taurocholate absorption from the ileum by 30% (p less than 0.05). These data support the idea that lecithin may depress FFA and bile salt absorption from the small intestine in pancreatic insufficiency.

Maltitol inhibits small intestinal glucose absorption and increases insulin mediated muscle glucose uptake ex vivo but not in normal and type 2 diabetic rats.

PubMed

Chukwuma, Chika Ifeanyi; Ibrahim, Mohammed Auwal; Islam, Md Shahidul

2017-02-01

This study investigated the effects of maltitol on intestinal glucose absorption and muscle glucose uptake using ex vivo and in vivo experimental models. The ex vivo experiment was conducted in isolated jejunum and psoas muscle from normal rats. The in vivo study investigated the effects of a single bolus dose of maltitol on gastric emptying, intestinal glucose absorption and digesta transit in normal and type 2 diabetic rats. Maltitol inhibited glucose absorption in isolated rat jejunum and increased glucose uptake in isolated rat psoas muscle in the presence of insulin but not in the absence of insulin. In contrast, maltitol did not significantly (p > 0.05) alter small intestinal glucose absorption or blood glucose levels as well as gastric emptying and digesta transit in normal or type 2 diabetic rats. The results suggest that maltitol may not be a suitable dietary supplement for anti-diabetic food and food products to improve glycemic control.

[Everted intestinal sac method for quick finding absorption ingredients of Wuzhuyu decoction].

PubMed

Gong, Muxin; Wang, Yaxun; Song, Yafang; Wang, Zhimin; Zhang, Qiwei; Wang, Weihao; Zhu, Jingjing

2010-06-01

To establish a method for quick finding the absorption ingredients of Wuzhuyu decoction in order to select the index to control its quality. The absorption of three concentration of Wuzhuyu decotion was investigated with the in vitro-everted intestinal sac model. The intestinal bag fluid of jejunum and ileum were collected in different time and the eight ingredients, which were evodiamine (Ev), rutaecarpine (Ru), limonin (Li), ginsenoside-Rb1, -Rg1, -Re (Rb1, Rg1, Re), isorhamnetin-3-O-beta-D-glucosyl(6''-->1'")-alpha-L-rhamnoside (Irs)and 6-gingerol (6-Gi), were detected by HPLC as the represent constituents in samples. Eight ingredients except Ru in samples could be detected, but Ev could not be detected in high concentration samples. The ratios between absorption ingredients were different from in Wuzhuyu decotion. The in vitro-everted intestinal sac canc absorb the ingredients of Wuzhuyu decotion selectivity. Compare with the ileum, the jejunum can provide the more absorption information and faster, the best test time is 60-90 min.

Intestinal absorption of dideoxynucleosides: characterization using a multiloop in situ technique.

PubMed

Mirchandani, H L; Chien, Y W

1995-01-01

The intestinal absorption of dideoxynucleosides was studied in rabbits, using a closed-loop mesenteric-sampling in situ technique developed in this laboratory, and the kinetic profiles were characterized. Each of the dideoxynucleosides exhibited different dependence on the intestinal regions studied: 3'-azido-2',3'-dideoxythymidine was best absorbed from the ileum, while 2',3'-dideoxyinosine and 2',3'-dideoxycytidine were preferentially absorbed from the jejunum. The results were validated by the mass-balance approach; the percent of drug retained in the intestinal lumen and that degraded at the intestinal pH, by colonic flora, in the intestinal tissue, and in plasma were assessed.

An Assessment of the Intestinal Lumen as a Site for Intervention in Reducing Body Burdens of Organochlorine Compounds

PubMed Central

Jandacek, Ronald J.; Genuis, Stephen J.

2013-01-01

Many individuals maintain a persistent body burden of organochlorine compounds (OCs) as well as other lipophilic compounds, largely as a result of airborne and dietary exposures. Ingested OCs are typically absorbed from the small intestine along with dietary lipids. Once in the body, stored OCs can mobilize from adipose tissue storage sites and, along with circulating OCs, are delivered into the small intestine via hepatic processing and biliary transport. Retained OCs are also transported into both the large and small intestinal lumen via non-biliary mechanisms involving both secretion and desquamation from enterocytes. OCs and some other toxicants can be reabsorbed from the intestine, however, they take part in enterohepatic circulation(EHC). While dietary fat facilitates the absorption of OCs from the small intestine, it has little effect on OCs within the large intestine. Non-absorbable dietary fats and fat absorption inhibitors, however, can reduce the re-absorption of OCs and other lipophiles involved in EHC and may enhance the secretion of these compounds into the large intestine—thereby hastening their elimination. Clinical studies are currently underway to determine the efficacy of using non-absorbable fats and inhibitors of fat absorption in facilitating the elimination of persistent body burdens of OCs and other lipophilic human contaminants. PMID:23476122

Distinct intestinal adaptation for vitamin B12 and bile acid absorption revealed in a new mouse model of massive ileocecal resection.

PubMed

Matsumoto, Yuka; Mochizuki, Wakana; Akiyama, Shintaro; Matsumoto, Taichi; Nozaki, Kengo; Watanabe, Mamoru; Nakamura, Tetsuya

2017-09-15

Ileocecal resection (ICR), one of several types of intestinal resection that results in short bowel syndrome (SBS), causes severe clinical disease in humans. We here describe a mouse model of massive ICR in which 75% of the distal small intestine is removed. We demonstrate that mice underwent 75% ICR show severe clinical signs and high mortality, which may recapitulate severe forms of human SBS, despite an adaptive response throughout the remnant intestine. By using this model, we also investigated whether the epithelium of the remnant intestine shows enhanced expression of factors involved in region-specific functions of the ileum. Cubn mRNA and its protein product, which play an essential role in vitamin B12 absorption in the ileum, are not compensatory up-regulated in any part of the remnant intestine, demonstrating a clear contrast with post-operative up-regulation of genes involved in bile acid absorption. Our study suggests that functional adaptation by phenotypical changes in the intestinal epithelium is not a general feature for nutrient absorption systems that are confined to the ileum. We also propose that the mouse model developed in this study will become a unique system to facilitate studies on SBS with ICR in humans. © 2017. Published by The Company of Biologists Ltd.

Transcellular oxalate and Cl− absorption in mouse intestine is mediated by the DRA anion exchanger Slc26a3, and DRA deletion decreases urinary oxalate

PubMed Central

Freel, Robert W.; Whittamore, Jonathan M.

2013-01-01

Active transcellular oxalate transport in the mammalian intestine contributes to the homeostasis of this important lithogenic anion. Several members of the Slc26a gene family of anion exchangers have a measurable oxalate affinity and are expressed along the gut, apically and basolaterally. Mouse Slc26a6 (PAT1) targets to the apical membrane of enterocytes in the small intestine, and its deletion results in net oxalate absorption and hyperoxaluria. Apical exchangers of the Slc26a family that mediate oxalate absorption have not been established, yet the Slc26a3 [downregulated in adenoma (DRA)] protein is a candidate mediator of oxalate uptake. We evaluated the role of DRA in intestinal oxalate and Cl− transport by comparing unidirectional and net ion fluxes across short-circuited segments of small (ileum) and large (cecum and distal colon) intestine from wild-type (WT) and DRA knockout (KO) mice. In WT mice, all segments demonstrated net oxalate and Cl− absorption to varying degrees. In KO mice, however, all segments exhibited net anion secretion, which was consistently, and solely, due to a significant reduction in the absorptive unidirectional fluxes. In KO mice, daily urinary oxalate excretion was reduced 66% compared with that in WT mice, while urinary creatinine excretion was unchanged. We conclude that DRA mediates a predominance of the apical uptake of oxalate and Cl− absorbed in the small and large intestine of mice under short-circuit conditions. The large reductions in urinary oxalate excretion underscore the importance of transcellular intestinal oxalate absorption, in general, and, more specifically, the importance of the DRA exchanger in oxalate homeostasis. PMID:23886857

Investigation of the effective components of the flowers of Trollius chinensis from the perspectives of intestinal bacterial transformation and intestinal absorption.

PubMed

Guo, Lina; Qiao, Shanshan; Hu, Junhong; Li, Deli; Zheng, Shiqi; Shi, Duozhi; Liu, Junxiu; Wang, Rufeng

2017-12-01

The flowers of Trollius chinensis Bunge (Ranunculaceae), used for respiratory tract infections, mainly contain flavonoids, phenolic acids, and alkaloids; however, the effective components are debatable because of their unclear in vivo activities. This study investigates the effective components from the perspectives of biotransformation and absorption. Both single person derived- and multiple people-derived intestinal florae were used to investigate the biotransformation of aqueous extract of the flowers of T. chinensis (AEOF) at the concentrations of 15.0, 30.0, and 60.0 mg/mL, respectively, for 72 h. Both human colon adenocarcinoma cell line (Caco-2) monolayers and everted gut sacs were employed to evaluate the intestinal absorption of the intestinal bacterial transformed AEOF at the concentrations of 10, 20, and 30 mg/mL, respectively, for 180 min. 2″-O-β-l-Galactopyranosylorientin, orientin, vitexin, quercetin, veratric acid, proglobeflowery acid, and trolline in AEOF were not transformed by intestinal bacteria, while isoquercetin and trollioside were completely transformed. The P app values of 2″-O-β-l-galactopyranosylorientin, orientin, and vitexin calculated based on the experimental data of intestinal absorption were at the levels of 10 -5 , whereas those of veratric acid, proglobeflowery acid, and trolline were at 10 -4 . The mass ratio of flavonoids to phenolic acids to alkaloids changed from 16:10:7 to 9:12:8 before and after absorption. The dominant position of flavonoids was replaced by phenolic acids after absorption. In addition to flavonoids which are usually considered as the dominant effective ones, phenolic acids and alkaloids should be also very important for the efficacy of these flowers.

A Comparison of mucosal surface area and villous histology in small intestines of the Brazilian free-tailed bat (Tadarida brasiliensis) and the mouse (Mus musculus).

PubMed

Zhang, Zhi-Qiang; Brun, Antonio; Price, Edwin R; Cruz-Neto, Ariovaldo P; Karasov, William H; Caviedes-Vidal, Enrique

2015-01-01

Studies on birds have led to the hypothesis that increased intestinal absorption between enterocytes (paracellular) evolved as a compensation for smaller intestinal size in fliers, which was perhaps selected to minimize the mass of digesta carried. This hypothesis predicts that bats will also exhibit relatively reduced intestinal size and high paracellular absorption, compared with nonflying mammals. Published studies on three bat species indicate relatively high paracellular absorption. One mechanism for increasing paracellular absorption per cm2 small intestine (SI) is increased number of tight junctions (TJs) across which paracellular absorption occurs. To our knowledge, we provide the first comparative analysis of enterocyte size and number in flying and nonflying mammals. Intestines of insectivorous bats Tadarida brasiliensis were compared with Mus musculus using hematoxylin and eosin staining method. Bats had shorter and narrower SIs than mice, and after correction for body size difference by normalizing to mass3/4, the bats had 40% less nominal surface area than the mouse, as predicted. Villous enhancement of surface area was 90% greater in the bat than in the mouse, mainly because of longer villi and a greater density of villi in bat intestines. Bat and mouse were similar in enterocyte diameter. Bats exceeded mice by 54.4% in villous area per cm length SI and by 95% in number of enterocytes per cm2 of the nominal surface area of the SI. Therefore, an increased density of TJs per cm2 SI may be a mechanistic explanation that helps to understand the high paracellular absorption observed in bats compared to nonflying mammals. © 2014 Wiley Periodicals, Inc.

Improvement of intestinal transport, absorption and anti-diabetic efficacy of berberine by using Gelucire44/14: In vitro, in situ and in vivo studies.

PubMed

Sun, Jianmei; Bao, He; Peng, Yajie; Zhang, Haimin; Sun, Ya; Qi, Jiajun; Zhang, Hailong; Gao, Yang

2018-06-10

This study aims to evaluate the effects of Gelucire44/14 on the in vitro transport, in situ intestinal absorption, as well as in vivo antidiabetic efficacy of berberine (BBR). In the in vitro study, Gelucire44/14 (0.1%, v/v) increased the absorptive transport of BBR across the intestinal membrane of a rat and reduced the relative transport in the secretory direction, thus demonstrating its potential inhibitory effect on intestinal P-glycoprotein (P-gp). In the in situ absorption study, Gelucire44/14 (0.1%, v/v) increased BBR absorption, and this enhancing effect was more significant in the ileum than in the colon of a rat. Oral delivery of BBR with Gelucire44/14 (0.1%, v/v) to diabetic mice, compared with the BBR group, induced a significant hypoglycemic effect on day 7 and day 12 after administration. This result was well correlated with the results of the in vitro study, indicating the important contribution of the P-gp inhibitory effect of Gelucire44/14 to the improvement of the antidiabetic efficacy in vivo. In addition, Gelucire44/14 (0.1%, v/v) neither increased the levels of protein and lactate dehydrogenase in intestinal perfusion nor changed the morphology of the rat intestinal epithelium relative to those of the negative control. This finding suggested that 0.1% (v/v) Gelucire44/14 caused no apparent membrane damage to rat intestine. In conclusion, Gelucire44/14 exhibited potential for enhancing the oral absorption of BBR, thereby improving the antidiabetic efficacy of BBR. Copyright © 2018 Elsevier B.V. All rights reserved.

Cellular mechanism of oral absorption of solidified polymer micelles.

PubMed

Abramov, Eva; Cassiola, Flavia; Schwob, Ouri; Karsh-Bluman, Adi; Shapero, Mara; Ellis, James; Luyindula, Dema; Adini, Irit; D'Amato, Robert J; Benny, Ofra

2015-11-01

Oral delivery of poorly soluble and permeable drugs represents a significant challenge in drug development. The oral delivery of drugs remains to be the ultimate route of any drugs. However, in many cases, drugs are not absorbed well in the gastrointestinal tract, or they lose their activity. Polymer micelles were recognized as an effective carrier system for drug encapsulation, and are now studied as a vehicle for oral delivery of insoluble compounds. We characterized the properties of monomethoxy polyethylene glycol-poly lactic acid (mPEG-PLA) micelles, and visualized their internalization in mouse small intestine. Using Caco-2 cells as a cellular model, we studied the kinetics of particle uptake, their transport, and the molecular mechanism of their intestinal absorption. Moreover, by inhibiting specific endocytosis pathways, pharmacologically and genetically, we found that mPEG-PLA nanoparticle endocytosis is mediated by clathrin in an energy-dependent manner, and that the low-density lipoprotein receptor is involved. Many current drugs used are non-water soluble and indeed, the ability to deliver these drugs via the gastrointestinal tract remains the holy grail for many researchers. The authors in this paper developed monomethoxy polyethylene glycol-poly lactic acid (mPEG-PLA) micelles as a drug nanocarrier, and studied the mechanism of uptake across intestinal cells. The findings should improve our current understanding and point to the development of more nanocarriers. Copyright © 2015 Elsevier Inc. All rights reserved.

Intestinal absorption of 5 chromium compounds in young black ducks (Anas rubripes)

USGS Publications Warehouse

Eastin, W.C.; Haseltine, S.D.; Murray, H.C.

1980-01-01

An in vivo intestinal perfusion technique was used to measure the absorption rates of five Cr compounds in black ducks. Cr was absorbed from saline solutions of KCr(SO4 )2 and CrO3 at a rate about 1.5 to 2.0 times greater than from solutions of Cr, Cr(NO3 )3, and Cr(C5H7O2)3. These results suggest the ionic form of Cr in solution may be an important factor in determining absorption of Cr compounds from the small intestine.

Improved bioavailability and antiasthmatic efficacy of poorly soluble curcumin-solid dispersion granules obtained using fluid bed granulation.

PubMed

Jang, Dong-Jin; Kim, Sung Tae; Lee, Kooyeon; Oh, Euichaul

2014-01-01

The intestinal absorption and antiasthmatic efficacy of poorly water-soluble curcumin (CUR), which has low solubility and permeability, was increased by fabricating solid dispersion granules (SDGs). The SDG containing CUR (SDG-CUR) was prepared by dispersing CUR in excess Cremophor RH40 as a solubilizer and Ryoto sugar ester L-1695 as an absorption enhancer using fluid bed granulation. We evaluated the physicochemical properties such as crystallinity and dissolution, pharmacokinetics, and antiasthmatic efficacy of SDG-CUR. Our results showed that CUR was molecularly dispersed, and the dissolution of SDG-CUR was significantly higher than that of native CUR. In addition, the blood concentration of SDG-CUR in rats was much higher than that of native CUR. Compared to CUR, SDG-CUR showed a 9.1- and 13.1-fold increase in area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax), respectively. Further, SDG-CUR effectively alleviated airway hyperresponsiveness and levels of T-helper 2 cytokines (interleukin-4, interleukin-5, and interleukin-13) in a murine model of asthma. In conclusion, our results suggest that the SDGs could be considered as a potential oral formulation to enhance the absorption and efficacy of CUR.

Myo-inositol inhibits intestinal glucose absorption and promotes muscle glucose uptake: a dual approach study.

PubMed

Chukwuma, Chika Ifeanyi; Ibrahim, Mohammed Auwal; Islam, Md Shahidul

2016-12-01

The present study investigated the effects of myo-inositol on muscle glucose uptake and intestinal glucose absorption ex vivo as well as in normal and type 2 diabetes model of rats. In ex vivo study, both intestinal glucose absorption and muscle glucose uptake were studied in isolated rat jejunum and psoas muscle respectively in the presence of increasing concentrations (2.5 % to 20 %) of myo-inositol. In the in vivo study, the effect of a single bolus dose (1 g/kg bw) of oral myo-inositol on intestinal glucose absorption, blood glucose, gastric emptying and digesta transit was investigated in normal and type 2 diabetic rats after 1 h of co-administration with 2 g/kg bw glucose, when phenol red was used as a recovery marker. Myo-inositol inhibited intestinal glucose absorption (IC 50  = 28.23 ± 6.01 %) and increased muscle glucose uptake, with (GU 50  = 2.68 ± 0.75 %) or without (GU 50  = 8.61 ± 0.55 %) insulin. Additionally, oral myo-inositol not only inhibited duodenal glucose absorption and reduced blood glucose increase, but also delayed gastric emptying and accelerated digesta transit in both normal and diabetic animals. Results of this study suggest that dietary myo-inositol inhibits intestinal glucose absorption both in ex vivo and in normal or diabetic rats and also promotes muscle glucose uptake in ex vivo condition. Hence, myo-inositol may be further investigated as a possible anti-hyperglycaemic dietary supplement for diabetic foods and food products.

Regulation of Bicarbonate Secretion in Marine Fish Intestine by the Calcium-Sensing Receptor.

PubMed

Gregório, Sílvia F; Fuentes, Juan

2018-04-04

In marine fish, high epithelial intestinal HCO₃ − secretion generates luminal carbonate precipitates of divalent cations that play a key role in water and ion homeostasis. The present study was designed to expose the putative role for calcium and the calcium-sensing receptor (CaSR) in the regulation of HCO₃ − secretion in the intestine of the sea bream ( Sparus aurata L.). Effects on the expression of the CaSR in the intestine were evaluated by qPCR and an increase was observed in the anterior intestine in fed fish compared with unfed fish and with different regions of intestine. CaSR expression reflected intestinal fluid calcium concentration. In addition, anterior intestine tissue was mounted in Ussing chambers to test the putative regulation of HCO₃ − secretion in vitro using the anterior intestine. HCO₃ − secretion was sensitive to varying calcium levels in luminal saline and to calcimimetic compounds known to activate/block the CaSR i.e., R 568 and NPS-2143. Subsequent experiments were performed in intestinal sacs to measure water absorption and the sensitivity of water absorption to varying luminal levels of calcium and calcimimetics were exposed as well. It appears, that CaSR mediates HCO₃ − secretion and water absorption in marine fish as shown by responsiveness to calcium levels and calcimimetic compounds.

Studies on different iron source absorption by in situ ligated intestinal loops of broilers.

PubMed

Jia, Y F; Jiang, M M; Sun, J; Shi, R B; Liu, D S

2015-02-01

The objective of this study was to investigate the iron source absorption in the small intestine of broiler. In situ ligated intestinal loops of 70 birds were poured into one of seven solutions, including inorganic iron (FeSO4, Fe2(SO4)3), organic Fe glycine chelate (Fe-Gly(II), Fe-Gly(III)), the mixtures (FeSO4 with glycine (Fe+Gly(II)), Fe2(SO4)3 with glycine (Fe+Gly(III)), and no Fe source (control). The total volume of 3-mL solution (containing 1 mg of elemental Fe) was injected into intestinal loops, and then 120-min incubation was performed. Compared with inorganic iron groups, in which higher FeSO4 absorption than Fe2(SO4)3 was observed, supplementation with organic Fe glycine chelate significantly increased the Fe concentration in the duodenum and jejunum (P < 0.05), however, decreased DMT1 and DcytB messenger RNA (mRNA) levels (P < 0.05). Organic Fe glycine chelate (Fe-Gly(II), Fe-Gly(III)) increased serum iron concentration (SI), compared with inorganic 3 valence iron groups (Fe2(SO4)3 and Fe+Gly(III)) (P < 0.05); moreover, lower TIBC value was observed for the chelate (P < 0.05); however, mixture of inorganic iron and glycine did not have a positive role at DMT1 and DcytB mRNA levels, SI and Fe concentrations in the small intestine. Those results indicated that the absorption of organic Fe glycine chelate was more effective than that of inorganic Fe, and the orders of iron absorption in the small intestine were: Fe-Gly(II), Fe-Gly(III) > FeSO4, Fe+Gly(II) > Fe2(SO4)3, Fe+Gly(III). Additionally, the simple mixture of inorganic iron and glycine could not increase Fe absorption, and the duodenum was the main site of Fe absorption in the intestines of broilers and the ileum absorbed iron rarely.

Intestinal hormones and growth factors: Effects on the small intestine

PubMed Central

Drozdowski, Laurie; Thomson, Alan BR

2009-01-01

There are various hormones and growth factors which may modify the intestinal absorption of nutrients, and which might thereby be useful in a therapeutic setting, such as in persons with short bowel syndrome. In partI, we focus first on insulin-like growth factors, epidermal and transferring growth factors, thyroid hormones and glucocorticosteroids. Part II will detail the effects of glucagon-like peptide (GLP)-2 on intestinal absorption and adaptation, and the potential for an additive effect of GLP2 plus steroids. PMID:19152442

Low zinc status and absorption exist in infants with jejunostomies or ileostomies which persists after intestinal repair

USDA-ARS?s Scientific Manuscript database

There is very little data regarding trace mineral nutrition in infants with small intestinal ostomies. Here we evaluated 14 infants with jejunal or ileal ostomies to measure their zinc absorption and retention and biochemical zinc and copper status. Zinc absorption was measured using a dual-tracer s...

Biomarkers of Environmental Enteric Dysfunction Among Children in Rural Bangladesh.

PubMed

Campbell, Rebecca K; Schulze, Kerry J; Shaikh, Saijuddin; Mehra, Sucheta; Ali, Hasmot; Wu, Lee; Raqib, Rubhana; Baker, Sarah; Labrique, Alain; West, Keith P; Christian, Parul

2017-07-01

Environmental enteric dysfunction (EED) may inhibit growth and development in low- and middle-income countries, but available assessment methodologies limit its study. In rural Bangladesh, we measured EED using the widely used lactulose mannitol ratio (L:M) test and a panel of intestinal and systemic health biomarkers to evaluate convergence among biomarkers and describe risk factors for EED. In 539 18-month-old children finishing participation in a randomized food supplementation trial, serum, stool, and urine collected after lactulose and mannitol dosing were analyzed for biomarkers of intestinal absorption, inflammation, permeability and repair, and systemic inflammation. EED scores for each participant were developed using principal component analysis and partial least squares regression. Associations between scores and L:M and with child sociodemographic and health characteristics were evaluated using regression analysis. EED prevalence (L:M > 0.07) was 39.0%; 60% had elevated acute phase proteins (C-reactive protein >5 mg/L or α-1 acid glycoprotein >100 mg/dL). Correlations between intestinal biomarkers were low, with the highest between myeloperoxidase and α-1 antitrypsin (r = 0.33, P < 0.01), and biomarker values did not differ by supplementation history. A 1-factor partial least squares model with L:M as the dependent variable explained only 8.6% of L:M variability. In adjusted models, L:M was associated with child sex and socioeconomic status index, whereas systemic inflammation was predicted mainly by recent illness, not EED. Impaired intestinal health is widespread in this setting of prevalent stunting, but a panel of serum and stool biomarkers demonstrated poor agreement with L:M. Etiologies of intestinal and systemic inflammation are likely numerous and complex in resource-poor settings, underscoring the need for a better case definition with corresponding diagnostic methods to further the study of EED.

Diabetes regulates fructose absorption through thioredoxin-interacting protein.

PubMed

Dotimas, James R; Lee, Austin W; Schmider, Angela B; Carroll, Shannon H; Shah, Anu; Bilen, Julide; Elliott, Kayla R; Myers, Ronald B; Soberman, Roy J; Yoshioka, Jun; Lee, Richard T

2016-10-11

Metabolic studies suggest that the absorptive capacity of the small intestine for fructose is limited, though the molecular mechanisms controlling this process remain unknown. Here we demonstrate that thioredoxin-interacting protein (Txnip), which regulates glucose homeostasis in mammals, binds to fructose transporters and promotes fructose absorption by the small intestine. Deletion of Txnip in mice reduced fructose transport into the peripheral bloodstream and liver, as well as the severity of adverse metabolic outcomes resulting from long-term fructose consumption. We also demonstrate that fructose consumption induces expression of Txnip in the small intestine. Diabetic mice had increased expression of Txnip in the small intestine as well as enhanced fructose uptake and transport into the hepatic portal circulation. The deletion of Txnip in mice abolished the diabetes-induced increase in fructose absorption. Our results indicate that Txnip is a critical regulator of fructose metabolism and suggest that a diabetic state can promote fructose uptake.

Measuring intestinal fluid transport in vitro: Gravimetric method versus non-absorbable marker.

PubMed

Whittamore, Jonathan M; Genz, Janet; Grosell, Martin; Wilson, Rod W

2016-04-01

The gut sac is a long-standing, widely used in vitro preparation for studying solute and water transport, and calculation of these fluxes requires an accurate assessment of volume. This is commonly determined gravimetrically by measuring the change in mass over time. While convenient this likely under-estimates actual net water flux (Jv) due to tissue edema. We evaluated whether the popular in vivo volume marker [(14)C]-PEG 4000, offers a more representative measure of Jvin vitro. We directly compared these two methods in five teleost species (toadfish, flounder, rainbow trout, killifish and tilapia). Net fluid absorption by the toadfish intestine based on PEG was significantly higher, by almost 4-fold, compared to gravimetric measurements, compatible with the latter under-estimating Jv. Despite this, PEG proved inconsistent for all of the other species frequently resulting in calculation of net secretion, in contrast to absorption seen gravimetrically. Such poor parallelism could not be explained by the absorption of [(14)C]-PEG (typically <1%). We identified a number of factors impacting the effectiveness of PEG. One was adsorption to the surface of sample tubes. While it was possible to circumvent this using unlabelled PEG 4000, this had a deleterious effect on PEG-based Jv. We also found sequestration of PEG within the intestinal mucus. In conclusion, the short-comings associated with the accurate representation of Jv by gut sac preparations are not overcome by [(14)C]-PEG. The gravimetric method therefore remains the most reliable measure of Jv and we urge caution in the use of PEG as a volume marker. Copyright © 2016 Elsevier Inc. All rights reserved.

The in vivo pharmacokinetics, tissue distribution and excretion investigation of mesaconine in rats and its in vitro intestinal absorption study using UPLC-MS/MS.

PubMed

Liu, Xiuxiu; Tang, Minghai; Liu, Taohong; Wang, Chunyan; Tang, Qiaoxin; Xiao, Yaxin; Yang, Ruixin; Chao, Ruobing

2017-12-27

1. Mesaconine, an ingredient from Aconitum carmichaelii Debx., has been proven to have cardiac effect. For further development and better pharmacological elucidation, the in vivo process and intestinal absorptive behavior of mesaconine should be investigated comprehensively. 2. An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantitation of mesaconine in rat plasma, tissue homogenates, urine and feces to investigate the in vivo pharmacokinetic profiles, tissue distribution and excretion. The intestinal absorptive behavior of mesaconine was investigated using in vitro everted rat gut sac model. 3. Mesaconine was well distributed in tissues and a mass of unchanged form was detected in feces. It was difficultly absorbed into blood circulatory system after oral administration. The insufficient oral bioavailability of mesaconine may be mainly attributed to its low intestinal permeability due to a lack of lipophilicity. The absorption of mesaconine in rat's intestine is a first-order process with the passive diffusion mechanism.

Evaluation of intestinal absorption of amtolmetin guacyl in rats: breast cancer resistant protein as a primary barrier of oral bioavailability.

PubMed

Rong, Zhihui; Xu, Yanjiao; Zhang, Chengliang; Xiang, Daochun; Li, Xiping; Liu, Dong

2013-02-27

The purpose of the present study was to investigate the role of efflux transporters on the intestinal absorption of amtolmetin guacyl (MED-15). The effects of P-glycoprotein (P-gp), multiple resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP) inhibitors on intestinal absorption amount of MED-5 (tolmetin-glycine amide derivative), the metabolite formed from MED-15 in the intestinal epithelial cells were studied in the in vitro everted gut sac experiments. Moreover, the in situ single-pass intestine perfusion was adopted to clarify the role of efflux transporters in excreting MED-5 in knockout mice. The plasma concentration of MED-5 and tolmetin, the metabolite formed from MED-5 was determined in Bcrp1 knockout mice and wild-type mice. BCRP inhibitor Ko143 (50 μM and 100 μM) significantly increased the intestinal absorption amount in jejunum, ileum and colon (p<0.05). However, no effect was observed in the presence of P-gp inhibitor verapamil and MRP2 inhibitor MK571 in each intestinal segment. Furthermore, the plasma concentration MED-5 and tolmetin, metabolites of MED-15, increased 2-fold and 4-fold, respectively, in Bcrp1 knockout mice compared with wild-type mice after the single-pass perfusion of small intestine with MED-15. It may be concluded that BCRP plays an important role in the intestinal efflux of MED-5 and limits the bioavailability after oral administration of MED-15. Copyright © 2013. Published by Elsevier Inc.

Normal cadmium uptake in microcytic anemia mk/mk mice suggests that DMT1 is not the only cadmium transporter in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Suzuki, Tomohito; Momoi, Kanae; Hosoyamada, Makoto

2008-03-15

Divalent metal transporter 1 (DMT1) is a mammalian iron (Fe) transporter and also transports Cadmium (Cd) in vitro. This study compared Cd absorption in DMT1-dysfunctional MK/Rej-{sup mk}/{sub mk} mice (mk/mk mice) and in DMT1-functional, Fe-deficient wild-type (WT) mice, to clarify the role of DMT1 in intestinal Cd absorption in vivo. Mice were given 1 ppm CdCl{sub 2} aq in drinking water for 2 weeks, and the concentrations of Cd and Fe in liver, kidney, and intestinal epithelium were subsequently determined. The Fe concentration in intestinal epithelia of WT mice was decreased in proportion to the level of dietary Fe limitation,more » while Cd accumulation under the same conditions was increased. DMT1 mRNA expression in the small intestine of Fe-deficient WT mice was clearly increased compared to that in Fe-sufficient WT mice. Iron deficiency resulted in up-regulation of Cd uptake in the intestine of Fe-deficient WT mice. The mk/mk mice have a mutation in DMT1 and loss of its function led to decreased intestinal Fe concentration. However, intestinal Cd accumulation was the same as in WT mice and it was also increased in Fe-deficient situation. There is the possibility that an unknown Cd pathway has taken a role on Cd intestinal absorption in vivo and that this pathway is regulated by food Fe concentrations. Therefore, DMT1 is not the sole transporter of intestinal cadmium absorption in vivo.« less

HCO3− secretion and CaCO3 precipitation play major roles in intestinal water absorption in marine teleost fish in vivo

PubMed Central

Cooper, Christopher A.; Wilson, Rod W.

2010-01-01

The intestine of marine teleosts must effectively absorb fluid from ingested seawater to avoid dehydration. This fluid transport has been almost exclusively characterized as driven by NaCl absorption. However, an additional feature of the osmoregulatory role of the intestine is substantial net HCO3− secretion. This is suggested to drive additional fluid absorption directly (via Cl−/HCO3− exchange) and indirectly by precipitating ingested Ca2+ as CaCO3, thus creating the osmotic gradient for additional fluid absorption. The present study tested this hypothesis by perfusing the intestine of the European flounder in vivo with varying [Ca2+]: 10 (control), 40, and 90 mM. Fractional fluid absorption increased from 47% (control) to 73% (90 mM Ca2+), where almost all secreted HCO3− was excreted as CaCO3. This additional fluid absorption could not be explained by NaCl cotransport. Instead, a significant positive relationship between Na+-independent fluid absorption and total HCO3− secretion was consistent with the predicted roles for anion exchange and CaCO3 precipitation. Further analysis suggested that Na+-independent fluid absorption could be accounted for by net Cl− and H+ absorption (from Cl−/HCO3− exchange and CO2 hydration, respectively). There was no evidence to suggest that CaCO3 alone was responsible for driving fluid absorption. However, by preventing the accumulation of luminal Ca2+ it played a vital role by dynamically maintaining a favorable osmotic gradient all along the intestine, which permits substantially higher rates of solute-linked fluid absorption. To overcome the resulting hyperosmotic and highly acidic absorbate, it is proposed that plasma HCO3− buffers the absorbed H+ (from HCO3− production), and consequently reduces the osmolarity of the absorbed fluid entering the body. PMID:20130226

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pavelka, M.; Gangl, A.

The involvement of microtubules in the transepithelial transport of exogenous lipid in intestinal absorptive cells has been suggested. Using electronmicroscopic, biochemical, and radiochemical methods, researchers have studied the effects of the antimicrotubular agent colchicine on the intestinal mucosa and on the intestinal transport of endogenous lipid of rats in the fasting state. After colchicine treatment, the concentration of triglycerides in intestinal mucosa of rats fasted for 24 h doubled, and electron microscopic studies showed a striking accumulation of lipid particles in absorptive epithelial cells of the tips of jejunal villi. These findings suggest that colchicine interferes with the intestinal transepithelialmore » transport of endogenous lipoproteins. Additional studies, using an intraduodenal pulse injection of (/sup 14/C)linoleic acid, showed that colchicine does not affect the uptake of fatty acids by intestinal mucosa. However, it had divergent effects on fatty acid esterification, enhancing their incorporation into triglycerides relative to phospholipids, and caused a significant accumulation of endogenous diglycerides, triglycerides, and cholesterol esters within the absorptive intestinal epithelium. Detailed ultrastructural and morphometric studies revealed a decrease of visible microtubules, and a displacement of the smooth and rough endoplasmic reticulum and Golgi apparatus. Furthermore, it is shown that after colchicine treatment, microvilli appear at the lateral plasma membrane of intestinal absorptive cells, a change not previously reported to our knowledge. Thus, our study shows that colchicine causes significant changes in enterocyte ultrastructure and colchicine perturbs the reesterification of absorbed endogenous fatty acids and their secretion in the form of triglyceride-rich lipoproteins from the enterocyte.« less

Oral exposure to polystyrene nanoparticles affects iron absorption

NASA Astrophysics Data System (ADS)

Mahler, Gretchen J.; Esch, Mandy B.; Tako, Elad; Southard, Teresa L.; Archer, Shivaun D.; Glahn, Raymond P.; Shuler, Michael L.

2012-04-01

The use of engineered nanoparticles in food and pharmaceuticals is expected to increase, but the impact of chronic oral exposure to nanoparticles on human health remains unknown. Here, we show that chronic and acute oral exposure to polystyrene nanoparticles can influence iron uptake and iron transport in an in vitro model of the intestinal epithelium and an in vivo chicken intestinal loop model. Intestinal cells that are exposed to high doses of nanoparticles showed increased iron transport due to nanoparticle disruption of the cell membrane. Chickens acutely exposed to carboxylated particles (50 nm in diameter) had a lower iron absorption than unexposed or chronically exposed birds. Chronic exposure caused remodelling of the intestinal villi, which increased the surface area available for iron absorption. The agreement between the in vitro and in vivo results suggests that our in vitro intestinal epithelium model is potentially useful for toxicology studies.

Prediction of Human Intestinal Absorption of Compounds Using Artificial Intelligence Techniques.

PubMed

Kumar, Rajnish; Sharma, Anju; Siddiqui, Mohammed Haris; Tiwari, Rajesh Kumar

2017-01-01

Information about Pharmacokinetics of compounds is an essential component of drug design and development. Modeling the pharmacokinetic properties require identification of the factors effecting absorption, distribution, metabolism and excretion of compounds. There have been continuous attempts in the prediction of intestinal absorption of compounds using various Artificial intelligence methods in the effort to reduce the attrition rate of drug candidates entering to preclinical and clinical trials. Currently, there are large numbers of individual predictive models available for absorption using machine learning approaches. Six Artificial intelligence methods namely, Support vector machine, k- nearest neighbor, Probabilistic neural network, Artificial neural network, Partial least square and Linear discriminant analysis were used for prediction of absorption of compounds. Prediction accuracy of Support vector machine, k- nearest neighbor, Probabilistic neural network, Artificial neural network, Partial least square and Linear discriminant analysis for prediction of intestinal absorption of compounds was found to be 91.54%, 88.33%, 84.30%, 86.51%, 79.07% and 80.08% respectively. Comparative analysis of all the six prediction models suggested that Support vector machine with Radial basis function based kernel is comparatively better for binary classification of compounds using human intestinal absorption and may be useful at preliminary stages of drug design and development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Paroxetine decreased plasma exposure of glyburide partly via inhibiting intestinal absorption in rats.

PubMed

Jiang, Shuwen; Zhao, Weiman; Chen, Yang; Zhong, Zeyu; Zhang, Mian; Li, Feng; Xu, Ping; Zhao, Kaijing; Li, Ying; Liu, Li; Liu, Xiaodong

2015-06-01

Accumulating evidences have shown that diabetes is often accompanied with depression, thus it is possible that oral antidiabetic agent glyburide and antidepressive agent paroxetine are co-administered in diabetic patients. The aim of this study was to assess interactions between glyburide and paroxetine in rats. Effect of paroxetine on pharmacokinetics of orally administered glyburide was investigated. Effect of naringin (NAR), an inhibitor of rat intestinal organic anion transporting polypeptides 1a5 (Oatp1a5), on pharmacokinetics of glyburide was also studied. The results showed that co-administration of paroxetine markedly reduced plasma exposure and prolonged Tmax of glyburide, accompanied by significant increase in fecal excretion of glyburide. Co-administration of naringin also significantly decreased plasma exposure of glyburide. Data from intestinal perfusion experiments showed that both paroxetine and naringin significantly inhibited intestinal absorption of glyburide. Caco-2 cells were used to investigate whether paroxetine and naringin affected intestinal transport of glyburide and fexofenadine (a substrate of Oatp1a5). The results showed that both paroxetine and naringin greatly inhibited absorption of glyburide and fexofenadine. All results gave a conclusion that co-administration of paroxetine decreased plasma exposure of glyburide in rats via inhibiting intestinal absorption of glyburide, which may partly be attributed to the inhibition of intestinal Oatp1a5 activity. Copyright © 2015 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Short Bowel Syndrome

MedlinePlus

... in the intestine hypomotility agents to increase the time it takes food to travel through the intestines, leading to increased nutrient absorption ... dilated segment of the small intestine slow the time it takes for food to travel through the small intestine lengthen the small intestine ...

Anthocyanin Absorption and Metabolism by Human Intestinal Caco-2 Cells—A Review

PubMed Central

Kamiloglu, Senem; Capanoglu, Esra; Grootaert, Charlotte; Van Camp, John

2015-01-01

Anthocyanins from different plant sources have been shown to possess health beneficial effects against a number of chronic diseases. To obtain any influence in a specific tissue or organ, these bioactive compounds must be bioavailable, i.e., effectively absorbed from the gut into the circulation and transferred to the appropriate location within the body while still maintaining their bioactivity. One of the key factors affecting the bioavailability of anthocyanins is their transport through the gut epithelium. The Caco-2 cell line, a human intestinal epithelial cell model derived from a colon carcinoma, has been proven to be a good alternative to animal studies for predicting intestinal absorption of anthocyanins. Studies investigating anthocyanin absorption by Caco-2 cells report very low absorption of these compounds. However, the bioavailability of anthocyanins may be underestimated since the metabolites formed in the course of digestion could be responsible for the health benefits associated with anthocyanins. In this review, we critically discuss recent findings reported on the anthocyanin absorption and metabolism by human intestinal Caco-2 cells. PMID:26370977

The use of metabolic balance studies in the objective discrimination between intestinal insufficiency and intestinal failure.

PubMed

Prahm, August P; Brandt, Christopher F; Askov-Hansen, Carsten; Mortensen, Per B; Jeppesen, Palle B

2017-09-01

Background : In research settings that use metabolic balance studies (MBSs) of stable adult patients with short bowel syndrome, intestinal failure (IF) and dependence on parenteral support (PS) have been defined objectively as energy absorption <84% of calculated basal metabolic rate (BMR), wet weight (WW) absorption <23 g · kg body weight -1 · d -1 , or both. Objective: This study aimed to explore and validate these borderlines in the clinical setting. Design: Intestinal absorption was measured from April 2003 to March 2015 in 175 consecutive patients with intestinal insufficiency (INS) in 96-h MBSs. They had not received PS 3 mo before referral. Results: To avoid the need for PS, the minimum absorptive requirements were energy absorption of ≥81% of BMR and WW absorption of ≥21 g · kg body weight -1 · d -1 , which were equivalent to findings in research settings (differences of 3.6% and 8.7%; P = 0.65 and 0.60, respectively). Oral failure defined as energy intake <130% of calculated BMR or WW intake <40 g · kg body weight -1 · d -1 was seen in 71% and 82% of the 10% of patients with the lowest energy absorption and WW absorption, respectively. Conclusions: In clinical settings, the borderlines between INS and IF were not significantly different from those in research settings, even in an unselected patient population in which oral failure was also a predominant cause of nutritional dyshomeostasis. MBSs may be recommended to identify the individual patient in the spectrum from INS to IF, to objectivize the cause of nutritional dyshomeostasis (oral failure, malabsorption, or both), and to quantify the effects of treatment. © 2017 American Society for Nutrition.

Pyruvate-enriched oral rehydration solution improved intestinal absorption of water and sodium during enteral resuscitation in burns.

PubMed

Hu, Sen; Liu, Wei-wei; Zhao, Ying; Lin, Zhi-long; Luo, Hong-min; Bai, Xiao-dong; Sheng, Zhi-yong; Zhou, Fang-qiang

2014-06-01

To investigate alteration in intestinal absorption during enteral resuscitation with pyruvate-enriched oral rehydration solution (Pyr-ORS) in scalded rats. To compare pyruvate-enriched oral rehydration solution (Pyr-ORS) with World Health Organisation oral rehydration solution (WHO-ORS), 120 rats were randomly divided into 6 groups and 2 subgroups. At 1.5 and 4.5 h after a 35% TBSA scald, the intestinal absorption rate, mucosal blood flow (IMBF), Na(+)-K(+)-ATPase activity and aquaporin-1 (AQP-1) expression were determined (n = 10), respectively. The intestinal Na(+)-K(+)-ATPase activity, AQP-1 expression and IMBF were markedly decreased in scald groups, but they were profoundly preserved by enteral resuscitation with WHO-ORS and further improved significantly with Pyr-ORS at both time points. Na(+)-K+-ATPase activities remained higher in enteral resuscitation with Pyr-ORS (Group SP) than those with WHO-ORS (Group SW) at 4.5 h. AQP-1 and IMBF were significantly greater in Group SP than in Group SW at both time points. Intestinal absorption rates of water and sodium were obviously inhibited in scald groups; however, rates were also significantly preserved in Group SP than in Group SW with an over 20% increment at both time points. The Pyr-ORS may be superior to the standard WHO-ORS in the promotion of intestinal absorption of water and sodium during enteral resuscitation. Copyright © 2013 Elsevier Ltd and ISBI. All rights reserved.

Changes in intestinal absorption of nutrients and brush border glycoproteins after total parenteral nutrition in rats.

PubMed Central

Miura, S; Tanaka, S; Yoshioka, M; Serizawa, H; Tashiro, H; Shiozaki, H; Imaeda, H; Tsuchiya, M

1992-01-01

The effect of total parenteral nutrition on nutrients absorption and glycoprotein changes of brush border membrane was examined in rat small intestine. In total parenteral nutrition rats, a marked decrease in activity of brush border enzymes was observed mainly in the proximal and middle segments of the intestine. Galactose perfusion of jejunal segment showed that hexose absorption was significantly inhibited, while intestinal absorption of glycine or dipeptide, glycylglycine was not significantly affected by total parenteral nutrition treatment. When brush border membrane glycoprotein profile was examined by [3H]-glucosamine or [3H]-fucose incorporation into jejunal loops, significant changes were observed in the glycoprotein pattern of brush border membrane especially in the high molecular weight range over 120 kDa after total parenteral nutrition treatment, suggesting strong dependency of glycoprotein synthesis on luminal substances. Molecular weight of sucrase isomaltase in brush border membrane detected by specific antibody showed no significant difference, however, in total parenteral nutrition and control rats. Also, molecular weight of specific sodium glucose cotransporter of intestinal brush border membrane detected by selective photoaffinity labelling was not altered in total parenteral nutrition rats. It may be that prolonged absence of oral food intake may produce significant biochemical changes in brush border membrane glycoprotein and absorptive capacity of small intestine, but these changes were not observed in all brush border membrane glycoproteins. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:1582592

Studies on Inhibition of Intestinal Absorption of Radioactive Strontium

PubMed Central

Skoryna, Stanley C.; Paul, T. M.; Edward, Deirdre Waldron

1964-01-01

A method is reported which permits selective suppression of absorption of radioactive strontium from ingested food material, permitting the calcium to be available to the body. Studies were carried out in vivo by injection of Sr89 and Ca45 in the presence of inert carrier into ligated intestinal segments in rats, and the amount of absorption was measured by standard monitoring techniques. The pattern of absorption of both ions is very similar but the rate of absorption is different. It was found that the polyelectrolyte, sodium alginate, obtained from brown algae (Phaeophyceae), injected simultaneously with radiostrontium effectively reduces the absortion of Sr89 from all segments of the intestine by as much as 50-80% of the control values. No significant reduction in absorption of Ca45 was observed in equivalent concentrations. The reduction in blood levels of Sr89 and in bone uptake corresponded to the absorption pattern. The difference in the effect on strontium and calcium absorption may be due to differences in the binding capacity of sodium alginate from the two metal ions under the conditions present in vivo. PMID:14180534

New approaches to increase intestinal length: Methods used for intestinal regeneration and bioengineering

PubMed Central

Shirafkan, Ali; Montalbano, Mauro; McGuire, Joshua; Rastellini, Cristiana; Cicalese, Luca

2016-01-01

Inadequate absorptive surface area poses a great challenge to the patients suffering a variety of intestinal diseases causing short bowel syndrome. To date, these patients are managed with total parenteral nutrition or intestinal transplantation. However, these carry significant morbidity and mortality. Currently, by emergence of tissue engineering, anticipations to utilize an alternative method to increase the intestinal absorptive surface area are increasing. In this paper, we will review the improvements made over time in attempting elongating the intestine with surgical techniques as well as using intestinal bioengineering. Performing sequential intestinal lengthening was the preliminary method applied in humans. However, these methods did not reach widespread use and has limited outcome. Subsequent experimental methods were developed utilizing scaffolds to regenerate intestinal tissue and organoids unit from the intestinal epithelium. Stem cells also have been studied and applied in all types of tissue engineering. Biomaterials were utilized as a structural support for naive cells to produce bio-engineered tissue that can achieve a near-normal anatomical structure. A promising novel approach is the elongation of the intestine with an acellular biologic scaffold to generate a neo-formed intestinal tissue that showed, for the first time, evidence of absorption in vivo. In the large intestine, studies are more focused on regeneration and engineering of sphincters and will be briefly reviewed. From the review of the existing literature, it can be concluded that significant progress has been achieved in these experimental methods but that these now need to be fully translated into a pre-clinical and clinical experimentation to become a future viable therapeutic option. PMID:27011901

MicroRNAs as regulators of drug transporters, drug-metabolizing enzymes, and tight junctions: implication for intestinal barrier function.

PubMed

Ikemura, Kenji; Iwamoto, Takuya; Okuda, Masahiro

2014-08-01

Drug transporters, drug-metabolizing enzymes, and tight junctions in the small intestine function as an absorption barrier and sometimes as a facilitator of orally administered drugs. The expression of these proteins often fluctuates and thereby causes individual pharmacokinetic variability. MicroRNAs (miRNAs), which are small non-coding RNAs, have recently emerged as a new class of gene regulator. MiRNAs post-transcriptionally regulate gene expression by binding to target mRNA to suppress its translation or regulate its degradation. They have been shown to be key regulators of proteins associated with pharmacokinetics. Moreover, the role of miRNAs on the expression of some proteins expressed in the small intestine has recently been clarified. In this review, we summarize current knowledge regarding the role of miRNAs in the regulation of drug transporters, drug-metabolizing enzymes, and tight junctions as well as its implication for intestinal barrier function. MiRNAs play vital roles in the differentiation, architecture, and barrier function of intestinal epithelial cells, and directly and/or indirectly regulate the expression and function of proteins associated with drug absorption in intestinal epithelial cells. Moreover, the variation of miRNA expression caused by pathological and physiological conditions as well as genetic factors should affect the expression of these proteins. Therefore, miRNAs could be significant factors affecting inter- and intra-individual variations in the pharmacokinetics and intestinal absorption of drugs. Overall, miRNAs could be promising targets for personalized pharmacotherapy or other attractive therapies through intestinal absorption of drugs. Copyright © 2014 Elsevier Inc. All rights reserved.

Titanium Dioxide Nanoparticle Ingestion Alters Nutrient Absorption in an In Vitro Model of the Small Intestine

PubMed Central

Guo, Zhongyuan; Martucci, Nicole J.; Moreno-Olivas, Fabiola; Tako, Elad; Mahler, Gretchen J.

2017-01-01

Ingestion of titanium dioxide (TiO2) nanoparticles from products such as agricultural chemicals, processed food, and nutritional supplements is nearly unavoidable. The gastrointestinal tract serves as a critical interface between the body and the external environment, and is the site of essential nutrient absorption. The goal of this study was to examine the effects of ingesting the 30 nm TiO2 nanoparticles with an in vitro cell culture model of the small intestinal epithelium, and to determine how acute or chronic exposure to nano-TiO2 influences intestinal barrier function, reactive oxygen species generation, proinflammatory signaling, nutrient absorption (iron, zinc, fatty acids), and brush border membrane enzyme function (intestinal alkaline phosphatase). A Caco-2/HT29-MTX cell culture model was exposed to physiologically relevant doses of TiO2 nanoparticles for acute (four hours) or chronic (five days) time periods. Exposure to TiO2 nanoparticles significantly decreased intestinal barrier function following chronic exposure. Reactive oxygen species (ROS) generation, proinflammatory signaling, and intestinal alkaline phosphatase activity all showed increases in response to nano-TiO2. Iron, zinc, and fatty acid transport were significantly decreased following exposure to TiO2 nanoparticles. This is because nanoparticle exposure induced a decrease in absorptive microvilli in the intestinal epithelial cells. Nutrient transporter protein gene expression was also altered, suggesting that cells are working to regulate the transport mechanisms disturbed by nanoparticle ingestion. Overall, these results show that intestinal epithelial cells are affected at a functional level by physiologically relevant exposure to nanoparticles commonly ingested from food. PMID:28944308

Inhibition of cholesterol absorption associated with a PPAR alpha-dependent increase in ABC binding cassette transporter A1 in mice.

PubMed

Knight, Brian L; Patel, Dilip D; Humphreys, Sandy M; Wiggins, David; Gibbons, Geoffrey F

2003-11-01

Dietary supplementation with the peroxisome proliferator-activated receptor alpha (PPAR alpha) ligand WY 14,643 gave rise to a 4- to 5-fold increase in the expression of mRNA for the ATP binding cassette transporter A1 (ABCA1) in the intestine of normal mice. There was no effect in the intestine of PPAR alpha-null mice. Consumption of a high-cholesterol diet also increased intestinal ABCA1 expression. The effects of WY 14,643 and the high-cholesterol diet were not additive. WY 14,643 feeding reduced intestinal absorption of cholesterol in the normal mice, irrespective of the dietary cholesterol concentration, and this resulted in lower diet-derived cholesterol and cholesteryl ester concentrations in plasma and liver. At each concentration of dietary cholesterol, there was a similar significant inverse correlation between intestinal ABCA1 mRNA content and the amount of cholesterol absorbed. The fibrate-induced changes in the intestines of the normal mice were accompanied by an increased concentration of the mRNA encoding the sterol-regulatory element binding protein-1c gene (SREBP-1c), a known target gene for the oxysterol receptor liver X receptor alpha (LXR alpha). There was a correlation between intestinal ABCA1 mRNA and SREBP-1c mRNA contents, but not between SREBP-1c mRNA content and cholesterol absorption. These results suggest that PPAR alpha influences cholesterol absorption through modulating ABCA1 activity in the intestine by a mechanism involving LXR alpha.

Diabetes regulates fructose absorption through thioredoxin-interacting protein

PubMed Central

Dotimas, James R; Lee, Austin W; Schmider, Angela B; Carroll, Shannon H; Shah, Anu; Bilen, Julide; Elliott, Kayla R; Myers, Ronald B; Soberman, Roy J; Yoshioka, Jun; Lee, Richard T

2016-01-01

Metabolic studies suggest that the absorptive capacity of the small intestine for fructose is limited, though the molecular mechanisms controlling this process remain unknown. Here we demonstrate that thioredoxin-interacting protein (Txnip), which regulates glucose homeostasis in mammals, binds to fructose transporters and promotes fructose absorption by the small intestine. Deletion of Txnip in mice reduced fructose transport into the peripheral bloodstream and liver, as well as the severity of adverse metabolic outcomes resulting from long-term fructose consumption. We also demonstrate that fructose consumption induces expression of Txnip in the small intestine. Diabetic mice had increased expression of Txnip in the small intestine as well as enhanced fructose uptake and transport into the hepatic portal circulation. The deletion of Txnip in mice abolished the diabetes-induced increase in fructose absorption. Our results indicate that Txnip is a critical regulator of fructose metabolism and suggest that a diabetic state can promote fructose uptake. DOI: http://dx.doi.org/10.7554/eLife.18313.001 PMID:27725089

Dietary glutamine supplementation effects on amino acid metabolism, intestinal nutrient absorption capacity and antioxidant response of gilthead sea bream (Sparus aurata) juveniles.

PubMed

Coutinho, F; Castro, C; Rufino-Palomares, E; Ordóñez-Grande, B; Gallardo, M A; Oliva-Teles, A; Peres, H

2016-01-01

A study was undertaken to evaluate dietary glutamine supplementation effects on gilthead sea bream performance, intestinal nutrient absorption capacity, hepatic and intestinal glutamine metabolism and oxidative status. For that purpose gilthead sea bream juveniles (mean weight 13.0g) were fed four isolipidic (18% lipid) and isonitrogenous (43% protein) diets supplemented with 0, 0.5, 1 and 2% glutamine for 6weeks. Fish performance, body composition and intestinal nutrient absorption capacity were not affected by dietary glutamine levels. Hepatic and intestinal glutaminase (GlNase), glutamine synthetase (GSase), alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase activities were also unaffected by dietary glutamine supplementation. In the intestine GlNase activity was higher and GSase/GlNase ratio was two-fold lower than in the liver, suggesting a higher use of glutamine for energy production by the intestine than by the liver. The liver showed higher catalase and glucose-6-phosphate dehydrogenase activities, while the intestine presented higher glutathione peroxidase and glutathione reductase activities and oxidised glutathione content, which seems to reveal a higher glutathione dependency of the intestinal antioxidant response. Total and reduced glutathione contents in liver and intestine and superoxide dismutase activity in the intestine were enhanced by dietary glutamine, though lipid peroxidation values were not affected. Overall, differences between liver and intestine glutamine metabolism and antioxidant response were identified and the potential of dietary glutamine supplementation to gilthead sea bream's antioxidant response was elucidated. Copyright © 2015 Elsevier Inc. All rights reserved.

Exogenous glucagon-like peptide-1 attenuates glucose absorption and reduces blood glucose concentration after small intestinal glucose delivery in critical illness.

PubMed

Miller, Asaf; Deane, Adam M; Plummer, Mark P; Cousins, Caroline E; Chapple, Lee-Anne S; Horowitz, Michael; Chapman, Marianne J

2017-03-01

To evaluate the effect of exogenous glucagonlike peptide-1 (GLP-1) on small intestinal glucose absorption and blood glucose concentrations during critical illness. A prospective, blinded, placebo-controlled, cross-over, randomised trial in a mixed medical-surgical adult intensive care unit, with 12 mechanically ventilated critically ill patients, who were suitable for receiving small intestinal nutrient. On consecutive days, in a randomised order, participants received intravenous GLP-1 (1.2 pmol/ kg/min) or placebo (0.9% saline) as a continuous infusion over 270 minutes. After 6 hours of fasting, intravenous infusions of GLP-1 or placebo began at T = -30 min (in which T = time), with the infusion maintained at a constant rate until study completion at T = 240 min. At T = 0 min, a 100 mL bolus of mixed liquid nutrient meal (1 kcal/mL) containing 3 g of 3-O-methyl-D-gluco-pyranose (3-OMG), a marker of glucose absorption, was administered directly into the small intestine, via a post-pyloric catheter, over 6 minutes. Blood samples were taken at regular intervals for the measurement of plasma glucose and 3-OMG concentrations. Intravenous GLP-1 attenuated initial small intestinal glucose absorption (mean area under the curve [AUC] 0-30 for 3-OMG: GLP-1 group, 4.4 mmol/L/min [SEM, 0.9 mmol/L/min] v placebo group, 6.5 mmol/L/min [SEM, 1.0 mmol/L/min]; P = 0.01), overall small intestinal glucose absorption (mean AUC 0-240 for 3-OMG: GLP-1, 68.2 mmol/L/ min [SEM, 4.7 mmol/L/min] v placebo, 77.7 mmol/L/min [SEM, 4.4 mmol/lLmin]; P = 0.02), small intestinal glucose absorption and overall blood glucose concentration (mean AUC 0-240 for blood glucose: GLP-1, 2062 mmol/L/min [SEM, 111 mmol/L/min] v placebo 2328 mmol/L/min [SEM, 145 mmol/L/min]; P = 0.005). Short-term administration of exogenous GLP-1 reduces small intestinal glucose absorption for up to 4 hours during critical illness. This is likely to be an additional mechanism for the glucose-lowering effect of this agent.

Cathepsin B is a novel gender-dependent determinant of cholesterol absorption from the intestine[S

PubMed Central

Wong, Winifred P. S.; Altemus, Jessica B.; Hester, James F.; Chan, Ernest R.; Côté, Jean-François; Serre, David; Sehayek, Ephraim

2013-01-01

We used a mouse C57BL/6J×CASA/Rk intercross to map a locus on chromosome 14 that displayed a gender-dependent effect on cholesterol absorption from the intestine. Studies in congenic animals revealed a complex locus with multiple operating genetic determinants resulting in alternating gender-dependent phenotypic effects. Fine-mapping narrowed the locus to a critical 6.3 Mb interval. Female subcongenics, but not males, of the critical interval displayed a decrease of 33% in cholesterol absorption. RNA-Seq analysis of female subcongenic jejunum revealed that cysteine protease cathepsin B (Ctsb) is a candidate to explain the interval effect. Consistent with the phenotype in critical interval subcongenics, female Ctsb knockout mice, but not males, displayed a decrease of 31% in cholesterol absorption. Although studies in Ctsb knockouts revealed a gender-dependent effect on cholesterol absorption, further fine-mapping dismissed a role for Ctsb in determining the effect of the critical 6.3 Mb interval on cholesterol absorption. PMID:23248330

L-Theanine Administration Modulates the Absorption of Dietary Nutrients and Expression of Transporters and Receptors in the Intestinal Mucosa of Rats.

PubMed

Yan, Qiongxian; Tong, Haiou; Tang, Shaoxun; Tan, Zhiliang; Han, Xuefeng; Zhou, Chuanshe

2017-01-01

L-theanine has various advantageous functions for human health; whether or not it could mediate the nutrients absorption is unknown yet. The effects of L-theanine on intestinal nutrients absorption were investigated using rats ingesting L-theanine solution (0, 50, 200, and 400 mg/kg body weight) per day for two weeks. The decline of insulin secretion and glucose concentration in the serum was observed by L-theanine. Urea and high-density lipoprotein were also reduced by 50 mg/kg L-theanine. Jejunal and ileac basic amino acids transporters SLC7a1 and SLC7a9 , neutral SLC1a5 and SLC16a10 , and acidic SLC1a1 expression were upregulated. The expression of intestinal SGLT3 and GLUT5 responsible for carbohydrates uptake and GPR120 and FABP2 associated with fatty acids transport were inhibited. These results indicated that L-theanine could inhibit the glucose uptake by downregulating the related gene expression in the small intestine of rats. Intestinal gene expression of transporters responding to amino acids absorption was stimulated by L-theanine administration.

Intestinal absorption and biomagnification of organochlorines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gobas, F.A.P.C.; McCorquodale, J.R.; Haffner, G.D.

1993-03-01

Dietary uptake rates of several organochlorines from diets with different lipid contents were measured in goldfish (Carassius auratus) to investigate the mechanism of intestinal absorption and biomagnification of organic chemical. The results suggest that intestinal absorption is predominantly controlled by chemical diffusion rather than lipid cotransport. Data for chemical uptake in human infants are presented to illustrate that biomagnification is caused by the digestion of food in the gastrointestinal tract. The findings are discussed in the context of two conflicting theories for the mechanism of biomagnification, and a mechanistic model is presented for the dietary uptake and biomagnification of organicmore » chemicals in fish and mammals.« less

Involvement of intestinal permeability in the oral absorption of clarithromycin and telithromycin.

PubMed

Togami, Kohei; Hayashi, Yoshiaki; Chono, Sumio; Morimoto, Kazuhiro

2014-09-01

The involvement of intestinal permeability in the oral absorption of clarithromycin (CAM), a macrolide antibiotic, and telithromycin (TEL), a ketolide antibiotic, in the presence of efflux transporters was examined. In order independently to examine the intestinal and hepatic availability, CAM and TEL (10 mg/kg) were administered orally, intraportally and intravenously to rats. The intestinal and hepatic availability was calculated from the area under the plasma concentration-time curve (AUC) after administration of CAM and TEL via different routes. The intestinal availabilities of CAM and TEL were lower than their hepatic availabilities. The intestinal availability after oral administration of CAM and TEL increased by 1.3- and 1.6-fold, respectively, after concomitant oral administration of verapamil as a P-glycoprotein (P-gp) inhibitor. Further, an in vitro transport experiment was performed using Caco-2 cell monolayers as a model of intestinal epithelial cells. The apical-to-basolateral transport of CAM and TEL through the Caco-2 cell monolayers was lower than their basolateral-to-apical transport. Verapamil and bromosulfophthalein as a multidrug resistance-associated proteins (MRPs) inhibitor significantly increased the apical-to-basolateral transport of CAM and TEL. Thus, the results suggest that oral absorption of CAM and TEL is dependent on intestinal permeability that may be limited by P-gp and MRPs on the intestinal epithelial cells. Copyright © 2014 John Wiley & Sons, Ltd.

Active intestinal absorption of fluoroquinolone antibacterial agent ciprofloxacin by organic anion transporting polypeptide, Oatp1a5.

PubMed

Arakawa, Hiroshi; Shirasaka, Yoshiyuki; Haga, Makoto; Nakanishi, Takeo; Tamai, Ikumi

2012-09-01

Fluoroquinolone antimicrobial drugs are absorbed efficiently after oral administration despite of their hydrophilic nature, implying an involvement of carrier-mediated transport in their membrane transport process. It has been that several fluoroquinolones are substrates of organic anion transporter polypeptides OATP1A2 expressed in human intestine derived Caco-2 cells. In the present study, to clarify the involvement of OATP in intestinal absorption of ciprofloxacin, the contribution of Oatp1a5, which is expressed at the apical membranes of rat enterocytes, to intestinal absorption of ciprofloxacin was investigated in rats. The intestinal membrane permeability of ciprofloxacin was measured by in situ and the vascular perfused closed loop methods. The disappeared and absorbed amount of ciprofloxacin from the intestinal lumen were increased markedly in the presence of 7,8-benzoflavone, a breast cancer resistance protein inhibitor, and ivermectin, a P-glycoprotein inhibitor, while it was decreased significantly in the presence of these inhibitors in combination with naringin, an Oatp1a5 inhibitor. Furthermore, the Oatp1a5-mediated uptake of ciprofloxacin was saturable with a K(m) value of 140 µm, and naringin inhibited the uptake with an IC(50) value of 18 µm by Xenopus oocytes expressing Oatp1a5. Naringin reduced the permeation of ciprofloxacin from the mucosal-to-serosal side, with an IC(50) value of 7.5 µm by the Ussing-type chamber method. The estimated IC(50) values were comparable to that of Oatp1a5. These data suggest that Oatp1a5 is partially responsible for the intestinal absorption of ciprofloxacin. In conclusion, the intestinal absorption of ciprofloxacin could be affected by influx transporters such as Oatp1a5 as well as the efflux transporters such as P-gp and Bcrp. Copyright © 2012 John Wiley & Sons, Ltd.

The effects of three absorption-modifying critical excipients on the in vivo intestinal absorption of six model compounds in rats and dogs.

PubMed

David, Dahlgren; Carl, Roos; Pernilla, Johansson; Christer, Tannergren; Anders, Lundqvist; Peter, Langguth; Markus, Sjöblom; Erik, Sjögren; Hans, Lennernäs

2018-05-11

Pharmaceutical excipients that may affect gastrointestinal (GI) drug absorption are called critical pharmaceutical excipients (CPEs), or absorption-modifying excipients (AMEs) if they act by altering the integrity of the intestinal epithelial cell membrane. Some of these excipients increase intestinal permeability, and subsequently the absorption and bioavailability of the drug. This could have implications for both the assessment of bioequivalence and the efficacy of the absorption-enhancing drug delivery system. The absorption-enhancing effects of AMEs/CPEs with different mechanisms (chitosan, sodium caprate, sodium dodecyl sulfate (SDS)) have previously been evaluated in the rat single-pass intestinal perfusion (SPIP) model. However, it remains unclear whether these SPIP data are predictive in a more in vivo like model. The same excipients were in this study evaluated in rat and dog intraintestinal bolus models. SDS and chitosan did exert an absorption-enhancing effect in both bolus models, but the effect was substantially lower than those observed in the rat SPIP model. This illustrates the complexity of the AME/CPE effects, and indicates that additional GI physiological factors need to be considered in their evaluation. We therefore recommend that AME/CPE evaluations obtained in transit-independent, preclinical permeability models (e.g. Ussing, SPIP) should be verified in animal models better able to predict in vivo relevant GI effects, at multiple excipient concentrations. Copyright © 2018. Published by Elsevier B.V.

Gastrointestinal and renal responses to variable water intake in whitebellied sunbirds and New Holland honeyeaters.

PubMed

Purchase, Cromwell; Napier, Kathryn R; Nicolson, Susan W; McWhorter, Todd J; Fleming, Patricia A

2013-05-01

Nectarivores face a constant challenge in terms of water balance, experiencing water loading or dehydration when switching between food plants or between feeding and fasting. To understand how whitebellied sunbirds and New Holland honeyeaters meet the challenges of varying preformed water load, we used the elimination of intramuscular-injected [(14)C]-l-glucose and (3)H2O to quantify intestinal and renal water handling on diets varying in sugar concentration. Both sunbirds and honeyeaters showed significant modulation of intestinal water absorption, allowing excess water to be shunted through the intestine when on dilute diets. Despite reducing their fractional water absorption, both species showed linear increases in water flux and fractional body water turnover as water intake increased (both afternoon and morning), suggesting that the modulation of fractional water absorption was not sufficient to completely offset dietary water loads. In both species, glomerular filtration rate was independent of water gain (but was higher for the afternoon), as was renal fractional water reabsorption (measured in the afternoon). During the natural overnight fast, both sunbirds and honeyeaters arrested whole kidney function. Evaporative water loss in sunbirds was variable but correlated with water gain. Both sunbirds and honeyeaters appear to modulate intestinal water absorption as an important component of water regulation to help deal with massive preformed water loads. Shutting down glomerular filtration rate during the overnight fast is another way of saving energy for osmoregulatory function. Birds maintain osmotic balance on diets varying markedly in preformed water load by varying both intestinal water absorption and excretion through the intestine and kidneys.

pH-sensitive polymeric nanoparticles to improve oral bioavailability of peptide/protein drugs and poorly water-soluble drugs.

PubMed

Wang, Xue-Qing; Zhang, Qiang

2012-10-01

pH-sensitive polymeric nanoparticles are promising for oral drug delivery, especially for peptide/protein drugs and poorly water-soluble medicines. This review describes current status of pH-sensitive polymeric nanoparticles for oral drug delivery and introduces the mechanisms of drug release from them as well as possible reasons for absorption improvement, with emphasis on our contribution to this field. pH-sensitive polymeric nanoparticles are prepared mainly with polyanions, polycations, their mixtures or cross-linked polymers. The mechanisms of drug release are the result of carriers' dissolution, swelling or both of them at specific pH. The possible reasons for improvement of oral bioavailability include the following: improve drug stability, enhance mucoadhesion, prolong resident time in GI tract, ameliorate intestinal permeability and increase saturation solubility and dissolution rate for poorly water-soluble drugs. As for the advantages of pH-sensitive nanoparticles over conventional nanoparticles, we conclude that (1) most carriers used are enteric-coating materials and their safety has been approved. (2) The rapid dissolution or swelling of carriers at specific pH results in quick drug release and high drug concentration gradient, which is helpful for absorption. (3) At the specific pH carriers dissolve or swell, and the bioadhesion of carriers to mucosa becomes high because nanoparticles turn from solid to gel, which can facilitate drug absorption. Copyright © 2012 Elsevier B.V. All rights reserved.

Influence of Chronic Social Defeat Stress on Digestive System Functioning in Rats.

PubMed

Toyoda, Atsushi; Iio, Wataru; Matsukawa, Noriko; Tsukahara, Takamitsu

2015-01-01

Mental disorders are caused by chronic psychosocial stress, and can cause various symptoms related to the digestive system. We focused on the conjugation of intestinal absorptive and enzymatic mechanisms between chronic social defeat stress (CSDS) model rats and healthy controls to obtain general biochemical data about the intestine of the model in this study. The small intestine was divided into three regions: proximal (PI), middle (MI), and distal (DI); mRNA expression associated with a nutrient absorption, glucose absorption activity, and activities of the digestive enzymes such as maltase, sucrase and lactase was measured. Expression of both sodium-dependent glucose transporter 1 (Sglt1) and glucose transporter 2 gene tended to be higher in the stress group compared to the control group in PI. Glucose absorption was also higher in PI of the CSDS group. Sglt1 and peptide transporter 1 gene expressions in the CSDS group were significantly higher than those in the control group in DI. Furthermore, in PI, expression of the aquaporin 1 gene was significantly higher in the CSDS group compared to the control group. Thus, absorption of some nutrients might be higher in the small intestine of the CSDS rat.

Net Intestinal Transport of Oxalate Reflects Passive Absorption and SLC26A6-mediated Secretion

PubMed Central

Knauf, Felix; Ko, Narae; Jiang, Zhirong; Robertson, William G.; Van Itallie, Christina M.; Anderson, James M.

2011-01-01

Mice lacking the oxalate transporter SLC26A6 develop hyperoxalemia, hyperoxaluria, and calcium-oxalate stones as a result of a defect in intestinal oxalate secretion, but what accounts for the absorptive oxalate flux remains unknown. We measured transepithelial absorption of [14C]oxalate simultaneously with the flux of [3H]mannitol, a marker of the paracellular pathway, across intestine from wild-type and Slc26a6-null mice. We used the anion transport inhibitor DIDS to investigate other members of the SLC26 family that may mediate transcellular oxalate absorption. Absorptive flux of oxalate in duodenum was similar to mannitol, insensitive to DIDS, and nonsaturable, indicating that it is predominantly passive and paracellular. In contrast, in wild-type mice, secretory flux of oxalate in duodenum exceeded that of mannitol, was sensitive to DIDS, and saturable, indicating transcellular secretion of oxalate. In Slc26a6-null mice, secretory flux of oxalate was similar to mannitol, and no net flux of oxalate occurred. Absorptive fluxes of both oxalate and mannitol varied in parallel in different segments of small and large intestine. In epithelial cell lines, modulation of the charge selectivity of the claudin-based pore pathway did not affect oxalate permeability, but knockdown of the tight-junction protein ZO-1 enhanced permeability to oxalate and mannitol in parallel. Moreover, formation of soluble complexes with cations did not affect oxalate absorption. In conclusion, absorptive oxalate flux occurs through the paracellular “leak” pathway, and net absorption of dietary oxalate depends on the relative balance between absorption and SLC26A6-dependent transcellular secretion. PMID:22021714

Viable, lyophilized lactobacilli do not increase iron absorption from a lactic acid-fermented meal in healthy young women, and no iron absorption occurs in the distal intestine.

PubMed

Bering, Stine; Sjøltov, Laila; Wrisberg, Seema S; Berggren, Anna; Alenfall, Jan; Jensen, Mikael; Højgaard, Liselotte; Tetens, Inge; Bukhave, Klaus

2007-11-01

Lactic acid-fermented foods have been shown to increase Fe absorption in human subjects, possibly by lowering pH, activation of phytases, production of organic acids, or by the viable lactic acid bacteria. In this study the effect of a heat-inactivated lactic acid-fermented oat gruel with and without added viable, lyophilized Lactobacillus plantarum 299v on non-haem Fe absorption was investigated. Furthermore, Fe absorption in the distal intestine was determined. In a randomized, double-blinded crossover trial eighteen healthy young women aged 22 (SD 3) years with low Fe status (serum ferritin < 30 microg/l) were served the two test gruels, extrinsically labelled with 59Fe and served with two enterocoated capsules (containing 55Fe(II) and 55Fe(III), respectively) designed to disintegrate in the ileum. The meals were consumed on two consecutive days, e.g. in the order AA followed by BB in a second period. Non-haem Fe absorption was determined from 59Fe whole-body retention and isotope activities in blood samples. The concentrations of Fe, lactate, phytate, and polyphenols, and the pH were similar in the heat-inactivated lactic acid-fermented oat gruels with and without added L. plantarum 299v, and no difference in Fe absorption was observed between the test gruels (1.4 and 1.3%, respectively). Furthermore, no absorption of Fe in the distal intestine was observed. In conclusion, addition of viable, lyophilized lactobacillus to a heat-inactivated lactic acid-fermented oat gruel does not affect Fe absorption, and no absorption seems to occur in the distal part of the intestine from low Fe bioavailability meals in these women.

Intestinal "bioavailability" of solutes and water: we know how but not why.

PubMed Central

Charney, A. N.

1996-01-01

Only minimal quantities of ingested and normally secreted solutes and water are excreted in the stool. This near 100% bioavailability means that the diet and kidneys are relatively more important determinants of solute, water and acid-base balance than the intestine. Intestinal bioavailability is based on excess transport capacity under normal conditions and the ability to adapt to altered or abnormal conditions. Indeed, the regulatory system of the intestine is as complex, segmented and multi factorial as in the kidney. Alterations in the rate and intestinal site of absorption reflect this regulation, and the diagnosis and treatment of various clinical abnormalities depend on the integrity of intestinal absorptive processes. However, the basis for this regulation an bioavailability are uncertain. Perhaps they had survival value for mammals, a phylogenic class that faced the twin threats of intestinal pathogens and shortages of solutes and water. PMID:9273987

Histomorphometry and macroscopic intestinal lesions in broilers infected with Eimeria acervulina.

PubMed

Assis, R C L; Luns, F D; Beletti, M E; Assis, R L; Nasser, N M; Faria, E S M; Cury, M C

2010-03-25

This study aimed at measuring intestinal villi and assessing the intestinal absorptive area in broilers infected with Eimeria acervulina under different treatments to control coccidiosis. The experiment was divided into two stages, carried out in successive housings, raised in the same environment (or aviary). In the first stage, on 25 May 2008, fifty 12-day-old birds were orally inoculated with 3 x 10(3) oocysts of E. acervulina. In the second stage, on July 2008, other 50 birds were allocated on litter contaminated by the feces of birds on the first housing (natural infection by oocysts present in the reused litter). The experiment was arranged in a complete randomized design with five treatments and three replicates of 10 chicks per treatment. Broiler chicks were housed at 1 day of age and autopsies were performed at 21 days of age. Three 2-cm-long segments of the duodenum were excised from each bird and fixed in 10% buffered formalin. A total of 30 slides were prepared for each treatment, totaling 150 evaluated histological sections using H&E staining. Villus morphology was carried out by the HL Image 97 software. The intestinal absorptive area was calculated and macroscopic lesions were classified according to standard lesion scores. Results showed that intestinal villus measurements and absorptive area are directly affected by E. acervulina and that there is direct and positive correlation between the macro and microscopic findings observed in intestinal coccidiosis. E. acervulina causes shortening of villi and reduction in the intestinal absorptive area, affecting broiler growth. The prevention method of litter fermentation during the interval between housings and oral administration of Diclazuril can reduce the severity of intestinal lesions by E. acervulina in broilers impairing oocyst virulence or viability.

Regulation of intestinal health by branched-chain amino acids.

PubMed

Zhou, Hua; Yu, Bing; Gao, Jun; Htoo, John Khun; Chen, Daiwen

2018-01-01

Besides its primary role in the digestion and absorption of nutrients, the intestine also interacts with a complex external milieu, and is the first defense line against noxious pathogens and antigens. Dysfunction of the intestinal barrier is associated with enhanced intestinal permeability and development of various gastrointestinal diseases. The branched-chain amino acids (BCAAs) are important nutrients, which are the essential substrates for protein biosynthesis. Recently, emerging evidence showed that BCAAs are involved in maintaining intestinal barrier function. It has been reported that dietary supplementation with BCAAs promotes intestinal development, enhances enterocyte proliferation, increases intestinal absorption of amino acids (AA) and glucose, and improves the immune defenses of piglets. The underlying mechanism of these effects is mediated by regulating expression of genes and proteins associate with various signaling pathways. In addition, BCAAs promote the production of beneficial bacteria in the intestine of mice. Compelling evidence supports the notion that BCAAs play important roles in both nutrition and intestinal health. Therefore, as functional amino acids with various physiological effects, BCAAs hold key roles in promoting intestinal development and health in animals and humans. © 2017 Japanese Society of Animal Science.

Hepcidin expression does not rescue the iron-poor phenotype of Kupffer cells in Hfe-null mice after liver transplantation.

PubMed

Garuti, Cinzia; Tian, Yinghua; Montosi, Giuliana; Sabelli, Manuela; Corradini, Elena; Graf, Rolf; Ventura, Paolo; Vegetti, Alberto; Clavien, Pierre-Alain; Pietrangelo, Antonello

2010-07-01

Hemochromatosis is a common hereditary disease caused by mutations in HFE and characterized by increased absorption of iron in the intestine. However, the intestine does not appear to be the site of mutant HFE activity in the disease; we investigated the role of the liver-the source of the iron regulatory hormone hepcidin-in pathogenesis in mice. We exchanged livers between Hfe wild-type (+/+) and Hfe null (-/-) mice by orthotopic liver transplantation (OLT) and assessed histopathology, serum and tissue iron parameters, and hepatic hepcidin messenger RNA expression. At 6-8 months after OLT, Hfe(-/-) mice that received Hfe(-/-) livers maintained the hemochromatosis phenotype: iron accumulation in hepatocytes but not Kupffer cells (KC), increased transferrin levels, and low levels of iron in the spleen. Hfe(+/+) mice that received Hfe(-/-) livers had increased levels of iron in serum and liver and low levels of iron in spleen. However, they did not develop the iron-poor KCs that characterize hemochromatosis: KCs appeared iron rich, although hepatic hepcidin expression was low. Transplantation of Hfe(+/+) livers into Hfe(-/-) mice prevented hepatic iron accumulation but did not return spleen and plasma levels of iron to normal; KCs still appeared to be iron poor, despite normal hepcidin expression. In Hfe(-/-) mice, transplantation of livers from Hfe(+/+) mice reversed the iron-loading phenotype associated with hemochromatosis (regardless of Hfe expression in intestine). However, KCs still had low levels of iron that were not affected by hepatic hepcidin expression. These findings indicate an independent, iron-modifying effect of HFE in KCs. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Shiga toxin 1 interaction with enterocytes causes apical protein mistargeting through the depletion of intracellular galectin-3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Laiko, Marina; Murtazina, Rakhilya; Malyukova, Irina

Shiga toxins (Stx) 1 and 2 are responsible for intestinal and systemic sequelae of infection by enterohemorrhagic Escherichia coli (EHEC). However, the mechanisms through which enterocytes are damaged remain unclear. While secondary damage from ischemia and inflammation are postulated mechanisms for all intestinal effects, little evidence excludes roles for more primary toxin effects on intestinal epithelial cells. We now document direct pathologic effects of Stx on intestinal epithelial cells. We study a well-characterized rabbit model of EHEC infection, intestinal tissue and stool samples from EHEC-infected patients, and T84 intestinal epithelial cells treated with Stx1. Toxin uptake by intestinal epithelial cellsmore » in vitro and in vivo causes galectin-3 depletion from enterocytes by increasing the apical galectin-3 secretion. This Shiga toxin-mediated galectin-3 depletion impairs trafficking of several brush border structural proteins and transporters, including villin, dipeptidyl peptidase IV, and the sodium-proton exchanger 2, a major colonic sodium absorptive protein. The mistargeting of proteins responsible for the absorptive function might be a key event in Stx1-induced diarrhea. These observations provide new evidence that human enterocytes are directly damaged by Stx1. Conceivably, depletion of galectin-3 from enterocytes and subsequent apical protein mistargeting might even provide a means whereby other pathogens might alter intestinal epithelial absorption and produce diarrhea.« less

Pharmacokinetic studies of active triterpenoid saponins and the total secondary saponin from Anemone raddeana Regel.

PubMed

Zhang, Dandan; Lei, Tianli; Lv, Chongning; Zhao, Huimin; Xu, Haiyan; Lu, Jincai

2017-02-15

The rhizome of Anemone raddeana Regel, a Traditional Chinese Medicine (TCM) which has a robust history treating rheumatism and neuralgia. The total secondary saponin (TSS) from it has demonstrated antitumor activity. In this study, a rapid and validated LC-MS/MS method was developed to simultaneously determine the active compounds (Hederacolchiside A1 and Eleutheroside K). Analytes were separated on a reverse-phase C18 column with acetonitrile-water (5mmol/L ammonium acetate) as the mobile phase. This assay showed acceptable linearity (r>0.99) over the concentration range 5-1000 nmol/L for two analytes. The intra- and inter-day precision was within 8.06% and accuracy was ranged from -3.16% to 3.34% for two analytes. The mean extraction recoveries of analytes and IS from rat plasma were all more than 76.0%. Under the developed analytical conditions, the obtained values of main pharmacokinetic parameters (C max and AUC 0-t ) indicated that the pure compounds were more efficient than the TSS extract in Hederacolchiside A1 and Eleutheroside K absorption. In addition, pharmacokinetic studies of two individual compounds demonstrated their poor oral absorption in rat ( a F%, 0.019-1.521). In the study of absorption and transportation of Hederacolchiside A1 and Eleutheroside K in Caco-2 cell monolayer model, the uptake permeability was in 10 -6 cm/sec range suggesting poor absorption, which confirmed the previous pharmacokinetic profiles in vivo. Interestingly, the uptake ratio of them declined significantly when treated with phloridzin (SGLT1 inhibitor). It indicated that the absorption of Hederacolchiside A1 in intestine was mainly through positive transport and SGLT1 might participate in its active absorption. Copyright © 2017 Elsevier B.V. All rights reserved.

Mass Spectrometry Imaging proves differential absorption profiles of well-characterised permeability markers along the crypt-villus axis.

PubMed

Nilsson, Anna; Peric, Alexandra; Strimfors, Marie; Goodwin, Richard J A; Hayes, Martin A; Andrén, Per E; Hilgendorf, Constanze

2017-07-25

Knowledge about the region-specific absorption profiles from the gastrointestinal tract of orally administered drugs is a critical factor guiding dosage form selection in drug development. We have used a novel approach to study three well-characterized permeability and absorption marker drugs in the intestine. Propranolol and metoprolol (highly permeable compounds) and atenolol (low-moderate permeability compound) were orally co-administered to rats. The site of drug absorption was revealed by high spatial resolution matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and complemented by quantitative measurement of drug concentration in tissue homogenates. MALDI-MSI identified endogenous molecular markers that illustrated the villi structures and confirmed the different absorption sites assigned to histological landmarks for the three drugs. Propranolol and metoprolol showed a rapid absorption and shorter transit distance in contrast to atenolol, which was absorbed more slowly from more distal sites. This study provides novel insights into site specific absorption for each of the compounds along the crypt-villus axis, as well as confirming a proximal-distal absorption gradient along the intestine. The combined analytical approach allowed the quantification and spatial resolution of drug distribution in the intestine and provided experimental evidence for the suggested absorption behaviour of low and highly permeable compounds.

Effect of intravenous ranitidine and omeprazole on intestinal absorption of water, sodium, and macronutrients in patients with intestinal resection

PubMed Central

Jeppesen, P; Staun, M; Tjellesen, L; Mortensen, P

1998-01-01

Background—H2 receptor blockers and proton pump inhibitors reduce intestinal output in patients with short bowel syndrome. 
Aims—To evaluate the effect of intravenous omeprazole and ranitidine on water, electrolyte, macronutrient, and energy absorption in patients with intestinal resection. 
Methods—Thirteen patients with a faecal weight above 1.5 kg/day (range 1.7-5.7 kg/day and a median small bowel length of 100cm were studied. Omeprazole 40 mg twice daily or ranitidine 150mg twice daily were administered for five days in a randomised, double blind, crossover design followed by a three day control period with no treatment. Two patients with a segment of colon in continuation were excluded from analysis which, however, had no influence on the results. 
Results—Omeprazole increased median intestinal wet weight absorption compared with no treatment and ranitidine (p<0.03). The effect of ranitidine was not significant. Four patients with faecal volumes below 2.6 kg/day did not respond to omeprazole; in two absorption increased by 0.5-1 kg/day; and in five absorption increased by 1−2 kg/day. Absorption of sodium, calcium, magnesium, nitrogen, carbohydrate, fat, and total energy was unchanged. Four high responders continued on omeprazole for 12-15 months, but none could be weaned from parenteral nutrition. 
Conclusion—Omeprazole increased water absorption in patients with faecal output above 2.50 kg/day. The effect varied significantly and was greater in patients with a high output, but did not allow parenteral nutrition to be discontinued. Absorption of energy, macronutrients, electrolytes, and divalent cations was not improved. The effect of ranitidine was not significant, possibly because the dose was too low. 

 Keywords: short bowel syndrome; human; diarrhoea; ranitidine; omeprazole PMID:9824602

Intestinal adaptations to a combination of different diets with and without endurance exercise.

PubMed

Daniels, Janice L; Bloomer, Richard J; van der Merwe, Marie; Davis, Samantha L; Buddington, Karyl K; Buddington, Randal K

2016-01-01

Endurance athletes search for diet regimens that will improve performance and decrease gastrointestinal disturbances during training and events. Although the intestine can adapt to changes in the amount and composition of dietary inputs, the responses to the combination of endurance exercise and diet are poorly understood. We evaluated small intestinal dimensions and mucosal architecture and calculated the capacities of the entire small intestine to digest maltose and maltodextrin and absorb glucose in response to two different diet types; a western human diet and the Daniel Fast, a vegan style diet, and with moderate intensity endurance training or a no-exercise sedentary lifestyle for a 13 week period (n = 7 per group). The influences of diet and exercise, alone and in combination, were analyzed by analysis of variation. Rats fed the western diet gained more weight (P < 0.05) due to more fat mass (P < 0.05), with a similar response for the sedentary compared with the exercised rats in each diet group (P < 0.05). The Daniel Fast rats had longer and heavier intestines with deeper crypts with villi that were wider (P < 0.05), but not taller. Despite increased energetic demands, the exercised rats had shorter and lighter intestines with shorter villi (P < 0.05). Yet, the percentage of mucosa did not differ among groups. Total small intestinal activities for maltase and α-glucoamylase, and capacities for glucose absorption were similar regardless of diet or exercise. These findings indicate the structural responses of the small intestine to a vegan style diet are modified by exercise, but without altering the capacities of the brush border membrane to digest and absorb carbohydrates.

Characterization of a gastrointestinal tract microscale cell culture analog used to predict drug toxicity

USDA-ARS?s Scientific Manuscript database

The lining of the gastrointestinal (GI) tract is the largest surface exposed to the external environment in the human body. One of the main functions of the small intestine is absorption, and intestinal absorption is a route used by essential nutrients, chemicals, and pharmaceuticals to enter the sy...

Ezetimibe selectively inhibits intestinal cholesterol absorption in rodents in the presence and absence of exocrine pancreatic function

PubMed Central

van Heek, Margaret; Farley, Constance; Compton, Douglas S; Hoos, Lizbeth; Davis, Harry R

2001-01-01

Ezetimibe potently inhibits the transport of cholesterol across the intestinal wall, thereby reducing plasma cholesterol in preclinical animal models of hypercholesterolemia. The effect of ezetimibe on known absorptive processes was determined in the present studies.Experiments were conducted in the hamster and/or rat to determine whether ezetimibe would affect the absorption of molecules other than free cholesterol, namely cholesteryl ester, triglyceride, ethinylestradiol, progesterone, vitamins A and D, and taurocholic acid. In addition, to determine whether exocrine pancreatic function is involved in the mechanism of action of ezetimibe, a biliary anastomosis model, which eliminates exocrine pancreatic function from the intestine while maintaining bile flow, was established in the rat.Ezetimibe reduced plasma cholesterol and hepatic cholesterol accumulation in cholesterol-fed hamsters with an ED50 of 0.04 mg kg−1. Utilizing cholesteryl esters labelled on either the cholesterol or the fatty acid moiety, we demonstrated that ezetimibe did not affect cholesteryl ester hydrolysis and the absorption of fatty acid thus generated in both hamsters and rats. The free cholesterol from this hydrolysis, however, was not absorbed (92 – 96% inhibition) in the presence of ezetimibe. Eliminating pancreatic function in rats abolished hydrolysis of cholesteryl esters, but did not affect the ability of ezetimibe to block absorption of free cholesterol (−94%). Ezetimibe did not affect the absorption of triglyceride, ethinylestradiol, progesterone, vitamins A and D, and taurocholic acid in rats.Ezetimibe is a potent inhibitor of intestinal free cholesterol absorption that does not require exocrine pancreatic function for activity. Ezetimibe does not affect the absorption of triglyceride as a pancreatic lipase inhibitor (Orlistat) would, nor does it affect the absorption of vitamin A, D or taurocholate, as a bile acid sequestrant (cholestyramine) would. PMID:11564660

Antioxidant and antiapoptotic properties of melatonin restore intestinal calcium absorption altered by menadione.

PubMed

Carpentieri, A; Marchionatti, A; Areco, V; Perez, A; Centeno, V; Tolosa de Talamoni, N

2014-02-01

The intestinal Ca²⁺ absorption is inhibited by menadione (MEN) through oxidative stress and apoptosis. The aim of this study was to elucidate whether the antioxidant and antiapoptotic properties of melatonin (MEL) could protect the gut against the oxidant MEN. For this purpose, 4-week-old chicks were divided into four groups: (1) controls, (2) treated i.p. with MEN (2.5 μmol/kg of b.w.), (3) treated i.p. with MEL (10 mg/kg of b.w.), and (4) treated with 10 mg MEL/kg of b.w after 2.5 μmol MEN/kg of b.w. Oxidative stress was assessed by determination of glutathione (GSH) and protein carbonyl contents as well as antioxidant enzyme activities. Apoptosis was assayed by the TUNEL technique, protein expression, and activity of caspase 3. The data show that MEL restores the intestinal Ca²⁺ absorption altered by MEN. In addition, MEL reversed the effects caused by MEN such as decrease in GSH levels, increase in the carbonyl content, alteration in mitochondrial membrane permeability, and enhancement of superoxide dismutase and catalase activities. Apoptosis triggered by MEN in the intestinal cells was arrested by MEL, as indicated by normalization of the mitochondrial membrane permeability, caspase 3 activity, and DNA fragmentation. In conclusion, MEL reverses the inhibition of intestinal Ca²⁺ absorption produced by MEN counteracting oxidative stress and apoptosis. These findings suggest that MEL could be a potential drug of choice for the reversal of impaired intestinal Ca²⁺ absorption in certain gut disorders that occur with oxidative stress and apoptosis.

Protective Effects of Tinospora cordifolia on Hepatic and Gastrointestinal Toxicity Induced by Chronic and Moderate Alcoholism.

PubMed

Sharma, Bhawana; Dabur, Rajesh

2016-01-01

Heavy alcohol intake depletes the plasma vitamins due to hepatotoxicity and decreased intestinal absorption. However, moderate alcohol intake is often thought to be healthy. Therefore, effects of chronic moderate alcohol intake on liver and intestine were studied using urinary vitamin levels. Furthermore, effects of Tinospora cordifolia water extract (TCE) (hepatoprotective) on vitamin excretion and intestinal absorption were also studied. In the study, asymptomatic moderate alcoholics (n = 12) without chronic liver disease and healthy volunteers (n = 14) of mean age 39 ± 2.2 (mean ± SD) were selected and divided into three groups. TCE treatment was performed for 14 days. The blood and urine samples were collected on Day 0 and 14 after treatment with TCE and analyzed. In alcoholics samples, a significant increase in the levels of gamma-glutamyl transferase, aspartate transaminase, alanine transaminase, Triglyceride, Cholesterol, HDL and LDL (P < 0.05) was observed but their level get downregulated after TCE intervention. Multivariate analysis of metabolites without missing values showed an increased excretion of 7-dehydrocholesterol, orotic acid, pyridoxine, lipoamide and niacin and TCE intervention depleted their levels (P < 0.05). In contrast, excretion of biotin, xanthine, vitamin D2 and 2-O-p-coumaroyltartronic acid (CA, an internal marker of intestinal absorption) were observed to be decreased in alcoholic samples; however, TCE intervention restored the CA and biotin levels. Vitamin metabolism biomarkers, i.e. homocysteine and xanthurenic acid, were also normalized after TCE intervention. Overall data depict that moderate alcohol intake is also hepatotoxic and decreases intestinal absorption. However, TCE treatment effectively increased the intestinal absorption and retaining power of liver that regulated alcohol-induced multivitamin deficiency. © The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.

Genetics Home Reference: hereditary folate malabsorption

MedlinePlus

... PCFT is important for normal functioning of intestinal epithelial cells, which are cells that line the walls of the intestine. ... intestinal absorption and transport into systemic compartments and tissues. Expert Rev Mol Med. 2009 Jan 28;11: ...

Critical Problems Stalling Progress in Natural Bioactive Polysaccharide Research and Development.

PubMed

Han, Quan-Bin

2018-05-09

Natural polysaccharides are attracting increasing attention from food and pharmaceutical industries for their wide range of valuable biological activities. However, the poor repeatability of the methods used in sample preparation and chemical characterization is hampering both research and product development. The unstandardized quality, in turn, undermines efforts to understand the mechanism by which they work via oral dose, which is essential to realize the full beneficial potential of polysaccharides. Some scientists believe polysaccharides work by direct gut absorption; however, increasing evidence points to the gut microbiome and intestinal Peyer's patches as holding the keys to how they work.

Relationship of /sup 65/Zn absorption kinetics to intestinal metallothionein in rats: effects of zinc depletion and fasting

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoadley, J.E.; Leinart, A.S.; Cousins, R.J.

1988-04-01

Intestinal 65Zn transport and metallothionein levels were examined in rats fed zinc-adequate and zinc-deficient diets and in rats subjected to an overnight fast. 65Zn uptake by intestines perfused with 1.5 microM 65Zn was greater in both zinc-deficient and fasted groups than in the control group. Mucosal retention of 65Zn was also greater in the zinc-deficient group but not in the fasted group. The greater 65Zn uptake in the fasted group was associated with a compartment that readily released 65Zn back into the lumen. Kinetic analysis of the rate of 65Zn transfer to the vascular space (absorption) showed that 65Zn absorptionmore » involved approximately 3% of mucosal 65Zn in a 40-min perfusion period. The half-life (t1/2) of this mucosal 65Zn rapid transport pool corresponded directly to changes in intestinal metallothionein levels. Both metallothionein and t1/2 were higher in the fasted group and lower in the zinc-deficient group than in controls. While the rate of 65Zn transport from this rapid transport pool decreased with increasing metallothionein level, the predicted pool size increased when the metallothionein level was elevated by fasting. These results indicate that the rate of zinc absorption is inversely related to intestinal metallothionein levels, but the portion of mucosal 65Zn available for absorption is directly related to intestinal metallothionein.« less

Functionalized PLA-PEG nanoparticles targeting intestinal transporter PepT1 for oral delivery of acyclovir.

PubMed

Gourdon, Betty; Chemin, Caroline; Moreau, Amélie; Arnauld, Thomas; Baumy, Philippe; Cisternino, Salvatore; Péan, Jean-Manuel; Declèves, Xavier

2017-08-30

Targeting intestinal di- and tri-peptide transporter PepT1 with prodrugs is a successful strategy to improve oral drug bioavailability, as demonstrated with valacyclovir, a prodrug of acyclovir. The aim of this new drug delivery strategy is to over-concentrate a poorly absorbed drug on the intestinal membrane surface by targeting PepT1 with functionalized polymer nanoparticles. In the present study, poly(lactic acid)-poly(ethylene glycol)-ligand (PLA-PEG-ligand) nanoparticles were obtained by nanoprecipitation. A factorial experimental design allowed us to identify size-influent parameters and to obtain optimized ≈30nm nanoparticles. Valine, Glycylsarcosine, Valine-Glycine, and Tyrosine-Valine were chemically linked to PLA-PEG. In Caco-2 cell monolayer model, competition between functionalized nanoparticles and [ 3 H]Glycylsarcosine, a strong substrate of PepT1, reduced [ 3 H]Glycylsarcosine transport from 22 to 46%. Acyclovir was encapsulated with a drug load of ≈10% in valine-functionalized nanoparticles, resulting in a 2.7-fold increase in permeability as compared to the free drug. An in vivo pharmacokinetic study in mice compared oral absorption of acyclovir after administration of 25mg/kg of valacyclovir, free or encapsulated acyclovir in functionalized nanoparticles. Acyclovir encapsulation did not statistically modify AUC or C max , but increased t 1/2 and MRT 1.3-fold as compared to free acyclovir. This new strategy is promising for poorly absorbed drugs by oral administration. Copyright © 2017 Elsevier B.V. All rights reserved.

Administration of Inulin-Supplemented Gluten-Free Diet Modified Calcium Absorption and Caecal Microbiota in Rats in a Calcium-Dependent Manner.

PubMed

Krupa-Kozak, Urszula; Markiewicz, Lidia H; Lamparski, Grzegorz; Juśkiewicz, Jerzy

2017-07-06

In coeliac disease (CD), the risk of adverse calcium balance and reduced bone density is induced mainly by the disease, but also by a gluten-free diet (GFD), the only accepted CD therapy. Prebiotics through the beneficial impact on intestinal microbiota may stimulate calcium (Ca) absorption. In the present study, we hypothesised that the dietary inulin in GFD would influence positively the intestinal microbiota, and by that will stimulate the absorption of calcium (Ca), especially in the conditions of Ca malnutrition. In a six-weeks nutritional experiment on growing a significant ( p < 0.05) luminal acidification, decrease in ammonia concentration and stimulation of short chain fatty acids formation indicated inulin-mediated beneficial effects on the caecal microbiota. However, the effect of inulin on characteristics of intestinal microbiota and mineral utilization depended on the dietary Ca intake from GFDs. Inulin stimulated bifidobacteria, in particular B. animalis species, only if a recommended amount of Ca was provided. Most benefits to mineral utilization from inulin consumption were seen in rats fed Ca-restricted GFD where it increased the relative Ca absorption. Administration of inulin to a GFDs could be a promising dietary strategy for beneficial modulation of intestinal ecosystem and by that for the improvement the Ca absorption.

Altered intestinal absorption of L-thyroxine caused by coffee.

PubMed

Benvenga, Salvatore; Bartolone, Luigi; Pappalardo, Maria Angela; Russo, Antonia; Lapa, Daniela; Giorgianni, Grazia; Saraceno, Giovanna; Trimarchi, Francesco

2008-03-01

To report eight case histories, and in vivo and in vitro studies showing coffee's potential to impair thyroxine (T4) intestinal absorption. Of eight women with inappropriately high or nonsuppressed thyroid-stimulating hormone (TSH) when T4 was swallowed with coffee/espresso, six consented to the evaluation of their T4 intestinal absorption. This in vivo test was also administered to nine volunteers. In three separate tests, two 100 microg T4 tablets were swallowed with coffee, water, or water followed, 60 minutes later, by coffee. Serum T4 was assayed over the 4-hour period of the test. Two patients and two volunteers also agreed on having tested the intestinal absorption of T4 swallowed with solubilized dietary fibers. In the in vitro studies, classical recovery tests on known concentrations of T4 were performed in the presence of saline, coffee, or known T4 sequestrants (dietary fibers, aluminium hydroxide, and sucralfate). For the in vivo test, average and peak incremental rise of serum T4 (AIRST4 and PIRST4), time of maximal incremental rise of serum T4 (TMIRST4), and area under the curve (AUC) were determined. In patients and volunteers, the four outcome measures were similar in the water and water + coffee tests. In patients and volunteers, compared to water, coffee lowered AIRST4 (by 36% and 29%), PIRST4 (by 30% and 19%), and AUC (by 36% and 27%) and delayed TMIRST4 (by 38 and 43 minutes); bran was a superior interferer. In the in vitro studies, coffee was weaker than known T4 sequestrants. Coffee should be added to the list of interferers of T4 intestinal absorption, and T4 to the list of compounds whose absorption is affected by coffee.

Mass balance approaches for estimating the intestinal absorption and metabolism of peptides and analogues: theoretical development and applications

NASA Technical Reports Server (NTRS)

Sinko, P. J.; Leesman, G. D.; Amidon, G. L.

1993-01-01

A theoretical analysis for estimating the extent of intestinal peptide and peptide analogue absorption was developed on the basis of a mass balance approach that incorporates convection, permeability, and reaction. The macroscopic mass balance analysis (MMBA) was extended to include chemical and enzymatic degradation. A microscopic mass balance analysis, a numerical approach, was also developed and the results compared to the MMBA. The mass balance equations for the fraction of a drug absorbed and reacted in the tube were derived from the general steady state mass balance in a tube: [formula: see text] where M is mass, z is the length of the tube, R is the tube radius, Pw is the intestinal wall permeability, kr is the reaction rate constant, C is the concentration of drug in the volume element over which the mass balance is taken, VL is the volume of the tube, and vz is the axial velocity of drug. The theory was first applied to the oral absorption of two tripeptide analogues, cefaclor (CCL) and cefatrizine (CZN), which degrade and dimerize in the intestine. Simulations using the mass balance equations, the experimental absorption parameters, and the literature stability rate constants yielded a mean estimated extent of CCL (250-mg dose) and CZN (1000-mg dose) absorption of 89 and 51%, respectively, which was similar to the mean extent of absorption reported in humans (90 and 50%). It was proposed previously that 15% of the CCL dose spontaneously degraded systematically; however, our simulations suggest that significant CCL degradation occurs (8 to 17%) presystemically in the intestinal lumen.(ABSTRACT TRUNCATED AT 250 WORDS).

Plasma concentrations of remoxipride and the gastrointestinal transit of 111In-marked extended-release coated spheres

DOE Office of Scientific and Technical Information (OSTI.GOV)

Graffner, C.; Wagner, Z.; Nilsson, M.I.

1990-01-01

To explore the oral absorption of remoxipride, spheres of remoxipride were labeled with indium-111 colloid before coating with a release-controlling ethylcellulose membrane. Since the labeling remained inside the coating, it was suitable as a marker. Eight healthy volunteers were given a single dose of 100 mg remoxipride in 111In-marked spheres as a multiple-unit capsule. The radioactivity and the position of the spheres (microcapsules) were followed externally for 30 hr by gamma scintigraphy. Parallel to this, plasma concentrations were drawn for 48 hr to confirm the extended dissolution and absorption of remoxipride. The hard gelatin, multiple-unit capsule released the microcapsules withinmore » the stomach. These were then rapidly emptied into the small intestine, within 0.5-1 hr. There was then an immediate distribution in the upper small intestine before collection in the lower portion, within 2-5 hr. After passing into the large intestine, there was again extended distribution of the microcapsules. A mean Cmax of 2.7 microM remoxipride was achieved 4 hr after drug administration and a mean AUC of 26.1 mumol.L-1.hr was achieved. Judging from the absorption versus time profile, calculated according to the Wagner-Nelson method, and the scintigraphic images, it is concluded that the main absorption occurs from the small intestine. Data from four volunteers, however, indicated a comparatively good absorption also from the large intestine. Due to the good absorption properties, it is reasonable to expect a low variation in the extent of bioavailability of remoxipride after administration in an extended-release, multiple-unit capsule formulation.« less

Presence of leptin receptors in rat small intestine and leptin effect on sugar absorption.

PubMed

Lostao, M P; Urdaneta, E; Martínez-Ansó, E; Barber, A; Martínez, J A

1998-02-27

Leptin is involved in food intake and thermogenesis regulation. Since leptin receptor expression has been found in several tissues including small intestine, a possible role of leptin in sugar absorption by the intestine was investigated. Leptin inhibited D-galactose uptake by rat small intestinal rings 33% after 5 min of incubation. The inhibition increased to 56% after 30 min. However, neither at 5 min nor at 30 min did leptin prevent intracellular galactose accumulation. This leptin effect was accompanied by a decrease of the active sugar transport apparent Vmax (20 vs. 4.8 micromol/g wet weight 5 min) and apparent Km (15.8 vs. 5.3 mM) without any change in the phlorizin-resistant component. On the other hand, immunohistochemical experiments using anti-leptin monoclonal antibodies recognized leptin receptors in the plasma membrane of immune cells located in the lamina propria. These results indicate for the first time that leptin has a rapid inhibitory effect on sugar absorption and demonstrate the presence of leptin receptors in the intestinal mucosa.

Dietary Phospholipids and Intestinal Cholesterol Absorption

PubMed Central

Cohn, Jeffrey S.; Kamili, Alvin; Wat, Elaine; Chung, Rosanna W. S.; Tandy, Sally

2010-01-01

Experiments carried out with cultured cells and in experimental animals have consistently shown that phospholipids (PLs) can inhibit intestinal cholesterol absorption. Limited evidence from clinical studies suggests that dietary PL supplementation has a similar effect in man. A number of biological mechanisms have been proposed in order to explain how PL in the gut lumen is able to affect cholesterol uptake by the gut mucosa. Further research is however required to establish whether the ability of PLs to inhibit cholesterol absorption is of therapeutic benefit. PMID:22254012

Morphogenesis and maturation of the embryonic and postnatal intestine.

PubMed

Chin, Alana M; Hill, David R; Aurora, Megan; Spence, Jason R

2017-06-01

The intestine is a vital organ responsible for nutrient absorption, bile and waste excretion, and a major site of host immunity. In order to keep up with daily demands, the intestine has evolved a mechanism to expand the absorptive surface area by undergoing a morphogenetic process to generate finger-like units called villi. These villi house specialized cell types critical for both absorbing nutrients from food, and for protecting the host from commensal and pathogenic microbes present in the adult gut. In this review, we will discuss mechanisms that coordinate intestinal development, growth, and maturation of the small intestine, starting from the formation of the early gut tube, through villus morphogenesis and into early postnatal life when the intestine must adapt to the acquisition of nutrients through food intake, and to interactions with microbes. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

[Important application of intestinal transporters and metabolism enzymes on gastrointestinal disposal of active ingredients of Chinese materia medica].

PubMed

Bi, Xiaolin; Du, Qiu; Di, Liuqing

2010-02-01

Oral drug bioavailability depends on gastrointestinal absorption, intestinal transporters and metabolism enzymes are the important factors in drug gastrointestinal absorption and they can also be induced or inhibited by the active ingredients of Chinese materia medica. This article presents important application of intestinal transporters and metabolism enzymes on gastrointestinal disposal of the active ingredients of Chinese materia medica, and points out the importance of research on transport and metabolism of the active ingredients of Chinese materia medica in Chinese extract and Chinese medicinal formulae.

Ontogeny and distribution of alkaline and acid phosphatases in the digestive system of California halibut larvae (Paralichthys californicus).

PubMed

Zacarias-Soto, Magali; Barón-Sevilla, Benjamín; Lazo, Juan P

2013-10-01

Studies aimed to assess the digestive physiology of marine fish larvae under culture conditions are important to further understand the functional characteristics and digestive capacities of the developing larvae. Most studies to date concentrate on intestinal lumen digestion and little attention to the absorption process. Thus, the objectives of this study were to histochemically detect and quantify some of the enzymes responsible for absorption and intracellular digestion of nutrients in the anterior and posterior intestine of California halibut larvae. Alkaline and acid phosphatases were detected from the first days post-hatch (dph). Alkaline phosphatase maintained a high level of activity during the first 20 dph in both intestinal regions. Thereafter, a clear intestinal regionalization of the activity was observed with the highest levels occurring in the anterior intestine. Acid phosphatase activity gradually increased in both intestinal regions during development, and a regionalization of the activity was not observed until late in development, once the ocular migration began. Highest levels were observed in the anterior intestine at the end of metamorphosis concomitant with the stomach development. The results from this study show some morphological and physiological changes are occurring during larval development and a clear regionalization of the absorption process as the larvae develops. These ontological changes must be considered in the elaboration of diets according to the digestive capacity of the larvae.

[Impact of high-fat diet induced obesity on glucose absorption in small intestinal mucose in rats].

PubMed

Huang, Wei; Liu, Rui; Guo, Wei; Wei, Na; Qiang, Ou; Li, Xian; Ou, Yan; Tang, Chengwei

2012-11-01

To investigate whether high-fat diet induced obesity was associated with variation of glucose absorption in small intestinal mucosa of rats. 46 male SD rats were randomly divided into high-fat diet group (n = 31) and control group (n = 15), fed with high-fat diet and normal diet for 24 weeks, respectively. After 24 weeks, the rats were divided into obese (n = 16) and obesity-resistant group (n = 10) according to their body weight. Rats' body weight, abdominal fat weight, plasma glucose level, maltase, sucrase activity in small intestinal mucosa were measured. SGLT-1 expression in intestinal mucosa was detected by immunohistochemistry, RT-PCR and Western blot. Mean body weight, abdominal fat weight, fast plasma glucose levels, maltase activities and SGLT-1 protein expression in intestinal mucosa of obese rats were significantly higher than those in the control and obesity-resistant rats (P < 0.05). Sucrase activities in intestinal mucosa showed no statistical difference among the three groups (P > 0.05). The SGLT-1 mRNA expression in obese group was increased by 12.5% and 23% when compare with the control and obesity-resistant group, respectively. But the difference was not statistical significant (P > 0.05). High-fat diet induced obesity was associated with the increased intestinal maltase activity and expression of SGLT-1 in rats, the key molecule in glucose absorption.

Intestinal absorption of the antiepileptic drug substance vigabatrin is altered by infant formula in vitro and in vivo.

PubMed Central

Nøhr, Martha Kampp; Thale, Zia I; Brodin, Birger; Hansen, Steen H; Holm, René; Nielsen, Carsten Uhd

2014-01-01

Vigabatrin is an antiepileptic drug substance mainly used in pediatric treatment of infantile spasms. The main source of nutrition for infants is breast milk and/or infant formula. Our hypothesis was that infant formula may affect the intestinal absorption of vigabatrin. The aim was therefore to investigate the potential effect of coadministration of infant formula with vigabatrin on the oral absorption in vitro and in vivo. The effect of vigabatrin given with an infant formula on the oral uptake and transepithelial transport was investigated in vitro in Caco-2 cells. In vivo effects of infant formula and selected amino acids on the pharmacokinetic profile of vigabatrin was investigated after oral coadministration to male Sprague–Dawley rats using acetaminophen as a marker for gastric emptying. The presence of infant formula significantly reduced the uptake rate and permeability of vigabatrin in Caco-2 cells. Oral coadministration of vigabatrin and infant formula significantly reduced Cmax and prolonged tmax of vigabatrin absorption. Ligands for the proton-coupled amino acid transporter PAT1, sarcosine, and proline/l-tryptophan had similar effects on the pharmacokinetic profile of vigabatrin. The infant formula decreased the rate of gastric emptying. Here we provide experimental evidence for an in vivo role of PAT1 in the intestinal absorption of vigabatrin. The effect of infant formula on the oral absorption of vigabatrin was found to be due to delayed gastric emptying, however, it seems reasonable that infant formula may also directly affect the intestinal absorption rate of vigabatrin possibly via PAT1. PMID:25505585

Influence of betaine and salinomycin on intestinal absorption of methionine and glucose and on the ultrastructure of intestinal cells and parasite developmental stages in chicks infected with Eimeria acervulina.

PubMed

Augustine, P C; Danforth, H D

1999-01-01

The effect of betaine and salinomycin on absorption of methionine and glucose in tissue from the duodenal loops of Eimeria acervulina-infected chicks was determined. Differences in the ultrastructure of the intestinal cells and parasite developmental stages were also examined. With a drug-resistant isolate of E. acervulina, methionine absorption was significantly higher in chicks fed a basal diet supplemented with 0.15% betaine as compared with absorption in chicks fed the unsupplemented basal diet. Addition of 66 ppm salinomycin to the diet containing betaine did not further enhance absorption. Conversely, with a drug-sensitive isolate, methionine absorption was significantly higher in chicks fed a diet supplemented with both betaine and salinomycin than in chicks fed the unsupplemented basal diet. Tissue from chicks fed any of the supplemented diets was usually significantly heavier than that from chicks fed the unsupplemented diet, even when weight gains of the birds were similar. Glucose absorption was similar in all diet groups. Epithelial cells in coccidia-infected and uninfected chicks fed diets supplemented with betaine or betaine plus salinomycin were less electron dense than cells from chicks fed diets that were not supplemented with betaine. Merozoites of E. acervulina in chicks fed diets supplemented with salinomycin had extensive membrane disruption and vacuolization, but the damage was prevented when betaine was added to the diet. Numerous merozoites and intact schizonts were seen in the intestinal lumen of chicks fed the diet containing betaine plus salinomycin.

Intestinal absorption of copper: influence of carbohydrates.

PubMed

Wapnir, R A; Balkman, C

1992-02-01

Macronutrients can modulate the intestinal absorption of trace elements by binding the metal or altering mucosal function. We investigated whether certain simple and complex carbohydrates modify copper (Cu) absorption, using an in vivo perfusion technique in the rat. Corn syrup solids, which contain a mixture of glucose polymers of diverse length, added at either 20 or 50 mosm/kg enhanced Cu absorption from a 31.5 microM (2 mg/liter) Cu solution (128 +/- 11 and 130 +/- 11 pmol/min x cm, respectively, vs 101 +/- 4 pmol/min x cm, P less than 0.05, in the absence of carbohydrate). This was concomitant with a stimulation of net water absorption (1.05 +/- 0.08 and 0.84 +/- 0.08 microliter/min x cm, respectively, vs 0.63 +/- 0.02 microliter/min x cm with no carbohydrate, P less than 0.05). Glucose, fructose, lactose, or sucrose had no influence on Cu absorption, although they altered water exchanges, an effect attributable to a reduction of the outflow component of fluid recirculation. Low concentrations of lactose resulted in a greater accumulation of Cu in the intestinal mucosa (8.75 +/- 0.71 micrograms/g vs 5.77 +/- 0.68 micrograms/g for controls, P less than 0.05). Hence, solutes that moderately stimulate mucosa-to-serosa fluid influx in a progressive manner, such as glucose polymers, may contribute to functionally increase Cu absorption. Conversely, conditions which tend to reduce water inflow or increase water outflow across the small intestinal mucosa, as may occur with high lactose diets or in cases of chronic diarrhea, may have negative effects.

Antibiotics Suppress Activation of Intestinal Mucosal Mast Cells and Reduce Dietary Lipid Absorption in Sprague-Dawley Rats.

PubMed

Sato, Hirokazu; Zhang, Linda S; Martinez, Kristina; Chang, Eugene B; Yang, Qing; Wang, Fei; Howles, Philip N; Hokari, Ryota; Miura, Soichiro; Tso, Patrick

2016-11-01

The gut microbiota affects intestinal permeability and mucosal mast cells (MMCs) responses. Activation of MMCs has been associated with absorption of dietary fat. We investigated whether the gut microbiota contributes to the fat-induced activation of MMCs in rats, and how antibiotics might affect this process. Adult male Sprague-Dawley rats were given streptomycin and penicillin for 4 days (n = 6-8) to reduce the abundance of their gut flora, or normal drinking water (controls, n = 6-8). They underwent lymph fistula surgery and after an overnight recovery were given an intraduodenal bolus of intralipid. We collected intestinal tissues and lymph fluid and assessed activation of MMCs, intestinal permeability, and fat transport parameters. Compared with controls, intestinal lymph from rats given antibiotics had reduced levels of mucosal mast cell protease II (produced by MMCs) and decreased activity of diamine oxidase (produced by enterocytes) (P < .05). Rats given antibiotics had reduced intestinal permeability in response to dietary lipid compared with controls (P < .01). Unexpectedly, antibiotics also reduced lymphatic transport of triacylglycerol and phospholipid (P < .01), concomitant with decreased levels of mucosal apolipoproteins B, A-I, and A-IV (P < .01). No differences were found in intestinal motility or luminal pancreatic lipase activity between rats given antibiotics and controls. These effects were not seen with an acute dose of antibiotics or 4 weeks after the antibiotic regimen ended. The intestinal microbiota appears to activate MMCs after the ingestion of fat in rats; this contributes to fat-induced intestinal permeability. We found that the gut microbiome promotes absorption of lipid, probably by intestinal production of apolipoproteins and secretion of chylomicrons. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Bile Acid-regulated Peroxisome Proliferator-activated Receptor-α (PPARα) Activity Underlies Circadian Expression of Intestinal Peptide Absorption Transporter PepT1/Slc15a1*

PubMed Central

Okamura, Ayako; Koyanagi, Satoru; Dilxiat, Adila; Kusunose, Naoki; Chen, Jia Jun; Matsunaga, Naoya; Shibata, Shigenobu; Ohdo, Shigehiro

2014-01-01

Digested proteins are mainly absorbed as small peptides composed of two or three amino acids. The intestinal absorption of small peptides is mediated via only one transport system: the proton-coupled peptide transporter-1 (PepT1) encoded from the soluble carrier protein Slc15a1. In mammals, intestinal expression of PepT1/Slc15a1 oscillates during the daily feeding cycle. Although the oscillation in the intestinal expression of PepT1/Slc15a1 is suggested to be controlled by molecular components of circadian clock, we demonstrated here that bile acids regulated the oscillation of PepT1/Slc15a1 expression through modulating the activity of peroxisome proliferator-activated receptor α (PPARα). Nocturnally active mice mainly consumed their food during the dark phase. PPARα activated the intestinal expression of Slc15a1 mRNA during the light period, and protein levels of PepT1 peaked before the start of the dark phase. After food intake, bile acids accumulated in intestinal epithelial cells. Intestinal accumulated bile acids interfered with recruitment of co-transcriptional activator CREB-binding protein/p300 on the promoter region of Slc15a1 gene, thereby suppressing PPARα-mediated transactivation of Slc15a1. The time-dependent suppression of PPARα-mediated transactivation by bile acids caused an oscillation in the intestinal expression of PepT1/Slc15a1 during the daily feeding cycle that led to circadian changes in the intestinal absorption of small peptides. These findings suggest a molecular clock-independent mechanism by which bile acid-regulated PPARα activity governs the circadian expression of intestinal peptide transporter. PMID:25016014

Ca2+-driven intestinal HCO3− secretion and CaCO3 precipitation in the European flounder in vivo: influences on acid-base regulation and blood gas transport

PubMed Central

Cooper, Christopher A.; Whittamore, Jonathan M.

2010-01-01

Marine teleost fish continuously ingest seawater to prevent dehydration and their intestines absorb fluid by mechanisms linked to three separate driving forces: 1) cotransport of NaCl from the gut fluid; 2) bicarbonate (HCO3−) secretion and Cl− absorption via Cl−/HCO3− exchange fueled by metabolic CO2; and 3) alkaline precipitation of Ca2+ as insoluble CaCO3, which aids H2O absorption). The latter two processes involve high rates of epithelial HCO3− secretion stimulated by intestinal Ca2+ and can drive a major portion of water absorption. At higher salinities and ambient Ca2+ concentrations the osmoregulatory role of intestinal HCO3− secretion is amplified, but this has repercussions for other physiological processes, in particular, respiratory gas transport (as it is fueled by metabolic CO2) and acid-base regulation (as intestinal cells must export H+ into the blood to balance apical HCO3− secretion). The flounder intestine was perfused in vivo with salines containing 10, 40, or 90 mM Ca2+. Increasing the luminal Ca2+ concentration caused a large elevation in intestinal HCO3− production and excretion. Additionally, blood pH decreased (−0.13 pH units) and plasma partial pressure of CO2 (Pco2) levels were elevated (+1.16 mmHg) at the highest Ca perfusate level after 3 days of perfusion. Increasing the perfusate [Ca2+] also produced proportional increases in net acid excretion via the gills. When the net intestinal flux of all ions across the intestine was calculated, there was a greater absorption of anions than cations. This missing cation flux was assumed to be protons, which vary with an almost 1:1 relationship with net acid excretion via the gill. This study illustrates the intimate link between intestinal HCO3− production and osmoregulation with acid-base balance and respiratory gas exchange and the specific controlling role of ingested Ca2+ independent of any other ion or overall osmolality in marine teleost fish. PMID:20130227

Ca2+-driven intestinal HCO(3)(-) secretion and CaCO3 precipitation in the European flounder in vivo: influences on acid-base regulation and blood gas transport.

PubMed

Cooper, Christopher A; Whittamore, Jonathan M; Wilson, Rod W

2010-04-01

Marine teleost fish continuously ingest seawater to prevent dehydration and their intestines absorb fluid by mechanisms linked to three separate driving forces: 1) cotransport of NaCl from the gut fluid; 2) bicarbonate (HCO(3)(-)) secretion and Cl(-) absorption via Cl(-)/HCO(3)(-) exchange fueled by metabolic CO(2); and 3) alkaline precipitation of Ca(2+) as insoluble CaCO(3), which aids H(2)O absorption). The latter two processes involve high rates of epithelial HCO(3)(-) secretion stimulated by intestinal Ca(2+) and can drive a major portion of water absorption. At higher salinities and ambient Ca(2+) concentrations the osmoregulatory role of intestinal HCO(3)(-) secretion is amplified, but this has repercussions for other physiological processes, in particular, respiratory gas transport (as it is fueled by metabolic CO(2)) and acid-base regulation (as intestinal cells must export H(+) into the blood to balance apical HCO(3)(-) secretion). The flounder intestine was perfused in vivo with salines containing 10, 40, or 90 mM Ca(2+). Increasing the luminal Ca(2+) concentration caused a large elevation in intestinal HCO(3)(-) production and excretion. Additionally, blood pH decreased (-0.13 pH units) and plasma partial pressure of CO(2) (Pco(2)) levels were elevated (+1.16 mmHg) at the highest Ca perfusate level after 3 days of perfusion. Increasing the perfusate [Ca(2+)] also produced proportional increases in net acid excretion via the gills. When the net intestinal flux of all ions across the intestine was calculated, there was a greater absorption of anions than cations. This missing cation flux was assumed to be protons, which vary with an almost 1:1 relationship with net acid excretion via the gill. This study illustrates the intimate link between intestinal HCO(3)(-) production and osmoregulation with acid-base balance and respiratory gas exchange and the specific controlling role of ingested Ca(2+) independent of any other ion or overall osmolality in marine teleost fish.

Oral absorption of peptides and nanoparticles across the human intestine: Opportunities, limitations and studies in human tissues.

PubMed

Lundquist, P; Artursson, P

2016-11-15

In this contribution, we review the molecular and physiological barriers to oral delivery of peptides and nanoparticles. We discuss the opportunities and predictivity of various in vitro systems with special emphasis on human intestine in Ussing chambers. First, the molecular constraints to peptide absorption are discussed. Then the physiological barriers to peptide delivery are examined. These include the gastric and intestinal environment, the mucus barrier, tight junctions between epithelial cells, the enterocytes of the intestinal epithelium, and the subepithelial tissue. Recent data from human proteome studies are used to provide information about the protein expression profiles of the different physiological barriers to peptide and nanoparticle absorption. Strategies that have been employed to increase peptide absorption across each of the barriers are discussed. Special consideration is given to attempts at utilizing endogenous transcytotic pathways. To reliably translate in vitro data on peptide or nanoparticle permeability to the in vivo situation in a human subject, the in vitro experimental system needs to realistically capture the central aspects of the mentioned barriers. Therefore, characteristics of common in vitro cell culture systems are discussed and compared to those of human intestinal tissues. Attempts to use the cell and tissue models for in vitro-in vivo extrapolation are reviewed. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

The Intestinal Copper Exporter CUA-1 Is Required for Systemic Copper Homeostasis in Caenorhabditis elegans*♦

PubMed Central

Chun, Haarin; Sharma, Anuj Kumar; Lee, Jaekwon; Chan, Jefferson; Jia, Shang; Kim, Byung-Eun

2017-01-01

Copper plays key catalytic and regulatory roles in biochemical processes essential for normal growth, development, and health. Defects in copper metabolism cause Menkes and Wilson's disease, myeloneuropathy, and cardiovascular disease and are associated with other pathophysiological states. Consequently, it is critical to understand the mechanisms by which organisms control the acquisition, distribution, and utilization of copper. The intestinal enterocyte is a key regulatory point for copper absorption into the body; however, the mechanisms by which intestinal cells transport copper to maintain organismal copper homeostasis are poorly understood. Here, we identify a mechanism by which organismal copper homeostasis is maintained by intestinal copper exporter trafficking that is coordinated with extraintestinal copper levels in Caenorhabditis elegans. Specifically, we show that CUA-1, the C. elegans homolog of ATP7A/B, localizes to lysosome-like organelles (gut granules) in the intestine under copper overload conditions for copper detoxification, whereas copper deficiency results in a redistribution of CUA-1 to basolateral membranes for copper efflux to peripheral tissues. Worms defective in gut granule biogenesis exhibit defects in copper sequestration and increased susceptibility to toxic copper levels. Interestingly, however, a splice isoform CUA-1.2 that lacks a portion of the N-terminal domain is targeted constitutively to the basolateral membrane irrespective of dietary copper concentration. Our studies establish that CUA-1 is a key intestinal copper exporter and that its trafficking is regulated to maintain systemic copper homeostasis. C. elegans could therefore be exploited as a whole-animal model system to study regulation of intra- and intercellular copper trafficking pathways. PMID:27881675

Corroboration of naringin effects on the intestinal absorption and pharmacokinetic behavior of candesartan cilexetil solid dispersions using in-situ rat models.

PubMed

Surampalli, Gurunath; K Nanjwade, Basavaraj; Patil, P A

2015-01-01

The aim of this study was to corroborate the effects of naringin, a P-glycoprotein inhibitor, on the intestinal absorption and pharmacokinetics of candesartan (CDS) from candesartan cilexetil (CAN) solid dispersions using in-situ rat models. Intestinal transport and absorption studies were examined by in-situ single pass perfusion and closed-loop models. We evaluated the intestinal membrane damage in the presence of naringin by measuring the release of protein and alkaline phosphatase (ALP). We noticed 1.47-fold increase in Peff of CDS from freeze-dried CAN-loaded solid dispersions with naringin (15 mg/kg, w/w) when compared with freeze-dried solid dispersion without naringin using in-situ single pass intestinal perfusion model. However, no intestinal membrane damage was observed in the presence of naringin. Our findings from in-situ closed-loop pharmacokinetic studies showed 1.34-fold increase in AUC with elevated Cmax and shortened tmax for freeze-dried solid dispersion with naringin as compared to freeze-dried solid dispersion without naringin. This study demonstrated that increased solubilization (favored by freeze-dried solid dispersion) and efflux pump inhibition (using naringin), the relative bioavailability of CDS can be increased, suggesting an alternative potential for improving oral bioavailability of CAN.

Insig proteins mediate feedback inhibition of cholesterol synthesis in the intestine.

PubMed

McFarlane, Matthew R; Liang, Guosheng; Engelking, Luke J

2014-01-24

Enterocytes are the only cell type that must balance the de novo synthesis and absorption of cholesterol, although the coordinate regulation of these processes is not well understood. Our previous studies demonstrated that enterocytes respond to the pharmacological blockade of cholesterol absorption by ramping up de novo sterol synthesis through activation of sterol regulatory element-binding protein-2 (SREBP-2). Here, we genetically disrupt both Insig1 and Insig2 in the intestine, two closely related proteins that are required for the feedback inhibition of SREBP and HMG-CoA reductase (HMGR). This double knock-out was achieved by generating mice with an intestine-specific deletion of Insig1 using Villin-Cre in combination with a germ line deletion of Insig2. Deficiency of both Insigs in enterocytes resulted in constitutive activation of SREBP and HMGR, leading to an 11-fold increase in sterol synthesis in the small intestine and producing lipidosis of the intestinal crypts. The intestine-derived cholesterol accumulated in plasma and liver, leading to secondary feedback inhibition of hepatic SREBP2 activity. Pharmacological blockade of cholesterol absorption was unable to further induce the already elevated activities of SREBP-2 or HMGR in Insig-deficient enterocytes. These studies confirm the essential role of Insig proteins in the sterol homeostasis of enterocytes.

Insig Proteins Mediate Feedback Inhibition of Cholesterol Synthesis in the Intestine*

PubMed Central

McFarlane, Matthew R.; Liang, Guosheng; Engelking, Luke J.

2014-01-01

Enterocytes are the only cell type that must balance the de novo synthesis and absorption of cholesterol, although the coordinate regulation of these processes is not well understood. Our previous studies demonstrated that enterocytes respond to the pharmacological blockade of cholesterol absorption by ramping up de novo sterol synthesis through activation of sterol regulatory element-binding protein-2 (SREBP-2). Here, we genetically disrupt both Insig1 and Insig2 in the intestine, two closely related proteins that are required for the feedback inhibition of SREBP and HMG-CoA reductase (HMGR). This double knock-out was achieved by generating mice with an intestine-specific deletion of Insig1 using Villin-Cre in combination with a germ line deletion of Insig2. Deficiency of both Insigs in enterocytes resulted in constitutive activation of SREBP and HMGR, leading to an 11-fold increase in sterol synthesis in the small intestine and producing lipidosis of the intestinal crypts. The intestine-derived cholesterol accumulated in plasma and liver, leading to secondary feedback inhibition of hepatic SREBP2 activity. Pharmacological blockade of cholesterol absorption was unable to further induce the already elevated activities of SREBP-2 or HMGR in Insig-deficient enterocytes. These studies confirm the essential role of Insig proteins in the sterol homeostasis of enterocytes. PMID:24337570

Isotope concentrations from 24-h urine and 3-h serum samples can be used to measure intestinal magnesium absorption in postmenopausal women

USDA-ARS?s Scientific Manuscript database

Studies suggest a link between magnesium status and osteoporosis. One barrier to more conclusive research on the potential relation is measuring intestinal magnesium absorption (MgA), which requires the use of stable isotopes and a >/= 6-d stool or 3-d urine collection. We evaluated alternative meth...

Effects of a single dose of menadione on the intestinal calcium absorption and associated variables.

PubMed

Marchionatti, Ana M; Díaz de Barboza, Gabriela E; Centeno, Viviana A; Alisio, Arturo E; Tolosa de Talamoni, Nori G

2003-08-01

The effect of a single large dose of menadione on intestinal calcium absorption and associated variables was investigated in chicks fed a normal diet. The data show that 2.5 micro mol of menadione/kg of b.w. causes inhibition of calcium transfer from lumen-to-blood within 30 min. This effect seems to be related to oxidative stress provoked by menadione as judged by glutathione depletion and an increment in the total carbonyl group content produced at the same time. Two enzymes presumably involved in calcium transcellular movement, such as alkaline phosphatase, located in the brush border membrane, and Ca(2+)- pump ATPase, which sits in the basolateral membrane, were also inhibited. The enzyme inhibition could be due to alterations caused by the appearance of free hydroxyl groups, which are triggered by glutathione depletion. Addition of glutathione monoester to the duodenal loop caused reversion of the menadione effect on both intestinal calcium absorption and alkaline phosphatase activity. In conclusion, menadione shifts the balance of oxidative and reductive processes in the enterocyte towards oxidation causing deleterious effects on intestinal Ca(2+) absorption and associated variables, which could be prevented by administration of oral glutathione monoester.

An Intestinal "Transformers"-like Nanocarrier System for Enhancing the Oral Bioavailability of Poorly Water-Soluble Drugs.

PubMed

Chuang, Er-Yuan; Lin, Kun-Ju; Huang, Tring-Yo; Chen, Hsin-Lung; Miao, Yang-Bao; Lin, Po-Yen; Chen, Chiung-Tong; Juang, Jyuhn-Huarng; Sung, Hsing-Wen

2018-06-06

Increasing the intestinal dissolution of orally administered poorly water-soluble drugs that have poor oral bioavailability to a therapeutically effective level has long been an elusive goal. In this work, an approach that can greatly enhance the oral bioavailability of a poorly water-soluble drug such as curcumin (CUR) is developed, using a "Transformers"-like nanocarrier system (TLNS) that can self-emulsify the drug molecules in the intestinal lumen to form nanoemulsions. Owing to its known anti-inflammation activity, the use of CUR in treating pancreatitis is evaluated herein. Structural changes of the TLNS in the intestinal environment to form the CUR-laden nanoemulsions are confirmed in vitro. The therapeutic efficacy of this TLNS is evaluated in rats with experimentally induced acute pancreatitis (AP). Notably, the CUR-laden nanoemulsions that are obtained using the proposed TLNS can passively target intestinal M cells, in which they are transcytosed and then transported into the pancreatic tissues via the intestinal lymphatic system. The pancreases in rats that are treated with the TLNS yield approximately 12 times stronger CUR signals than their counterparts receiving free CUR, potentially improving the recovery of AP. These findings demonstrate that the proposed TLNS can markedly increase the intestinal drug dissolution, making oral delivery a favorable noninvasive means of administering poorly water-soluble drugs.

Does apical membrane GLUT2 have a role in intestinal glucose uptake?

PubMed

Naftalin, Richard J

2014-01-01

It has been proposed that the non-saturable component of intestinal glucose absorption, apparent following prolonged exposure to high intraluminal glucose concentrations, is mediated via the low affinity glucose and fructose transporter, GLUT2, upregulated within the small intestinal apical border. The evidence that the non-saturable transport component is mediated via an apical membrane sugar transporter is that it is inhibited by phloretin, after exposure to phloridzin. Since the other apical membrane sugar transporter, GLUT5, is insensitive to inhibition by either cytochalasin B, or phloretin, GLUT2 was deduced to be the low affinity sugar transport route. As in its uninhibited state, polarized intestinal glucose absorption depends both on coupled entry of glucose and sodium across the brush border membrane and on the enterocyte cytosolic glucose concentration exceeding that in both luminal and submucosal interstitial fluids, upregulation of GLUT2 within the intestinal brush border will usually stimulate downhill glucose reflux to the intestinal lumen from the enterocytes; thereby reducing, rather than enhancing net glucose absorption across the luminal surface. These states are simulated with a computer model generating solutions to the differential equations for glucose, Na and water flows between luminal, cell, interstitial and capillary compartments. The model demonstrates that uphill glucose transport via SGLT1 into enterocytes, when short-circuited by any passive glucose carrier in the apical membrane, such as GLUT2, will reduce transcellular glucose absorption and thereby lead to increased paracellular flow. The model also illustrates that apical GLUT2 may usefully act as an osmoregulator to prevent excessive enterocyte volume change with altered luminal glucose concentrations.

Does apical membrane GLUT2 have a role in intestinal glucose uptake?

PubMed Central

Naftalin, Richard J

2014-01-01

It has been proposed that the non-saturable component of intestinal glucose absorption, apparent following prolonged exposure to high intraluminal glucose concentrations, is mediated via the low affinity glucose and fructose transporter, GLUT2, upregulated within the small intestinal apical border. The evidence that the non-saturable transport component is mediated via an apical membrane sugar transporter is that it is inhibited by phloretin, after exposure to phloridzin. Since the other apical membrane sugar transporter, GLUT5, is insensitive to inhibition by either cytochalasin B, or phloretin, GLUT2 was deduced to be the low affinity sugar transport route. As in its uninhibited state, polarized intestinal glucose absorption depends both on coupled entry of glucose and sodium across the brush border membrane and on the enterocyte cytosolic glucose concentration exceeding that in both luminal and submucosal interstitial fluids, upregulation of GLUT2 within the intestinal brush border will usually stimulate downhill glucose reflux to the intestinal lumen from the enterocytes; thereby reducing, rather than enhancing net glucose absorption across the luminal surface. These states are simulated with a computer model generating solutions to the differential equations for glucose, Na and water flows between luminal, cell, interstitial and capillary compartments. The model demonstrates that uphill glucose transport via SGLT1 into enterocytes, when short-circuited by any passive glucose carrier in the apical membrane, such as GLUT2, will reduce transcellular glucose absorption and thereby lead to increased paracellular flow. The model also illustrates that apical GLUT2 may usefully act as an osmoregulator to prevent excessive enterocyte volume change with altered luminal glucose concentrations. PMID:25671087

Intestinal Glucose Absorption Was Reduced by Vertical Sleeve Gastrectomy via Decreased Gastric Leptin Secretion.

PubMed

Du, Jinpeng; Hu, Chaojie; Bai, Jie; Peng, Miaomiao; Wang, Qingbo; Zhao, Ning; Wang, Yu; Wang, Guobin; Tao, Kaixiong; Wang, Geng; Xia, Zefeng

2018-06-18

The unique effects of gastric resection after vertical sleeve gastrectomy (VSG) on type 2 diabetes mellitus remain unclear. This work aimed to investigate the effects of VSG on gastric leptin expression and intestinal glucose absorption in high-fat diet-induced obesity. Male C57BL/6J mice were fed a high-fat diet (HFD) to induce obesity. HFD mice were randomized into VSG and sham-operation groups, and the relevant parameters were measured at 8 weeks postoperation. Higher gastric leptin expression and increased intestinal glucose transport were observed in the HFD mice. Furthermore, VSG reduced gastric leptin expression and the intestinal absorption of alimentary glucose. Both exogenous leptin replenishment during the oral glucose tolerance test (OGTT) and the addition of leptin into the everted isolated jejunum loops in vitro restored the glucose transport capacity in VSG-operated mice, and this effect was abolished when the glucose transporter GLUT2 was blocked with phloretin. Moreover, phloretin almost completely suppressed glucose transport in the HFD mice. Intestinal immunohistochemistry in the obese mice showed increased GLUT2 and diminished sodium glucose co-transporter 1 (SGLT-1) in the apical membrane of enterocytes. Decreased GLUT2 and enhanced SGLT1 were observed following VSG. VSG also reduced the phosphorylation status of protein kinase C isoenzyme β II (PKCβ II) in the jejunum, which was stimulated by the combination of leptin and glucose. Our data demonstrated that the decreased secretion of gastric leptin in VSG results in a decrease in intestinal glucose absorption via modulation of GLUT2 translocation.

Pancreatic cholera syndrome: effect of a synthetic somatostatin analog on intestinal water and ion transport.

PubMed

Santangelo, W C; O'Dorisio, T M; Kim, J G; Severino, G; Krejs, G J

1985-09-01

The effect of a synthetic somatostatin analog was studied in a patient with severe secretory diarrhea due to pancreatic cholera syndrome. Basal intestinal perfusion studies indicated an absence of water and sodium absorption, and active chloride secretion in the small bowel. Intravenous administration of the somatostatin analog (1 microgram/kg.h) changed zero net water movement to absorption (122 mL/30 cm of the jejunum per hour). Chloride secretion changed to absorption (5.0 to 7.9 meq/30 cm.h), and plasma vasoactive intestinal polypeptide concentration was reduced from 330 to 45 pmol/L (normal, less than 51). When the analog was given subcutaneously, 100 micrograms twice daily, stool weight decreased, and plasma vasoactive intestinal polypeptide concentration fell toward the normal range (67 pmol/L). Plasma concentration of pancreatic polypeptide was initially elevated and dropped during intravenous infusion of somatostatin analog but returned to baseline on maintenance therapy with the analog delivered subcutaneously. The patient has not had further diarrhea during 9 months of therapy.

Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue

PubMed Central

Incecayir, Tuba; Sun, Jing; Tsume, Yasuhiro; Xu, Hao; Gose, Tomoka; Nakanishi, Takeo; Tamai, Ikumi; Hilfinger, John; Lipka, Elke; Amidon, Gordon L.

2016-01-01

The goal of this study was to improve the intestinal mucosal cell membrane permeability of the poorly absorbed guanidino analogue of a neuraminidase inhibitor, oseltamivir carboxylate (GOC) using a carrier mediated strategy. Valyl amino acid prodrug of GOC with isopropyl-methylenedioxy linker (GOC-ISP-Val) was evaluated as the potential substrate for intestinal oligopeptide transporter, hPEPT1 in Xenopus laevis oocytes heterologously expressing hPEPT1 and an intestinal mouse perfusion system. The diastereomers of GOC-ISP-Val were assessed for chemical and metabolic stability. Permeability of GOC-ISP-Val was determined in Caco-2 cells and mice. Diastereomer 2 was about two times more stable than diastereomer 1 in simulated intestinal fluid and rapidly hydrolyzed to the parent drug in cell homogenates. The prodrug had a nine times enhanced apparent permeability (Papp) in Caco-2 cells compared to the parent drug. Both diastereomer exhibited high effective permeability (Peff ) in mice, 6.32±3.12 and 5.20±2.81 x10−5 cm/s for diastereomer 1 and 2, respectively. GOC-ISP-Val was found to be a substrate of hPEPT1. Overall, this study indicates that the prodrug, GOC-ISP-Val seems to be a promising oral anti-influenza agent that has sufficient stability at physiologically relevant pHs prior to absorption, significantly improved permeability via hPEPT1 and potentially rapid activation in the intestinal cells. PMID:26869437

[Construction of research system for processing mechanism of traditional Chinese medicine based on chemical composition transformation combined with intestinal absorption barrier].

PubMed

Sun, E; Xu, Feng-Juan; Zhang, Zhen-Hai; Wei, Ying-Jie; Tan, Xiao-Bin; Cheng, Xu-Dong; Jia, Xiao-Bin

2014-02-01

Based on practice of Epimedium processing mechanism for many years and integrated multidisciplinary theory and technology, this paper initially constructs the research system for processing mechanism of traditional Chinese medicine based on chemical composition transformation combined with intestinal absorption barrier, which to form an innovative research mode of the " chemical composition changes-biological transformation-metabolism in vitro and in vivo-intestinal absorption-pharmacokinetic combined pharmacodynamic-pharmacodynamic mechanism". Combined with specific examples of Epimedium and other Chinese herbal medicine processing mechanism, this paper also discusses the academic thoughts, research methods and key technologies of this research system, which will be conducive to systematically reveal the modem scientific connotation of traditional Chinese medicine processing, and enrich the theory of Chinese herbal medicine processing.

Intestinal absorption of strontium chloride in healthy volunteers: pharmacokinetics and reproducibility

PubMed Central

SIPS, A. J. A. M.; van der VIJGH, W. J. F.; BARTO, R.; NETELENBOS, J. C.

1996-01-01

1The absorption kinetics of orally administered strontium chloride and its reproducibility were investigated in healthy volunteers after administering strontium either under fasting conditions (study I, n=8) or in combination with a standardized meal (study II, n=8). Each subject received strontium orally at day 0, 14, and 28 and intravenously at day 42. The study was performed as part of a project in which a simple clinical test for measuring intestinal calcium absorption is being developed, based on the use of stable strontium as a marker. 2Plasma strontium concentration–time curves were analysed by noncompartment analysis and a four compartment disposition model. Within a volunteer each oral curve was fitted simultaneously with the intravenous curve, by which means a two segment model for absorption was revealed. 3Mean absolute bioavailability of strontium was 25% without a meal and 19% with a meal, whereas the intraindividual variation was 24% and 20%, respectively. 4Various limited sampling absorption parameters were determined in order to select a potential test parameter for measuring intestinal calcium absorption using strontium as a marker. Fractional absorption at 4 h (Fc240), obtained after co-ingestion of strontium with a meal, appeared to be the best test parameter, because it represented bioavailability well (r=0.90). PMID:8799520

Characterization of acyl-coenzyme A:diacylglycerol acyltransferase (DGAT) enzyme of human small intestine.

PubMed

Hiramine, Yasushi; Tanabe, Toshizumi

2011-06-01

Acyl-coenzyme A:diacylglycerol acyltransferase (DGAT) enzyme plays a significant role in dietary triacylglycerol (TAG) absorption in the small intestine. However, the characteristics of human intestinal DGAT enzyme have not been examined in detail. The aim of our study was to characterize the human intestinal DGAT enzyme by examining acyl-CoA specificity, temperature dependency, and selectivity for 1,2-diacylglycerol (DAG) or 1,3-DAG. We detected DGAT activity of human intestinal microsome and found that the acyl-CoA specificity and temperature dependency of intestinal DGAT coincided with those of recombinant human DGAT1. To elucidate the selectivity of human intestinal DGAT to 1,2-DAG or 1,3-DAG, we conducted acyl-coenzyme A:monoacylglycerol acyltransferase assays using 1- or 2-monoacylglycerol (MAG) as substrates. When 2-MAG was used as acyl acceptor, both 1,2-DAG and TAG were generated; however, when 1-MAG was used, 1,3-DAG was predominantly observed and little TAG was detected. These findings suggest that human small intestinal DGAT, which is mainly encoded by DGAT1, utilizes 1,2-DAG as the substrate to form TAG. This study will contribute to understand the lipid absorption profile in the small intestine.

Flavonoid interactions during digestion, absorption, distribution and metabolism: a sequential structure-activity/property relationship-based approach in the study of bioavailability and bioactivity.

PubMed

Gonzales, Gerard Bryan; Smagghe, Guy; Grootaert, Charlotte; Zotti, Moises; Raes, Katleen; Van Camp, John

2015-05-01

Flavonoids are a group of polyphenols that provide health-promoting benefits upon consumption. However, poor bioavailability has been a major hurdle in their use as drugs or nutraceuticals. Low bioavailability has been associated with flavonoid interactions at various stages of the digestion, absorption and distribution process, which is strongly affected by their molecular structure. In this review, we use structure-activity/property relationship to discuss various flavonoid interactions with food matrices, digestive enzymes, intestinal transporters and blood proteins. This approach reveals specific bioactive properties of flavonoids in the gastrointestinal tract as well as various barriers for their bioavailability. In the last part of this review, we use these insights to determine the effect of different structural characteristics on the overall bioavailability of flavonoids. Such information is crucial when flavonoid or flavonoid derivatives are used as active ingredients in foods or drugs.

Dietary fat and gut microbiota: mechanisms involved in obesity control.

PubMed

Coelho, Olívia Gonçalves Leão; Cândido, Flávia Galvão; Alfenas, Rita de Cássia Gonçalves

2018-05-31

Obesity is a serious global health problem that is directly related to various morbidities manifestation. Intestinal dysbiosis has been implicated on obesity pathogenesis. Diet composition can alter gut microbiota, regardless of energy intake. Dietary fatty acids quality may affect gut microbiota composition, which in turn may affect host metabolic health. The mechanisms by which the different type of FFA modulate gut microbiota is yet poor elucidate and there is a lack of studies regard to this. Fatty acids may act in cell membrane, interfere with energy production, inhibit enzymatic activities, impair nutrient absorption and generate toxic compounds to cells, leading to growth inhibition or even bacterial death. The beneficial effect of the consumption of n-3 polyunsaturated fatty acids (PUFA) and conjugated linoleic acid (CLA) on microbiota, unlike n-6 PUFA and saturated fatty acids has been suggested. n-3 PUFA consumption promotes desirable changes on obese intestinal microbiota making it similar to that of normal weight individuals. More studies are needed to better understand the effect of CLA on microbiota and host health. Long term human controlled clinical trials must be conducted to allow us to understand the complex interaction between dietary fat, intestinal microbiota and obesity.

Intestinal absorption of forsythoside A in in situ single-pass intestinal perfusion and in vitro Caco-2 cell models

PubMed Central

Zhou, Wei; Di, Liu-qing; Wang, Juan; Shan, Jin-jun; Liu, Shi-jia; Ju, Wen-zheng; Cai, Bao-chang

2012-01-01

Aim: To investigate the mechanisms underlying the intestinal absorption of the major bioactive component forsythoside A (FTA) extracted from Forsythiae fructus. Methods: An in vitro Caco-2 cell model and a single-pass intestinal perfusion in situ model in SD rats were used. Results: In the in vitro Caco-2 cell model, the mean apparent permeability value (Papp-value) was 4.15×10-7 cm/s in the apical-to-basolateral (AP-BL) direction. At the concentrations of 2.6–10.4 μg/mL, the efflux ratio of FTA in the bi-directional transport experiments was approximately 1.00. After the transport, >96% of the apically loaded FTA was retained on the apical side, while >97% of the basolaterally loaded FTA was retained on the basolateral side. The Papp-values of FTA were inversely correlated with the transepithelial electrical resistance. The paracellular permeability enhancers sodium caprate and EDTA, the P-gp inhibitor verapamil and the multidrug resistance related protein (MRP) inhibitors cyclosporine and MK571 could concentration-dependently increase the Papp-values, while the uptake (OATP) transporter inhibitors diclofenac sodium and indomethacin could concentration-dependently decrease the Papp-values. The intake transporter SGLT1 inhibitor mannitol did not cause significant change in the Papp-values. In the in situ intestinal perfusion model, both the absorption rate constant (Ka) and the effective permeability (Peff-values) following perfusion of FTA 2.6, 5.2 and 10.4 μg/mL via the duodenum, jejunum and ileum had no significant difference, although the values were slightly higher for the duodenum as compared to those in the jejunum and ileum. The low, medium and high concentrations of verapamil caused the largest increase in the Peff-values for duodenum, jejunum and ileum, respectively. Sodium caprate, EDTA and cyclosporine resulted in concentration-dependent increase in the Peff-values. Diclofenac sodium and indomethacin caused concentration-dependent decrease in the Peff-values. Mannitol did not cause significant change in the Papp-values for the duodenum, jejunum or ileum. Conclusion: The results suggest that the intestinal absorption of FTA may occur through passive diffusion, and the predominant absorption site may be in the upper part of small intestine. Paracellular transport route is also involved. P-gp, MRPs and OATP may participate in the absorption of FTA in the intestine. The low permeability of FTA contributes to its low oral bioavailability. PMID:22773077

Teduglutide for treatment of adult patients with short bowel syndrome.

PubMed

Billiauws, Lore; Bataille, Julie; Boehm, Vanessa; Corcos, Olivier; Joly, Francisca

2017-05-01

The European Society for Clinical Nutrition has published recommendations on the 'definition and classification of intestinal failure (IF)'. Two criteria must be present: a 'decreased absorption of macronutrients and/or water and electrolytes due to a loss of gut function' and the 'need for parenteral support'. Home parenteral support (HPS) is the primary treatment for chronic IF but is associated with complications. Areas covered: The principal cause of chronic IF is short bowel syndrome (SBS). The aim of treatment is to maximize intestinal absorption and reduce or eliminate the need for HPS to achieve the best possible quality of life. Teduglutide, an analog of glucagon-like peptide 2, improves intestinal rehabilitation by promoting mucosal growth, reducing intestinal loss and promoting intestinal absorption. This article provides an overview and opinion on teduglutide for SBS. Expert opinion: Teduglutide may provide a new treatment strategy for SBS patients with chronic IF. When prescribed, patients should be informed of the benefits and risks of the drug and must be closely monitored in an expert center. Furthermore, as this treatment is costly, cost-effectiveness analysis as well as the risk-benefit ratio needs to be better evaluated.

Bile Salt Micelles and Phospholipid Vesicles Present in Simulated and Human Intestinal Fluids: Structural Analysis by Flow Field-Flow Fractionation/Multiangle Laser Light Scattering.

PubMed

Elvang, Philipp A; Hinna, Askell H; Brouwers, Joachim; Hens, Bart; Augustijns, Patrick; Brandl, Martin

2016-09-01

Knowledge about colloidal assemblies present in human intestinal fluids (HIFs), such as bile salt micelles and phospholipid vesicles, is regarded of importance for a better understanding of the in vivo dissolution and absorption behavior of poorly soluble drugs (Biopharmaceutics Classification System class II/IV drugs) because of their drug-solubilizing ability. The characterization of these potential drug-solubilizing compartments is a prerequisite for further studies of the mechanistic interplays between drug molecules and colloidal structures within HIFs. The aim of the present study was to apply asymmetrical flow field-flow fractionation (AF4) in combination with multiangle laser light scattering in an attempt to reveal coexistence of colloidal particles in both artificial and aspirated HIFs and to determine their sizes. Asymmetrical flow field-flow fractionation/multiangle laser light scattering analysis of the colloidal phase of intestinal fluids allowed for a detailed insight into the whole spectrum of submicron- to micrometer-sized particles. With respect to the simulated intestinal fluids mimicking fasted and fed state (FaSSIF-V1 and FeSSIF-V1, respectively), FaSSIF contained one distinct size fraction of colloidal assemblies, whereas FeSSIF contained 2 fractions of colloidal species with significantly different sizes. These size fractions likely represent (1) mixed taurocholate-phospholipid-micelles, as indicated by a size range up to 70 nm (in diameter) and a strong UV absorption and (2) small phospholipid vesicles of 90-210 nm diameter. In contrast, within the colloidal phase of the fasted state aspirate of a human volunteer, 4 different size fractions were separated from each other in a consistent and reproducible manner. The 2 fractions containing large particles showed mean sizes of approximately 50 and 200 nm, respectively (intensity-weighted mean diameter, Dz), likely representing mixed cholate/phospholipid micelles and phospholipid vesicles, respectively. The sizes of the smaller 2 fractions being below the size range of multiangle laser light scattering analysis (<20 nm) and their strong UV absorption indicates that they represent either pure cholate micelles or small mixed micelles. Within the colloidal fraction of the fed-state human aspirate, similar colloidal assemblies were detected as in the fasted state human aspirates. The observed differences between SIF and HIF indicate that the simulated intestinal fluids (FaSSIF-V1 and FeSSIF-V1) represent rather simplified models of the real human intestinal environment in terms of coexisting colloidal particles. It is hypothesized that the different supramolecular assemblies detected differ in their lipid composition, which may affect their affinity toward drug compounds and thus the drug-solubilizing capabilities. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Loss of Cystic Fibrosis Transmembrane Regulator Impairs Intestinal Oxalate Secretion.

PubMed

Knauf, Felix; Thomson, Robert B; Heneghan, John F; Jiang, Zhirong; Adebamiro, Adedotun; Thomson, Claire L; Barone, Christina; Asplin, John R; Egan, Marie E; Alper, Seth L; Aronson, Peter S

2017-01-01

Patients with cystic fibrosis have an increased incidence of hyperoxaluria and calcium oxalate nephrolithiasis. Net intestinal absorption of dietary oxalate results from passive paracellular oxalate absorption as modified by oxalate back secretion mediated by the SLC26A6 oxalate transporter. We used mice deficient in the cystic fibrosis transmembrane conductance regulator gene (Cftr) to test the hypothesis that SLC26A6-mediated oxalate secretion is defective in cystic fibrosis. We mounted isolated intestinal tissue from C57BL/6 (wild-type) and Cftr -/- mice in Ussing chambers and measured transcellular secretion of [ 14 C]oxalate. Intestinal tissue isolated from Cftr -/- mice exhibited significantly less transcellular oxalate secretion than intestinal tissue of wild-type mice. However, glucose absorption, another representative intestinal transport process, did not differ in Cftr -/- tissue. Compared with wild-type mice, Cftr -/- mice showed reduced expression of SLC26A6 in duodenum by immunofluorescence and Western blot analysis. Furthermore, coexpression of CFTR stimulated SLC26A6-mediated Cl - -oxalate exchange in Xenopus oocytes. In association with the profound defect in intestinal oxalate secretion, Cftr -/- mice had serum and urine oxalate levels 2.5-fold greater than those of wild-type mice. We conclude that defective intestinal oxalate secretion mediated by SLC26A6 may contribute to the hyperoxaluria observed in this mouse model of cystic fibrosis. Future studies are needed to address whether similar mechanisms contribute to the increased risk for calcium oxalate stone formation observed in patients with cystic fibrosis. Copyright © 2016 by the American Society of Nephrology.

Association of mRNA expression of iron metabolism-associated genes and progression of non-alcoholic steatohepatitis in rats.

PubMed

Higuchi, Teruhisa; Moriyama, Mitsuhiko; Fukushima, Akiko; Matsumura, Hiroshi; Matsuoka, Shunichi; Kanda, Tatsuo; Sugitani, Masahiko; Tsunemi, Akiko; Ueno, Takahiro; Fukuda, Noboru

2018-05-25

Excess iron is associated with non-alcoholic steatohepatitis (NASH). mRNA expression of duodenal cytochrome b, divalent metal transporter 1, ferroportin 1, hepcidin, hephaestin and transferrin receptor 1 in liver were higher in high fat, high cholesterol-containing diet (HFCD) group than in normal diet (ND) group. mRNA levels of divalent metal transporter 1 and transferrin receptor 1, which stimulate iron absorption and excretion, were enhanced in small intestine. Epithelial mucosa of small intestine in HFCD group was characterized by plasma cell and eosinophil infiltration and increased vacuoles. Iron absorption was enhanced in this NASH model in the context of chronic inflammation of small intestinal epithelial cells, consequences of intestinal epithelial cell impairment caused by HFCD. Iron is transported to hepatocytes via portal blood, and abnormalities in iron absorption and excretion occur in small intestine from changes in iron transporter expression, which also occurs in NASH liver. Knockdown of hepcidin antimicrobial peptide led to enhanced heavy chain of ferritin expression in human hepatocytes, indicating association between hepcidin production and iron storage in hepatocytes. Iron-related transporters in liver and lower/upper portions of small intestine play critical roles in NASH development. Expression of iron metabolism-related genes in liver and small intestine was analyzed in stroke-prone spontaneously hypertensive rats (SHR-SP), which develop NASH. Five-week-old SHR-SP fed ND or HFCD were examined. mRNA and protein levels of iron metabolism-related genes in liver and small intestine from 12- and 19-week-old rats were evaluated by real-time RT-PCR and immunohistochemistry or Western blot.

Viper and Cobra Venom Neutralization by Alginate Coated Multicomponent Polyvalent Antivenom Administered by the Oral Route

PubMed Central

Bhattacharya, Sourav; Chakraborty, Mousumi; Mukhopadhyay, Piyasi; Kundu, P. P.; Mishra, Roshnara

2014-01-01

Background Snake bite causes greater mortality than most of the other neglected tropical diseases. Snake antivenom, although effective in minimizing mortality in developed countries, is not equally so in developing countries due to its poor availability in remote snake infested areas as, and when, required. An alternative approach in this direction could be taken by making orally deliverable polyvalent antivenom formulation, preferably under a globally integrated strategy, for using it as a first aid during transit time from remote trauma sites to hospitals. Methodology/Principal Findings To address this problem, multiple components of polyvalent antivenom were entrapped in alginate. Structural analysis, scanning electron microscopy, entrapment efficiency, loading capacity, swelling study, in vitro pH sensitive release, acid digestion, mucoadhesive property and venom neutralization were studied in in vitro and in vivo models. Results showed that alginate retained its mucoadhesive, acid protective and pH sensitive swelling property after entrapping antivenom. After pH dependent release from alginate beads, antivenom (ASVS) significantly neutralized phospholipaseA2 activity, hemolysis, lactate dehydrogenase activity and lethality of venom. In ex vivo mice intestinal preparation, ASVS was absorbed significantly through the intestine and it inhibited venom lethality which indicated that all the components of antivenom required for neutralization of venom lethality were retained despite absorption across the intestinal layer. Results from in vivo studies indicated that orally delivered ASVS can significantly neutralize venom effects, depicted by protection against lethality, decreased hemotoxicity and renal toxicity caused by russell viper venom. Conclusions/Significance Alginate was effective in entrapping all the structural components of ASVS, which on release and intestinal absorption effectively reconstituted the function of antivenom in neutralizing viper and cobra venom. Further research in this direction can strategize to counter such dilemma in snake bite management by promoting control release and oral antivenom rendered as a first aid. PMID:25102172

P-glycoprotein is responsible for the poor intestinal absorption and low toxicity of oral aconitine: In vitro, in situ, in vivo and in silico studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Cuiping, E-mail: yangsophia76@hotmail.com; Zhang, Tianhong, E-mail: wdzth@sina.com; Li, Zheng, E-mail: lizh2524@126.com

Aconitine (AC) is a highly toxic alkaloid from bioactive plants of the genus Aconitum, some of which have been widely used as medicinal herbs for thousands of years. In this study, we systematically evaluated the potential role of P-glycoprotein (P-gp) in the mechanisms underlying the low and variable bioavailability of oral AC. First, the bidirectional transport of AC across Caco-2 and MDCKII-MDR1 cells was investigated. The efflux of AC across monolayers of these two cell lines was greater than its influx. Additionally, the P-gp inhibitors, verapamil and cyclosporin A, significantly decreased the efflux of AC. An in situ intestinal perfusionmore » study in rats showed that verapamil co-perfusion caused a significant increase in the intestinal permeability of AC, from 0.22 × 10{sup −5} to 2.85 × 10{sup −5} cm/s. Then, the pharmacokinetic profile of orally administered AC with or without pre-treatment with verapamil was determined in rats. With pre-treatment of verapamil, the maximum plasma concentration (C{sub max}) of AC increased sharply, from 39.43 to 1490.7 ng/ml. Accordingly, a 6.7-fold increase in the area under the plasma concentration–time curve (AUC{sub 0–12} {sub h}) of AC was observed when co-administered with verapamil. In silico docking analyses suggested that AC and verapamil possess similar P-gp recognition mechanisms. This work demonstrated that P-gp is involved in limiting the intestinal absorption of AC and attenuating its toxicity to humans. Our data indicate that potential P-gp-mediated drug–drug interactions should be considered carefully in the clinical application of aconite and formulations containing AC. - Highlights: • Verapamil and cyclosporin A decreased the efflux of aconitine across Caco-2 cells. • Both inhibitors decreased the efflux of aconitine across MDCKII-MDR1 cells. • Co-perfusion with verapamil increased the intestinal permeability of aconitine. • Co-administration with verapamil sharply increased the C{sub max} and AUC of aconitine. • P-gp interacted with both verapamil and aconitine and recognized them similarly.« less

Quantitation of small intestinal permeability during normal human drug absorption

PubMed Central

2013-01-01

Background Understanding the quantitative relationship between a drug’s physical chemical properties and its rate of intestinal absorption (QSAR) is critical for selecting candidate drugs. Because of limited experimental human small intestinal permeability data, approximate surrogates such as the fraction absorbed or Caco-2 permeability are used, both of which have limitations. Methods Given the blood concentration following an oral and intravenous dose, the time course of intestinal absorption in humans was determined by deconvolution and related to the intestinal permeability by the use of a new 3 parameter model function (“Averaged Model” (AM)). The theoretical validity of this AM model was evaluated by comparing it to the standard diffusion-convection model (DC). This analysis was applied to 90 drugs using previously published data. Only drugs that were administered in oral solution form to fasting subjects were considered so that the rate of gastric emptying was approximately known. All the calculations are carried out using the freely available routine PKQuest Java (http://www.pkquest.com) which has an easy to use, simple interface. Results Theoretically, the AM permeability provides an accurate estimate of the intestinal DC permeability for solutes whose absorption ranges from 1% to 99%. The experimental human AM permeabilities determined by deconvolution are similar to those determined by direct human jejunal perfusion. The small intestinal pH varies with position and the results are interpreted in terms of the pH dependent octanol partition. The permeability versus partition relations are presented separately for the uncharged, basic, acidic and charged solutes. The small uncharged solutes caffeine, acetaminophen and antipyrine have very high permeabilities (about 20 x 10-4 cm/sec) corresponding to an unstirred layer of only 45 μm. The weak acid aspirin also has a large AM permeability despite its low octanol partition at pH 7.4, suggesting that it is nearly completely absorbed in the first part of the intestine where the pH is about 5.4. Conclusions The AM deconvolution method provides an accurate estimate of the human intestinal permeability. The results for these 90 drugs should provide a useful benchmark for evaluating QSAR models. PMID:23800230

Research progress on berberine with a special focus on its oral bioavailability.

PubMed

Liu, Chang-Shun; Zheng, Yu-Rong; Zhang, Ying-Feng; Long, Xiao-Ying

2016-03-01

The natural product berberine (BBR) has become a potential drug in the treatment of diabetes, hyperlipidemia, and cancer. However, the oral delivery of BBR is challenged by its poor bioavailability. It is necessary to improve the oral bioavailability of BBR before it can be used in many clinical applications. Understanding the pharmacokinetic characteristics of BBR will enable the development of suitable formulas that have improved oral bioavailability. The key considerations for BBR are how to enhance the drug absorption and to avoid the intestinal first-pass effect. This review summarizes the pharmacological activities of BBR and analyzes the factors that lead to its poor oral bioavailability. In particular, the therapeutic potential of BBR in new indications from the aspect of oral bioavailability is discussed. In conclusion, BBR is a promising drug candidate for metabolic disorders and cancer but faces considerable challenges due to its poor oral bioavailability. Copyright © 2016 Elsevier B.V. All rights reserved.

A computer model simulating human glucose absorption and metabolism in health and metabolic disease states

PubMed Central

Naftalin, Richard J.

2016-01-01

A computer model designed to simulate integrated glucose-dependent changes in splanchnic blood flow with small intestinal glucose absorption, hormonal and incretin circulation and hepatic and systemic metabolism in health and metabolic diseases e.g. non-alcoholic fatty liver disease, (NAFLD), non-alcoholic steatohepatitis, (NASH) and type 2 diabetes mellitus, (T2DM) demonstrates how when glucagon-like peptide-1, (GLP-1) is synchronously released into the splanchnic blood during intestinal glucose absorption, it stimulates superior mesenteric arterial (SMA) blood flow and by increasing passive intestinal glucose absorption, harmonizes absorption with its distribution and metabolism. GLP-1 also synergises insulin-dependent net hepatic glucose uptake (NHGU). When GLP-1 secretion is deficient post-prandial SMA blood flow is not increased and as NHGU is also reduced, hyperglycaemia follows. Portal venous glucose concentration is also raised, thereby retarding the passive component of intestinal glucose absorption.   Increased pre-hepatic sinusoidal resistance combined with portal hypertension leading to opening of intrahepatic portosystemic collateral vessels are NASH-related mechanical defects that alter the balance between splanchnic and systemic distributions of glucose, hormones and incretins.The model reveals the latent contribution of portosystemic shunting in development of metabolic disease. This diverts splanchnic blood content away from the hepatic sinuses to the systemic circulation, particularly during the glucose absorptive phase of digestion, resulting in inappropriate increases in insulin-dependent systemic glucose metabolism.  This hastens onset of hypoglycaemia and thence hyperglucagonaemia. The model reveals that low rates of GLP-1 secretion, frequently associated with T2DM and NASH, may be also be caused by splanchnic hypoglycaemia, rather than to intrinsic loss of incretin secretory capacity. These findings may have therapeutic implications on GLP-1 agonist or glucagon antagonist usage. PMID:27347379

Use of Saccharomyces cerevisiae To Reduce the Bioaccessibility of Mercury from Food.

PubMed

Jadán-Piedra, Carlos; Baquedano, Marta; Puig, Sergi; Vélez, Dinoraz; Devesa, Vicenta

2017-04-05

Food is the main pathway of exposure to inorganic mercury [Hg(II)] and methylmercury (CH 3 Hg). Intestinal absorption of these mercury species is influenced by their chemical form, the luminal pH, and the composition of the diet. In this regard, strategies have been proposed for reducing mercury absorption using dietary components. This study evaluates the capacity of Saccharomyces cerevisiae to reduce the amount of mercury solubilized after gastrointestinal digestion that is available for intestinal absorption (bioaccessibility). The results show that S. cerevisiae strains reduce mercury bioaccessibility from aqueous solutions of Hg(II) (89 ± 6%) and CH 3 Hg (83 ± 4%), and from mushrooms (19-77%), but not from seafood. The formation of mercury-cysteine or mercury-polypeptide complexes in the bioaccessible fraction may contribute to the reduced effect of yeasts on mercury bioaccessibility from seafood. Our study indicates that budding yeasts could be useful for reducing the extent of intestinal absorption of mercury present in water and some food matrices.

Intestinal absorption mechanism of tebipenem pivoxil, a novel oral carbapenem: involvement of human OATP family in apical membrane transport.

PubMed

Kato, Kazuhiko; Shirasaka, Yoshiyuki; Kuraoka, Erika; Kikuchi, Akihiro; Iguchi, Maki; Suzuki, Hisashi; Shibasaki, Shigeki; Kurosawa, Tohru; Tamai, Ikumi

2010-10-04

Tebipenem pivoxil (TBPM-PI) is an oral carbapenem antibiotic for treating otolaryngologic and respiratory infections in pediatric patients. This agent is a prodrug to improve intestinal absorption of TBPM, an active form, and an absorption rate of TBPM-PI is higher than those of other prodrug-type β-lactam antibiotics. In the present study, we hypothesized that a certain mechanism other than simple diffusion is involved in the process of improved intestinal absorption of TBPM-PI and examined the mechanism. TBPM-PI uptake by Caco-2 cells was decreased by ATP-depletion and lowering the temperature to 4 °C, suggesting the contribution of carrier-mediated transport mechanisms. This uptake was partially decreased by ACE inhibitors, and the reduction of the absorption by captopril was observed by in vivo study and in situ single-pass intestinal perfusion study in rat, supporting the contribution of influx transporters. Since some ACE inhibitors and β-lactam antibiotics are reported to be substrates of PEPT and OATP families, we measured transporting activity of TBPM-PI by intestinally expressed transporters, PEPT1, OATP1A2, and OATP2B1. As a result, significant transport activities were observed by both OATP1A2 and OATP2B1 but not by PEPT1. Interestingly, pH dependence of TBPM-PI transports was different between OATP1A2 and OATP2B1, showing highest activity by OATP1A2 at pH 6.5, while OATP2B1-mediated uptake was higher at neutral and weak alkaline pH. OATP1A2 exhibited higher affinity for TBPM-PI (K(m) = 41.1 μM) than OATP2B1 (K(m) > 1 mM) for this agent. These results suggested that TBPM-PI has high intestinal apical membrane permeability due to plural intestinal transport routes, including the uptake transporters such as OATP1A2 and OATP2B1 as well as simple diffusion.

Inhibition of small-intestinal sugar absorption mediated by sodium orthovanadate Na3VO4 in rats and its mechanisms

PubMed Central

Ai, Jing; Du, Jie; Wang, Ning; Du, Zhi-Min; Yang, Bao-Feng

2004-01-01

AIM: To investigate the inhibitory effects of sodium orthovanadate on small-intestinal glucose and maltose absorption in rats and its mechanism. METHODS: Normal Wistar rats were lavaged with sodium orthovanadate (16 mg/kg, 4 mg/kg and 1 mg/kg) for 6 d. Blood glucose values were measured after fasting and 0.5, 1, 1.5 and 2 h after glucose and maltose feeding with oxidation-enzyme method. α-glucosidase was abstracted from the upper small intestine, and its activity was examined. mRNA expression of α-glucosidase and glucose-transporter 2 (GLUT2) in epithelial cells of the small intestine was observed by in situ hybridization. RESULTS: Sodium orthovanadate could delay the increase of plasma glucose concentration after glucose and maltose loading, area under curve (AUC) in these groups was lower than that in control group. Sodium orthovanadate at dosages of 10 μmol/L, 100 μmol/L and 1000 μmol/L could suppress the activity of α-glucosidase in the small intestine of normal rats, with an inhibition rate of 68.18%, 87.22% and 91.91%, respectively. Sodium orthovanadate reduced mRNA expression of α-glucosidase and GLUT2 in epithelial cells of small intestine. CONCLUSION: Sodium orthovanadate can reduce and delay the absorption of glucose and maltose. The mechanism may be that it can inhibit the activity and mRNA expression of α-glucosidase, as well as mRNA expression of GLUT2 in small intestine. PMID:15534916

NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy.

PubMed

Takada, Tappei; Yamanashi, Yoshihide; Konishi, Kentaro; Yamamoto, Takehito; Toyoda, Yu; Masuo, Yusuke; Yamamoto, Hideaki; Suzuki, Hiroshi

2015-02-18

Vitamin K (VK) is a micronutrient that facilitates blood coagulation. VK antagonists, such as warfarin, are used in the clinic to prevent thromboembolism. Because VK is not synthesized in the body, its intestinal absorption is crucial for maintaining whole-body VK levels. However, the molecular mechanism of this absorption is unclear. We demonstrate that Niemann-Pick C1-like 1 (NPC1L1) protein, a cholesterol transporter, plays a central role in intestinal VK uptake and modulates the anticoagulant effect of warfarin. In vitro studies using NPC1L1-overexpressing intestinal cells and in vivo studies with Npc1l1-knockout mice revealed that intestinal VK absorption is NPC1L1-dependent and inhibited by ezetimibe, an NPC1L1-selective inhibitor clinically used for dyslipidemia. In addition, in vivo pharmacological studies demonstrated that the coadministration of ezetimibe and warfarin caused a reduction in hepatic VK levels and enhanced the pharmacological effect of warfarin. Adverse events caused by the coadministration of ezetimibe and warfarin were rescued by oral VK supplementation, suggesting that the drug-drug interaction effects observed were the consequence of ezetimibe-mediated VK malabsorption. This mechanism was supported by a retrospective evaluation of clinical data showing that, in more than 85% of warfarin-treated patients, the anticoagulant activity was enhanced by cotreatment with ezetimibe. Our findings provide insight into the molecular mechanism of VK absorption. This new drug-drug interaction mechanism between ezetimibe (a cholesterol transport inhibitor) and warfarin (a VK antagonist and anticoagulant) could inform clinical care of patients on these medications, such as by altering the kinetics of essential, fat-soluble vitamins. Copyright © 2015, American Association for the Advancement of Science.

Potential of single cationic amino acid molecule "Arginine" for stimulating oral absorption of insulin.

PubMed

Kamei, Noriyasu; Khafagy, El-Sayed; Hirose, Jun; Takeda-Morishita, Mariko

2017-04-15

We have reported that cell-penetrating peptides, such as oligoarginine, act as powerful absorption enhancers for the development of oral insulin delivery systems. However, the minimal essential sequence of oligoarginine that stimulates intestinal insulin absorption remains unclear. Therefore, the present study was conducted to clarify this minimum sequence of oligoarginine and to examine the effect of single cationic amino acid arginine on the intestinal and oral absorption of insulin. The results demonstrated that a remarkable enhancement of intestinal insulin absorption was observed after coadministration of insulin with l-arginine. The efficacy of d-forms of oligoarginine/arginine tended to decrease with a decreasing number of amino acid residues, whereas the effect of l-arginine was the strongest of any of the l-forms of oligoarginine/arginine. Interestingly, the effect of l-arginine was stronger than that of d-arginine at various concentrations, and the effect of other cationic amino acids such as lysine and histidine was relatively lower than that of arginine. In addition, no leakage of lactate dehydrogenase from the intestinal epithelium and no change in the transepithelial electrical resistance of a Caco-2 cell monolayer were detected after administration of l-arginine as the single amino acid, which suggests that there were no undesirable effects of arginine on the integrity of cell membranes and paracellular tight junctions. Oral administration study in mice demonstrated that the stronger hypoglycemic effects were observed after coadministration of insulin with l-arginine. In this study, we found that arginine is a key cationic amino acid for delivering insulin across intestinal epithelial barriers and hopefully accelerating the clinical development of oral insulin delivery systems. Copyright © 2017 Elsevier B.V. All rights reserved.

From wasting to obesity, changes in nutritional concerns in HIV/AIDS.

PubMed

Mankal, Pavan K; Kotler, Donald P

2014-09-01

Optimal nutrition is an important part of human immunodeficiency virus (HIV) care; to support the immune system, limit HIV-associated complications as well as maintain better quality of life and survival. The presentation and nature of malnutrition in patients with HIV has changed dramatically over the past 30 years from predominantly a wasting syndrome to lipodystrophy and, now, frailty. Nevertheless, we continue to see all 3 presentations in patient care today. The pathogenesis of poor nutrition in HIV-infected patients depends on caloric intake, intestinal nutrient absorption/translocation, and resting energy expenditure, which are features seen in all chronic diseases. Copyright © 2014 Elsevier Inc. All rights reserved.

Tracing the temporal-spatial transcriptome landscapes of the human fetal digestive tract using single-cell RNA-sequencing.

PubMed

Gao, Shuai; Yan, Liying; Wang, Rui; Li, Jingyun; Yong, Jun; Zhou, Xin; Wei, Yuan; Wu, Xinglong; Wang, Xiaoye; Fan, Xiaoying; Yan, Jie; Zhi, Xu; Gao, Yun; Guo, Hongshan; Jin, Xiao; Wang, Wendong; Mao, Yunuo; Wang, Fengchao; Wen, Lu; Fu, Wei; Ge, Hao; Qiao, Jie; Tang, Fuchou

2018-06-01

The development of the digestive tract is critical for proper food digestion and nutrient absorption. Here, we analyse the main organs of the digestive tract, including the oesophagus, stomach, small intestine and large intestine, from human embryos between 6 and 25 weeks of gestation as well as the large intestine from adults using single-cell RNA-seq analyses. In total, 5,227 individual cells are analysed and 40 cell types clearly identified. Their crucial biological features, including developmental processes, signalling pathways, cell cycle, nutrient digestion and absorption metabolism, and transcription factor networks, are systematically revealed. Moreover, the differentiation and maturation processes of the large intestine are thoroughly investigated by comparing the corresponding transcriptome profiles between embryonic and adult stages. Our work offers a rich resource for investigating the gene regulation networks of the human fetal digestive tract and adult large intestine at single-cell resolution.

Oral bioavailability assessment and intestinal lymphatic transport of Org 45697 and Org 46035, two highly lipophilic novel immunomodulator analogues.

PubMed

Caliph, Suzanne M; Faassen, W A Fried; Vogel, Gerard M; Porter, Christopher J H

2009-08-01

Org 45697 (MW 600.7, clogP 7.92, soybean oil solubility 50 mg/g) and Org 46035 (MW 601.6, clog P 8.46, soybean oil solubility 40 mg/g) are two poorly water soluble (<0.1 microg/ml), highly lipophilic drug candidates with immunomodulator activity and highly analogous chemical structures. After oral administration to conscious ambulatory rats in an aqueous-based methylcellulose/Tween 80 suspension, the bioavailability of both compounds was low (< 2% of administered dose). However, bioavailability was significantly increased (> 5 fold) after oral administration in a long chain triglyceride lipid (olive oil) formulation. Subsequent studies have explored the potential for solubilising formulations, including lipid-based formulations, to enhance the oral bioavailability of Org 45697 and Org 46035 and secondly to explore the potential contribution of intestinal lymphatic transport to intestinal absorption. The experimental data show that solubilising formulations may provide for significant increases in oral bioavailability for Org 45697 and Org 46035 and that after co-administration with lipid, 35-50% of the absorbed dose may be transported to the systemic circulation via the intestinal lymph. Interestingly, the lymphatic transport of the less lipid soluble analogue, Org 46035 was approximately 40% lower than that of Org 45697 suggesting that relatively subtle differences in lipid solubility can have significant impact on the extent of lymphatic transport.

Effect of dietary fat on plasma glutathione peroxidase levels and intestinal absorption of /sup 75/Se-labeled sodium selenite in chicks

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mutanen, M.L.; Mykkaenen, H.M.

1984-05-01

The effect of dietary fat on the availability of selenium was investigated in chicks fed either 4 or 20% butter, olive oil, rape oil, corn oil or sunflower oil in the diet for 3 weeks after hatching. Plasma glutathione peroxidase (GSH-Px) activity was used as an indicator of the body selenium status. In addition, the intestinal absorption of sodium selenite (/sup 75/Se-labeled) was determined by using both the in vivo ligated loop procedure and oral administration of the isotope. The plasma GSH-Px levels increased with increasing proportion of the polyunsaturated fatty acids in the diet. Increasing the amount of fatmore » from 4 to 20% significantly enhanced the GSH-Px activity in the groups receiving butter or olive oil, but had no effect in animals fed the unsaturated fats. The absorption of (/sup 75/Se)selenite from the ligated duodenal loops tended to be reduced in chicks fed corn oil or sunflower oil as compared to the animals receiving butter in their diet. On the other hand, the type of dietary fat did not appear to affect the absorption of the orally administered selenite. The present study demonstrates that the type of dietary fat can affect the plasma GSH-Px levels in chicks without altering the intestinal absorption of selenite. However, the results on the absorption of the intraduodenally injected sodium selenite suggest that dietary fat plays some role in the intestinal transport of selenium.« less

[PULMONARY AND INTESTINAL TUBERCULOSIS DEVELOPING ACUTE TUBERCULOUS PERFORATION OF THE INTESTINE DURING ANTITUBERCULOSIS THERAPY].

PubMed

Saitou, Miwako; Suzuki, Tomoko; Niitsuma, Katsunao

2015-09-01

Intestinal tuberculosis (TB) was recognized as the most common complication with a high frequency of active pulmonary TB during the TB epidemic period. However, intestinal TB has become a rare disease, and intestinal perforation due to intestinal TB is extremely rare. We herein report two cases of tuberculous intestinal perforation. A 41-year-old man was admitted to our hospital complaining of persistent cough and anorexia. He was in poor nutritional condition, and his body mass index (BMI) and prognostic nutrition index (PNI) were 13.4 and 36.4, respectively. He was diagnosed with pulmonary TB and received anti-TB therapy. On the 51st day of hospitalization, he developed intestinal perforation. Pathologically caseating epithelioid granulomas were noted at the ulcer lesion. A 61-year-old man was admitted to our hospital due to miliary TB caused by intestinal TB. He had taken oral immunosuppressive drugs and steroids for dermatomyositis over the previous eight years and had a poor nutritional condition, with a BMI of 13.4 and a PNI of 14.4. While receiving anti-TB therapy, he developed intestinal perforation on the 97th day of hospitalization. The patient's poor nutritional condition and immune reconstitution may have contributed to the intestinal perforation.

Sorbitol-based osmotic diarrhea: Possible causes and mechanism of prevention investigated in rats

PubMed Central

Islam, Md Shahidul; Sakaguchi, Ei

2006-01-01

AIM: To study the possible causes of sorbitol (S)-based diarrhea and its mechanism of reduction by rice gruel (RG) in cecectomized rats. METHODS: S was dissolved either in distilled water or in RG (50 g/L) and ingested as a single oral dose (1.2 g/kg body mass, containing 0.5 g/L phenol red as a recovery marker) by S (control) and S + RG groups (n = 7), respectively. This dose is over the laxative dose for humans. Animals were sacrificed exactly 1 h after dose ingestion, without any access to drinking water. The whole gastro-intestinal tract was divided into seven segments and sampled to analyze the S and marker remaining in its contents. RESULTS: Gastric-emptying and intestinal transit were comparatively slower in the S + RG group. Also, the S absorption index in the 3rd and last quarter of the small intestine (24.85 ± 18.88% vs 0.0 ± 0.0% and 39.09 ± 32.75% vs 0.0 ± 0.0%, respectively, P < 0.05) was significantly higher in the S + RG group than in the control group. The S absorption index and the intestinal fluid volume are inversely related to each other. CONCLUSION: The intestinal mal-absorption of S is the main reason for S-based osmotic diarrhea. Where RG enhanced the absorption of S through passive diffusion, the degree of diarrhea was reduced in cecectomized rats. PMID:17171792

Curcumin-loaded solid lipid nanoparticles with Brij78 and TPGS improved in vivo oral bioavailability and in situ intestinal absorption of curcumin.

PubMed

Ji, Hongyu; Tang, Jingling; Li, Mengting; Ren, Jinmei; Zheng, Nannan; Wu, Linhua

2016-01-01

The present study was to formulate curcumin solid lipid nanoparticles (Cur-SLNs) with P-gp modulator excipients, TPGS and Brij78, to enhance the solubility and bioavailability of curcumin. The formulation was optimized by Plackett-Burman screening design and Box-Behnken experiment design. Then physiochemical properties, entrapment efficiency and in vitro release of Cur-SLNs were characterized. In vivo pharmacokinetics study and in situ single-pass intestinal perfusion were performed to investigate the effects of Cur-SLNs on the bioavailability and intestinal absorption of curcumin. The optimized formulations showed an average size of 135.3 ± 1.5 nm with a zeta potential value of -24.7 ± 2.1 mV and 91.09% ± 1.23% drug entrapment efficiency, meanwhile displayed a sustained release profile. In vivo pharmacokinetic study showed AUC0→t for Cur-SLNs was 12.27-folds greater than curcumin suspension and the relative bioavailability of Cur-SLNs was 942.53%. Meanwhile, Tmax and t(1/2) of curcumin for Cur-SLNs were both delayed comparing to the suspensions (p < 0.01). The in situ intestinal absorption study revealed that the effective permeability (Peff) value of curcumin for SLNs was significantly improved (p < 0.01) comparing to curcumin solution. Cur-SLNs with TPGS and Brij78 could improve the oral bioavailability and intestinal absorption of curcumin effectively.

Probiotic Bacillus coagulans GBI-30, 6086 Improves Protein Absorption and Utilization.

PubMed

Jäger, Ralf; Purpura, Martin; Farmer, Sean; Cash, Howard A; Keller, David

2017-12-01

Probiotics offer numerous health benefits, including digestive and immune health. Improved digestive health is linked to a more efficient absorption of important nutrients from our diet. This review focused on the rationale of using the probiotic Bacillus coagulans GBI-30, 6086 to aid protein absorption and utilization. B. coagulans GBI-30, 6086 can withstand the acidic environment of the stomach to reach the intestine where it germinates. Once active in the small intestine after germination, it has been shown to aid the digestion of carbohydrates and proteins. Co-administration of B. coagulans GBI-30, 6086 with protein has been shown to increase protein absorption and to maximize the health benefits associated with protein supplementation.

P-gp is involved in the intestinal absorption and biliary excretion of afatinib in vitro and in rats.

PubMed

Zhang, Yan; Wang, Changyuan; Liu, Zhihao; Meng, Qiang; Huo, Xiaokui; Liu, Qi; Sun, Pengyuan; Yang, Xiaobo; Sun, Huijun; Ma, Xiaodong; Liu, Kexin

2018-04-01

Afatinib is an irreversible multi-targeted TKI, used in the treatment with EGFR mutated non-small cell lung cancer (NSCLC). The purpose of this study is to explore the molecular pharmacokinetic mechanism underlying the effect of P-gp inhibitors on the intestinal absorption and biliary excretion and to understand how P-gp inhibitors affect afatinib pharmacokinetics. Pharmacokinetics in vivo, in situ intestinal perfusion, perfused rat liver in situ, Caco-2 cells, P-gp ATPase activity, sandwich-cultured rat hepatocytes (SCRH) and transfected-cell transport were used in the evaluation. P-gp inhibitor verapamil (Ver) markedly increased the plasma concentrations and significantly decreased the biliary excretion of afatinib in vivo. Ver increased the intestinal absorption and decreased biliary excretion of afatinib in situ single-pass intestinal perfusion studies and in situ perfused rat liver, respectively. The accumulation of afatinib in Caco-2 cells was enhanced by Ver and Cyclosporin A (CsA). The biliary excretion index (BEI) of afatinib in SCRH was decreased by Ver and CsA, respectively. The net efflux ratio of afatinib was 2.3 across vector-/MDR1-MDCKII cell monolayers and was decreased by P-gp inhibitor. The activity of P-gp ATPase was induced by afatinib and the K m and V max were 1.05μM and 59.88nmol ATP/mg hP-gp/min, respectively. At least partly P-gp is involved in increasing the intestinal absorption and decreasing the biliary excretion of afatinib in rats. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

Involvement of concentrative nucleoside transporter 1 in intestinal absorption of trifluorothymidine, a novel antitumor nucleoside, in rats.

PubMed

Okayama, Takashige; Yoshisue, Kunihiro; Kuwata, Keizo; Komuro, Masahito; Ohta, Shigeru; Nagayama, Sekio

2012-02-01

ααα-Trifluorothymidine (TFT), an anticancer nucleoside analog, is a potent thymidylate synthase inhibitor. TFT exerts its antitumor activity primarily by inducing DNA fragmentation after incorporation of the triphosphate form of TFT into the DNA. Although an oral combination of TFT and a thymidine phosphorylase inhibitor has been clinically developed, there is little information regarding TFT absorption. Therefore, we investigated TFT absorption in the rat small intestine. After oral administration of TFT in rats, more than 75% of the TFT was absorbed. To identify the uptake transport system, uptake studies were conducted by using everted sacs prepared from rat small intestines. TFT uptake was saturable, significantly reduced under Na(+)-free conditions, and strongly inhibited by the addition of an endogenous pyrimidine nucleoside. From these results, we suggested the involvement of concentrative nucleoside transporters (CNTs) in TFT absorption into rat small intestine. In rat small intestines, the mRNAs coding for rat CNT1 (rCNT1) and rCNT2, but not for rCNT3, were predominantly expressed. To investigate the roles of rCNT1 and rCNT2 in TFT uptake, we conducted uptake assays by using Xenopus laevis oocytes injected with rCNT1 complementary RNA (cRNA) and rCNT2 cRNA. TFT uptake by X. laevis oocytes injected with rCNT1 cRNA, and not rCNT2 cRNA, was significantly greater than that by water-injected oocytes. In addition, in situ single-pass perfusion experiments performed using rat jejunum regions showed that thymidine, a substrate for CNT1, strongly inhibited TFT uptake. In conclusion, TFT is absorbed via rCNT1 in the intestinal lumen in rats.

Erythrocyte membrane nanoparticles improve the intestinal absorption of paclitaxel.

PubMed

Jiang, Xing; Wang, Kaikai; Zhou, Zaigang; Zhang, Yifan; Sha, Huizi; Xu, Qiuping; Wu, Jie; Wang, Juan; Wu, Jinhui; Hu, Yiqiao; Liu, Baorui

2017-06-24

Paclitaxel (PTX) is a cytotoxic chemotherapy drug with encouraging activity in human malignancies. However, free PTX has a very low oral bioavailability due to its low aqueous solubility and the gastrointestinal drug barrier. In order to overcome this obstacle, we have designed erythrocyte membrane nanoparticles (EMNP) using sonication method. The permeability of PTX by EMNP was 3.5-fold (P app  = 0.425 nm/s) and 16.2-fold (P app  = 394.1 nm/s) higher than free PTX in MDCK-MDR1 cell monolayers and intestinal mucosal tissue, respectively. The in vivo pharmacokinetics indicated that the AUC 0-t (μg/mL·h) and C max (μg/mL) of EMNP were 14.2-fold and 6.0-fold higher than that of free PTX, respectively. In summary, the EMNP appears to be a promising nanoformulation to enhance the oral bioavailability of insoluble and poorly permeable drugs. Copyright © 2017 Elsevier Inc. All rights reserved.

Dietary polyphenols increase fecal mucin and immunoglobulin A and ameliorate the disturbance in gut microbiota caused by a high fat diet.

PubMed

Taira, Toshio; Yamaguchi, Sayori; Takahashi, Azusa; Okazaki, Yukako; Yamaguchi, Akihiro; Sakaguchi, Hirohide; Chiji, Hideyuki

2015-11-01

The effects of dietary polyphenols on human health have mainly been discussed in the context of preventing degenerative diseases, particularly cardiovascular diseases and cancer. The antioxidant properties of polyphenols have been widely studied, but it has become clear that the mechanism of action of polyphenols extends beyond the modulation of oxidative stress, as they are poorly absorbed from the digestive tract. The purpose of this study was to clarify the effects of polyphenols on the colonic environment, intestinal barrier function, and gut microbiota. We demonstrated that dietary polyphenols derived from aronia, haskap, and bilberry, markedly elevated the amount of fecal mucin and immunoglobulin A (IgA) as an intestinal barrier function and ameliorated the disturbance in gut microbiota caused by a high fat diet in rats. These results suggest that dietary polyphenols play a significant role in the prevention of degenerative diseases through improvement of the colonic environment without any absorption from the digestive tract.

Dietary polyphenols increase fecal mucin and immunoglobulin A and ameliorate the disturbance in gut microbiota caused by a high fat diet

PubMed Central

Taira, Toshio; Yamaguchi, Sayori; Takahashi, Azusa; Okazaki, Yukako; Yamaguchi, Akihiro; Sakaguchi, Hirohide; Chiji, Hideyuki

2015-01-01

The effects of dietary polyphenols on human health have mainly been discussed in the context of preventing degenerative diseases, particularly cardiovascular diseases and cancer. The antioxidant properties of polyphenols have been widely studied, but it has become clear that the mechanism of action of polyphenols extends beyond the modulation of oxidative stress, as they are poorly absorbed from the digestive tract. The purpose of this study was to clarify the effects of polyphenols on the colonic environment, intestinal barrier function, and gut microbiota. We demonstrated that dietary polyphenols derived from aronia, haskap, and bilberry, markedly elevated the amount of fecal mucin and immunoglobulin A (IgA) as an intestinal barrier function and ameliorated the disturbance in gut microbiota caused by a high fat diet in rats. These results suggest that dietary polyphenols play a significant role in the prevention of degenerative diseases through improvement of the colonic environment without any absorption from the digestive tract. PMID:26566306

In vitro enzymic hydrolysis of chlorogenic acids in coffee.

PubMed

da Encarnação, Joana Amarante; Farrell, Tracy L; Ryder, Alexandra; Kraut, Nicolai U; Williamson, Gary

2015-02-01

Coffee is rich in quinic acid esters of phenolic acids (chlorogenic acids) but also contains some free phenolic acids. A proportion of phenolic acids appear in the blood rapidly after coffee consumption due to absorption in the small intestine. We investigated in vitro whether this appearance could potentially be derived from free phenolic acids in instant coffee or from hydrolysis of chlorogenic acids by pancreatic or brush border enzymes. We quantified six free phenolic acids in instant coffees using HPLC-DAD-mass spectrometry. The highest was caffeic acid, but all were present at low levels compared to the chlorogenic acids. Roasting and decaffeination significantly reduced free phenolic acid content. We estimated, using pharmacokinetic modelling with previously published data, that the contribution of these compounds to small intestinal absorption is minimal. Hydrolysis of certain chlorogenic acids was observed with human-differentiated Caco-2 cell monolayers and with porcine pancreatin, which showed maximal rates on 3- and 5-O-caffeoylquinic acids, respectively. The amounts of certain free phenolic acids in coffee could only minimally account for small intestinal absorption based on modelling. The hydrolysis of caffeoylquinic, but not feruloylquinic acids, by enterocyte and pancreatic esterases is potentially a contributing mechanism to small intestinal absorption. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Traditional Chinese medicine pairs (III)--effect of extract of Ginseng Radix et Rhizoma and Puerariae Lobatae Radix on intestinal absorption in rats].

PubMed

Chen, Yi-hang; Li, Meng-xuan; Meng, Zhao-qing; Yang, Jiao-jiao; Huang, Wen-zhe; Wang, Zhen-zhong; Wang, Yue-sheng; Xiao, Wei

2015-08-01

This study focused on the intestinal absorption of traditional Chinese medicines (TCM) to reveal the scientific connotation of the compatibility of TCM pairs. The single pass intestinal perfusion (SPIP) was used in rats to compare the absorption of single extracts from Puerariae Lobatae Radix, single extracts from Ginseng Radix et Rhizoma, combined extracts from Puerariae Lobatae Radix and Ginseng Radix et Rhizoma and Puerariae Lobatae Radix and Ginseng Radix et Rhizoma mixture in rats. The content of puerarin, ginsenoside Rg1, ginsenoside Re and ginsenoside Rb1 in liquid were tested by HPLC. The speed constant (Ka) and apparent permeability coefficients (Papp) were calculated and compared. Specifically, the order of puerarin Ka and Papp values from high to low was Ginseng Radix et Rhizoma and Puerariae Lobatae Radix mixture > single extracts from Puerariae Lobatae Radix > combined extracts from Ginseng Radix et Rhizoma and Puerariae Lobatae Radix; the order of ginsenosides Ka and Papp values from high to low was Ginseng Radix et Rhizoma and Puerariae Lobatae Radix mixture > single extracts from Ginseng Radix et Rhizoma > combined extracts from Ginseng Radix et Rhizoma and Puerariae Lobatae Radix. The combined administration of Ginseng Radix et Rhizoma and Puerariae Lobatae Radix may improve the absorption in the intestinal tract.

A metabolic way to investigate related hurdles causing poor bioavailability in oral delivery of isoacteoside in rats employing ultrahigh-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry.

PubMed

Cui, Qingling; Pan, Yingni; Yan, Xiaowei; Qu, Bao; Liu, Xiaoqiu; Xiao, Wei

2017-02-28

Isoacteoside (ISAT), a phenylethanoid glycoside that acts as the principal bioactive component in traditional Chinese medicines, possesses broad pharmacological effects such as neuroprotective, antihypertensive and hepatoprotective activities. However, its pharmaceutical development has been severely limited due to the poor oral bioavailability. It is essential and significant to investigate related hurdles leading to the poor bioavailability of isoacteoside. Whole animal metabolism studies were conducted in rats, followed by metabolic mechanism including gastrointestinal stability, intestinal flora metabolism and intestinal enzyme metabolism employing the powerful method ultrahigh-performance liquid chromatography combined with quadrupole time-of-flight tandem mass spectrometry (UPLC/QTOF-MS/MS). A simple, rapid and sensitive method has been developed which comprehensively revealed the underlying cause of poor bioavailability of ISAT in a metabolic manner. The prototype of ISAT and its combined metabolites have not been detected in plasma. Furthermore, the residual content of the parent compound in in vitro experiments was approximately 59%, 5% and barely none in intestinal bacteria, intestinal S9 and simulated intestinal juice at 6 h, respectively. The present work has demonstrated that the factors causing the poor bioavailability of isoacteoside should be attributed to the metabolism. In general, the metabolism that resulted from intestinal flora and intestinal enzymes were predominant reasons giving rise to the poor bioavailability of ISAT, which also suggested that metabolites might be responsible for the excellent pharmacological effect of ISAT. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Gastrointestinal citrate absorption in nephrolithiasis

NASA Technical Reports Server (NTRS)

Fegan, J.; Khan, R.; Poindexter, J.; Pak, C. Y.

1992-01-01

Gastrointestinal absorption of citrate was measured in stone patients with idiopathic hypocitraturia to determine if citrate malabsorption could account for low urinary citrate. Citrate absorption was measured directly from recovery of orally administered potassium citrate (40 mEq.) in the intestinal lavage fluid, using an intestinal washout technique. In 7 stone patients citrate absorption, serum citrate levels, peak citrate concentration in serum and area under the curve were not significantly different from those of 7 normal subjects. Citrate absorption was rapid and efficient in both groups, with 96 to 98% absorbed within 3 hours. The absorption of citrate was less efficient from a tablet preparation of potassium citrate than from a liquid preparation, probably due to a delayed release of citrate from wax matrix. However, citrate absorption from solid potassium citrate was still high at 91%, compared to 98% for a liquid preparation. Thus, hypocitraturia is unlikely to be due to an impaired gastrointestinal absorption of citrate in stone patients without overt bowel disease.

Impact of gastrointestinal lipolysis on oral lipid-based formulations and bioavailability of lipophilic drugs.

PubMed

Carrière, Frédéric

2016-06-01

Oil-in-water emulsions are common vehicles for lipids as nutrients and for the delivery of poorly water-soluble drugs. Enhancing oral bioavailability of these drugs using lipid-based formulations (LBF) or self-emulsifying drug delivery systems is one of the current challenges in pharmaceutical industry. Many of the compounds found in LBF (acylglycerols, surfactants with esterified fatty acids, …) are however potential substrates for digestive enzymes. Their digestion (or lipolysis) in the gastrointestinal (GI) tract is critical for drug dissolution and absorption: it can be beneficial (drug solubilization/dispersion) or deleterous (drug precipitation) depending on the drug-LBF association. A better understanding of the fate of LBF in the GI tract is therefore required to engineer efficient lipid-based drug delivery systems. In vitro models for testing simultaneously LBF digestion and drug dispersion are in development to predict drug solubilization and bioavailability, select the best drug-LBF association and obtain better in vitro-in vivo correlations. So far, research in this area has focused on LBF lipolysis under intestinal conditions because the small intestine is the main target for drug delivery and absorption, as well as the main site of digestion by pancreatic enzymes. Lipolysis however starts within the stomach through the action of gastric lipase, the first enzyme involved in fat digestion in humans. In vitro digestion experiments show that most LBFs are submitted to gastric lipolysis, and therefore, both intragastric and intestinal digestions are critical for the fate of LBF and drug solubility. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Human microsomal cyttrochrome P450-mediated reduction of oxysophocarpine, an active and highly toxic constituent derived from Sophora flavescens species, and its intestinal absorption and metabolism in rat.

PubMed

Wu, Lili; Zhong, Wanping; Liu, Junjin; Han, Weichao; Zhong, Shilong; Wei, Qiang; Liu, Shuwen; Tang, Lan

2015-09-01

Oxysophocarpine (OSC), an active and toxic quinolizidine alkaloid, is highly valued in Sophora flavescens Ait. and Subprostrate sophora Root. OSC is used to treat inflammation and hepatitis for thousands of years in China. This study aims to investigate the CYP450-mediated reduction responsible for metabolizing OSC and to evaluate the absorption and metabolism of OSC in rat in situ. Four metabolites were identified, with sophocarpine (SC) as the major metabolite. SC formation was rapid in human and rat liver microsomes (HLMs and RLMs, respectively). The reduction rates in the liver are two fold higher than in the intestine, both in humans and rats. In HLMs, inhibitors of CYP2C9, 3A4/5, 2D6, and 2B6 had strong inhibitory effects on SC formation. Meanwhile, inhibitors of CYP3A and CYP2D6 had significant inhibition on SC formation in RLMs. Human recombinant CYP3A4/5, 2B6, 2D6, and 2C9 contributed significantly to SC production. The permeability in rat intestine and the excretion rates of metabolites were highest in the duodenum (p<0.05), and the absorbed amount of OSC in duodenum and jejunum was concentration-dependent. The metabolism could be significantly decreased by CYP3A inhibitor ketoconazole. In conclusion, the liver was the main organ responsible for OSC metabolism. First-pass metabolism via CYP3A4/5, 2B6, 2D6, and 2C9 may be the main reason for the poor OSC bioavailability. Copyright © 2015 Elsevier B.V. All rights reserved.

Intestine-specific Disruption of Hypoxia-inducible Factor (HIF)-2α Improves Anemia in Sickle Cell Disease.

PubMed

Das, Nupur; Xie, Liwei; Ramakrishnan, Sadeesh K; Campbell, Andrew; Rivella, Stefano; Shah, Yatrik M

2015-09-25

Sickle cell disease (SCD) is caused by genetic defects in the β-globin chain. SCD is a frequently inherited blood disorder, and sickle cell anemia is a common type of hemoglobinopathy. During anemia, the hypoxic response via the transcription factor hypoxia-inducible factor (HIF)-2α is highly activated in the intestine and is essential in iron absorption. Intestinal disruption of HIF-2α protects against tissue iron accumulation in iron overload anemias. However, the role of intestinal HIF-2α in regulating anemia in SCD is currently not known. Here we show that in mouse models of SCD, disruption of intestinal HIF-2α significantly decreased tissue iron accumulation. This was attributed to a decrease in intestinal iron absorptive genes, which were highly induced in a mouse model of SCD. Interestingly, disruption of intestinal HIF-2α led to a robust improvement in anemia with an increase in RBC, hemoglobin, and hematocrit. This was attributed to improvement in RBC survival, hemolysis, and insufficient erythropoiesis, which is evident from a significant decrease in serum bilirubin, reticulocyte counts, and serum erythropoietin following intestinal HIF-2α disruption. These data suggest that targeting intestinal HIF-2α has a significant therapeutic potential in SCD pathophysiology. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

An update on the potential role of intestinal first-pass metabolism for the prediction of drug-drug interactions: the role of PBPK modeling.

PubMed

Alqahtani, Saeed; Bukhari, Ishfaq; Albassam, Ahmed; Alenazi, Maha

2018-05-28

The intestinal absorption process is a combination of several events that are governed by various factors. Several transport mechanisms are involved in drug absorption through enterocytes via active and/or passive processes. The transported molecules then undergo intestinal metabolism, which together with intestinal transport may affect the systemic availability of drugs. Many studies have provided clear evidence on the significant role of intestinal first-pass metabolism on drug bioavailability and degree of drug-drug interactions (DDIs). Areas covered: This review provides an update on the role of intestinal first-pass metabolism in the oral bioavailability of drugs and prediction of drug-drug interactions. It also provides a comprehensive overview and summary of the latest update in the role of PBPK modeling in prediction of intestinal metabolism and DDIs in humans. Expert opinion: The contribution of intestinal first-pass metabolism in the oral bioavailability of drugs and prediction of DDIs has become more evident over the last few years. Several in vitro, in situ, and in vivo models have been developed to evaluate the role of first-pass metabolism and to predict DDIs. Currently, physiologically based pharmacokinetic modeling is considered the most valuable tool for the prediction of intestinal first-pass metabolism and DDIs.

A kinetic approach to the study of absorption of solutes by isolated perfused small intestine

PubMed Central

Fisher, R. B.; Gardner, M. L. G.

1974-01-01

1. A new technique has been developed for making serial measurements of water and solute absorption from the lumen of isolated small intestine. 2. The isolated intestine is perfused in a single pass with a segmented flow of slugs of liquid separated by bubbles of oxygen-carbon dioxide mixture. Simultaneous collections are made of effluent from the lumen and of the fluid which is transported across the mucosa. This latter fluid appears to be a fair sample of the tissue fluid. 3. Conditions in the lumen can be changed within less than 5 min. The effects of two or more treatments applied to the same segment of intestine can be determined and the time course of a change in luminal conditions. 4. The rate of appearance of solutes on the serosal side depends on the rate of water absorption, and changes exponentially towards a steady state. The rate constant is a function of tissue fluid volume. 5. In the steady state the concentration of glucose in the tissue fluid is 71 mM when the luminal concentration is 28 mM, and is 45 mM when the luminal concentration is 8·3 mM. 6. For solutes such as glucose for which reflux from tissue fluid to lumen is small relative to flux from lumen to tissue fluid, the time of attainment of a steady state in secretion is usually 50-60 min. 7. For solutes such as sodium for which the reflux is relatively high, the steady state may be reached in 15-20 min. 8. The Km for glucose absorption (14-19 mM) is much lower than is found with unsegmented flow perfusion. 9. These findings emphasize problems in interpreting results from other types of intestinal preparation. 10. The rate of glucose absorption from the lumen falls only gradually when the luminal sodium concentration is reduced abruptly. In contrast the rate of glucose absorption falls suddenly when the luminal glucose concentration is reduced abruptly. This suggests that glucose absorption is not directly dependent on luminal sodium ions. ImagesPlate 1 PMID:4422346

Nonprotein nitrogen is absorbed from the large intestine and increases nitrogen balance in growing pigs fed a valine-limiting diet.

PubMed

Columbus, Daniel A; Lapierre, Hélène; Htoo, John K; de Lange, Cornelis F M

2014-05-01

Nitrogen absorption from the large intestine, largely as ammonia and possibly as amino acids (AAs), is generally thought to be of little nutritional value to nonruminant animals and humans. Ammonia-nitrogen absorbed from the large intestine, however, may be recycled into the small intestine as urea and incorporated into microbial AAs, which may then be used by the host. A cecal infusion study was performed to determine the form in which nitrogen is absorbed from the large intestine and the impact of large intestine nitrogen supply on nitrogen balance in growing pigs. Eighteen cecally cannulated barrows (initial body weight: 22.4 ± 1.2 kg) were used to determine the effect of supplying nitrogen into the large intestine from either casein or urea on whole-body nitrogen retention and urea kinetics. Treatments were cecal infusions of saline (control), casein, or urea with nitrogen infused at a rate of 40% of nitrogen intake. In a subsample of 9 pigs, (15)N(15)N-urea was infused via i.v. during the nitrogen-balance period to determine urea kinetics. All pigs were fed a valine-limiting cornstarch-soybean meal-based diet. More than 80% of infused nitrogen was apparently absorbed. Urea flux and urinary nitrogen excretion increased (P ≤ 0.05) by the same amount for both nitrogen sources, but this increase did not fully account for the increase in nitrogen absorption from the large intestine. Whole-body nitrogen retention improved with nitrogen infusions (129 vs. 114 g/d; P < 0.01) and did not differ (P > 0.05) between nitrogen sources. Absorption of nitrogen from the large intestine appears to be in the form of nonprotein nitrogen, which appears to be returned to the small intestine via urea and used there for microbial AA production and should therefore be considered when determining nitrogen and AA supply and requirements.

The Intestinal Copper Exporter CUA-1 Is Required for Systemic Copper Homeostasis in Caenorhabditis elegans.

PubMed

Chun, Haarin; Sharma, Anuj Kumar; Lee, Jaekwon; Chan, Jefferson; Jia, Shang; Kim, Byung-Eun

2017-01-06

Copper plays key catalytic and regulatory roles in biochemical processes essential for normal growth, development, and health. Defects in copper metabolism cause Menkes and Wilson's disease, myeloneuropathy, and cardiovascular disease and are associated with other pathophysiological states. Consequently, it is critical to understand the mechanisms by which organisms control the acquisition, distribution, and utilization of copper. The intestinal enterocyte is a key regulatory point for copper absorption into the body; however, the mechanisms by which intestinal cells transport copper to maintain organismal copper homeostasis are poorly understood. Here, we identify a mechanism by which organismal copper homeostasis is maintained by intestinal copper exporter trafficking that is coordinated with extraintestinal copper levels in Caenorhabditis elegans Specifically, we show that CUA-1, the C. elegans homolog of ATP7A/B, localizes to lysosome-like organelles (gut granules) in the intestine under copper overload conditions for copper detoxification, whereas copper deficiency results in a redistribution of CUA-1 to basolateral membranes for copper efflux to peripheral tissues. Worms defective in gut granule biogenesis exhibit defects in copper sequestration and increased susceptibility to toxic copper levels. Interestingly, however, a splice isoform CUA-1.2 that lacks a portion of the N-terminal domain is targeted constitutively to the basolateral membrane irrespective of dietary copper concentration. Our studies establish that CUA-1 is a key intestinal copper exporter and that its trafficking is regulated to maintain systemic copper homeostasis. C. elegans could therefore be exploited as a whole-animal model system to study regulation of intra- and intercellular copper trafficking pathways. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Starch and fiber properties affect their kinetics of digestion and thereby digestive physiology in pigs.

PubMed

Zijlstra, R T; Jha, R; Woodward, A D; Fouhse, J; van Kempen, T A T G

2012-12-01

Traditionally in swine nutrition, analyses of starch and fiber have focused on assessing quantity; however, both have a wide range of functional properties making them underappreciated nutrients. Starch ranging from low to high amylose changes from rapidly digestible in the upper gut to poorly digestible but fermentable in the lower gut thereby changing from a source of glucose to VFA source. Likewise, fibers ranging from low to high viscosity affect digesta flow and from slowly to rapidly fermentable alter production of VFA serving as energy for the gut or whole body. Our hypothesis is that total extent, kinetics, and site of digestion or fermentation of starch and fiber are important for whole body nutrient use and intestinal health. To elucidate their effects, we developed in vitro, lab-based methodologies to describe kinetics of digestion and fermentation and linked these with in vivo models including i) ileum cannulation to collect digesta, ii) portal-vein catheterization to sequentially sample blood, iii) slaughter method to collect site-specific intestinal tissue and digesta, and iv) indirect calorimetry. Using these methods, kinetics of nutrient absorption was associated with pancreatic and intestinal hormones released into the portal vein, intestinal microbiota, and gene expression in intestinal tissue and microbiota. These studies confirmed that slowly digestible starch is partially degraded in the distal small and large intestine and fermented into VFA including butyrate (10-fold increase in net portal appearance), which reduces insulin responses by 60% and whole body energy use. Starch entering the distal intestine altered mRNA abundance of nutrient transporters and was bifidogenic. Extremely viscous purified fiber dampened glycemic responses and reduced digesta passage rate by 50% thereby increasing ileal digestion of dietary nutrients whereas increased fiber in feed grains reduced nutrient digestibility. Fermentable fiber increased butyrate and insulin production. These methods will therefore support elucidation of mechanisms that link starch and fiber properties to whole body nutrient use and intestinal health.

Extensive Intestinal Resection Triggers Behavioral Adaptation, Intestinal Remodeling and Microbiota Transition in Short Bowel Syndrome

PubMed Central

Mayeur, Camille; Gillard, Laura; Le Beyec, Johanne; Bado, André; Joly, Francisca; Thomas, Muriel

2016-01-01

Extensive resection of small bowel often leads to short bowel syndrome (SBS). SBS patients develop clinical mal-absorption and dehydration relative to the reduction of absorptive area, acceleration of gastrointestinal transit time and modifications of the gastrointestinal intra-luminal environment. As a consequence of severe mal-absorption, patients require parenteral nutrition (PN). In adults, the overall adaptation following intestinal resection includes spontaneous and complex compensatory processes such as hyperphagia, mucosal remodeling of the remaining part of the intestine and major modifications of the microbiota. SBS patients, with colon in continuity, harbor a specific fecal microbiota that we called “lactobiota” because it is enriched in the Lactobacillus/Leuconostoc group and depleted in anaerobic micro-organisms (especially Clostridium and Bacteroides). In some patients, the lactobiota-driven fermentative activities lead to an accumulation of fecal d/l-lactates and an increased risk of d-encephalopathy. Better knowledge of clinical parameters and lactobiota characteristics has made it possible to stratify patients and define group at risk for d-encephalopathy crises. PMID:27681910

Absorption from a mixture of seventeen free amino acids by the isolated small intestine of the rat.

PubMed Central

Gardner, M L

1976-01-01

Absorption and secretion from a mixture of seventeen free amino acids has been measured in isolated perfused rat small intestine. 2. The absorption rate of an amino acid from this mixture is proportional to its concentration in the perfusate and independent of its chemical constitution. The constant of proportionality is the same as that previously observed when the perfusate contained peptides as well as amino acids. 3. Amino acids are concentrated, on average, sixfold during passage across the mucosa, and the free amino acid composition of the secretion into the tissue fluid is very similar to that of the luminal perfusate. 4. Peptides do not appear to be added to the tissue fluid during absorption of free amino acids. 5. It is concluded that the mechanisms for absorption of free amino acids are in general independent of those for absorption of peptides. PMID:1255532

The role of turmerones on curcumin transportation and P-glycoprotein activities in intestinal Caco-2 cells.

PubMed

Yue, Grace G L; Cheng, Sau-Wan; Yu, Hua; Xu, Zi-Sheng; Lee, Julia K M; Hon, Po-Ming; Lee, Mavis Y H; Kennelly, Edward J; Deng, Gary; Yeung, Simon K; Cassileth, Barrie R; Fung, Kwok-Pui; Leung, Ping-Chung; Lau, Clara B S

2012-03-01

The rhizome of Curcuma longa (turmeric) is often used in Asia as a spice and as a medicine. Its most well-studied component, curcumin, has been shown to exhibit poor bioavailability in animal studies and clinical trials. We hypothesized that the presence of lipophilic components (e.g., turmerones) in turmeric extract would affect the absorption of curcumin. The effects of turmerones on curcumin transport were evaluated in human intestinal epithelial Caco-2 cells. The roles of turmerones on P-glycoprotein (P-gp) activities and mRNA expression were also evaluated. Results showed that in the presence of α- and aromatic turmerones, the amount of curcumin transported into the Caco-2 cells in 2 hours was significantly increased. α-Turmerone and verapamil (a P-gp inhibitor) significantly inhibited the efflux of rhodamine-123 and digoxin (i.e., inhibited the activity of P-gp). It is interesting that aromatic turmerone significantly increased the rhodamine-123 efflux and P-gp (MDR1 gene) mRNA expression levels. The effects of α- and aromatic turmerones on curcumin transport as well as P-gp activities were shown here for the first time. The presence of turmerones did affect the absorption of curcumin in vitro. These findings suggest the potential use of turmeric extract (including curcumin and turmerones), rather than curcumin alone, for treating diseases.

The Role of Turmerones on Curcumin Transportation and P-Glycoprotein Activities in Intestinal Caco-2 Cells

PubMed Central

Yue, Grace G.L.; Cheng, Sau-Wan; Yu, Hua; Xu, Zi-Sheng; Lee, Julia K.M.; Hon, Po-Ming; Lee, Mavis Y.H.; Kennelly, Edward J.; Deng, Gary; Yeung, Simon K.; Cassileth, Barrie R.; Fung, Kwok-Pui; Leung, Ping-Chung

2012-01-01

Abstract The rhizome of Curcuma longa (turmeric) is often used in Asia as a spice and as a medicine. Its most well-studied component, curcumin, has been shown to exhibit poor bioavailability in animal studies and clinical trials. We hypothesized that the presence of lipophilic components (e.g., turmerones) in turmeric extract would affect the absorption of curcumin. The effects of turmerones on curcumin transport were evaluated in human intestinal epithelial Caco-2 cells. The roles of turmerones on P-glycoprotein (P-gp) activities and mRNA expression were also evaluated. Results showed that in the presence of α- and aromatic turmerones, the amount of curcumin transported into the Caco-2 cells in 2 hours was significantly increased. α-Turmerone and verapamil (a P-gp inhibitor) significantly inhibited the efflux of rhodamine-123 and digoxin (i.e., inhibited the activity of P-gp). It is interesting that aromatic turmerone significantly increased the rhodamine-123 efflux and P-gp (MDR1 gene) mRNA expression levels. The effects of α- and aromatic turmerones on curcumin transport as well as P-gp activities were shown here for the first time. The presence of turmerones did affect the absorption of curcumin in vitro. These findings suggest the potential use of turmeric extract (including curcumin and turmerones), rather than curcumin alone, for treating diseases. PMID:22181075

Evaluation of Intestinal Absorption and Bioavailability of a Bergenin-Phospholipid Complex Solid Dispersion in Rats.

PubMed

Gao, Haoshi; Wei, Yue; Xi, Long; Sun, Yuanyuan; Zhang, Tianhong

2018-05-01

Bergenin (BN) is a Biopharmaceutics Classification System class IV (BCS IV) drug with poor hydrophilicity and lipophilicity and is potentially eliminated by the efflux function of P-glycoprotein (P-gp). These factors may explain its low oral bioavailability. In the present study, a BN-phospholipid complex solid dispersion (BNPC-SD) was prepared by solvent evaporation and characterized based on differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, infrared diffraction, solubility, octanol-water partition coefficient, and in vitro dissolution. To investigate how P-gp can inhibit BN absorption in vivo, the P-gp inhibitor verapamil was co-administered with BNPC-SD to Sprague Dawley rats. By in situ single-pass intestinal perfusion, the membrane permeability of BN from BNPC-SD was higher than that of BN given alone and was improved further by co-administered verapamil. A pharmacokinetics study was done in Sprague Dawley rats, with plasma BN levels estimated by high-performance liquid chromatography. C max and AUC 0 → t values for BN were significantly higher for BNPC-SD than for BN given alone and were increased further by verapamil. Thus, the relative oral bioavailability of BNPC-SD as well as BNPC-SD co-administered with verapamil was 156.33 and 202.46%, respectively, compared with the value for BN given alone. These results showed that BNPC-SD can increase the oral bioavailability of BCS IV drugs.

Binding of navy bean (Phaseolus vulgaris) lectin to the intestinal cells of the rat and its effect on the absorption of glucose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Donatucci, D.A.; Liener, I.E.; Gross, C.J.

The main objectives of this investigation were to study the binding of a lectin from navy beans with the epithelial cells of the rat intestine and to assess the effect of such binding on the ability of the intestine to absorb glucose. A Scatchard plot, based on the binding of /sup 125/I-labeled lectin to isolated intestinal epithelial cells, was used to calculate an association constant (Ka) of 15 x 10(6)M-1 and the number of binding sites per cell, 12 x 10(6). Metabolic studies were conducted over a period of 5 d on groups of rats fed raw or autoclaved navymore » bean flour and casein with or without the purified lectin. Growth, protein digestibility, biological value and net protein utilization were significantly lower in animals that had been fed raw navy bean flour or casein plus lectin than in control groups fed diets containing autoclaved navy bean flour or casein alone. Vascular perfusion was used to measure the rate of uptake of glucose by the intestines of rats that had received the various dietary treatments. The rate of absorption of (/sup 14/C)glucose by intestines from rats fed raw navy bean flour or casein plus lectin was approximately one-half that of their counterparts fed the autoclaved flour or casein alone. These results provide evidence that the lectin, by virtue of its interference with intestinal absorption, is responsible, at least in part, for the nutritional inferiority of raw navy beans.« less

Regional intestinal drug permeation: biopharmaceutics and drug development.

PubMed

Lennernäs, Hans

2014-06-16

Over the last 25 years, profound changes have been seen in both the development and regulation of pharmaceutical dosage forms, due primarily to the extensive use of the biopharmaceutical classification system (BCS) in both academia and industry. The BCS and the FDA scale-up and post-approval change guidelines were both developed during the 1990s and both are currently widely used to claim biowaivers. The development of the BCS and its wide acceptance were important steps in pharmaceutical science that contributed to the more rational development of oral dosage forms. The effective permeation (Peff) of drugs through the intestine often depends on the combined outcomes of passive diffusion and multiple parallel transport processes. Site-specific jejunal Peff cannot reflect the permeability of the whole intestinal tract, since this varies along the length of the intestine, but is a useful approximation of the fraction of the oral dose that is absorbed. It appears that drugs with a jejunal Peff>1.5×10(-4)cm/s will be completely absorbed no matter which transport mechanisms are utilized. In this paper, historical clinical data originating from earlier open, single-pass perfusion studies have been used to calculate the Peff of different substances from sites in the jejunum and ileum. More exploratory in vivo studies are required in order to obtain reliable data on regional intestinal drug absorption. The development of experimental and theoretical methods of assessing drug absorption from both small intestine and various sites in the colon is encouraged. Some of the existing human in vivo data are discussed in relation to commonly used cell culture models. It is crucial to accurately determine the input parameters, such as the regional intestinal Peff, as these will form the basis for the expected increase in modeling and simulation of all the processes involved in GI drug absorption, thus facilitating successful pharmaceutical development in the future. It is suggested that it would be feasible to use open, single-pass perfusion studies for the in vivo estimation of regional intestinal Peff, but that care should be taken in the study design to optimize the absorption conditions. Copyright © 2013 Elsevier B.V. All rights reserved.

Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue.

PubMed

Incecayir, Tuba; Sun, Jing; Tsume, Yasuhiro; Xu, Hao; Gose, Tomoka; Nakanishi, Takeo; Tamai, Ikumi; Hilfinger, John; Lipka, Elke; Amidon, Gordon L

2016-02-01

The goal of this study was to improve the intestinal mucosal cell membrane permeability of the poorly absorbed guanidino analogue of a neuraminidase inhibitor, oseltamivir carboxylate (GOC) using a carrier-mediated strategy. Valyl amino acid prodrug of GOC with isopropyl-methylene-dioxy linker (GOC-ISP-Val) was evaluated as the potential substrate for intestinal oligopeptide transporter, hPEPT1 in Xenopus laevis oocytes heterologously expressing hPEPT1, and an intestinal mouse perfusion system. The diastereomers of GOC-ISP-Val were assessed for chemical and metabolic stability. Permeability of GOC-ISP-Val was determined in Caco-2 cells and mice. Diastereomer 2 was about 2 times more stable than diastereomer 1 in simulated intestinal fluid and rapidly hydrolyzed to the parent drug in cell homogenates. The prodrug had a 9 times-enhanced apparent permeability (P(app)) in Caco-2 cells compared with the parent drug. Both diastereomer exhibited high effective permeability (P(eff)) in mice, 6.32 ± 3.12 and 5.20 ± 2.81 × 10(-5) cm/s for diastereomer 1 and 2, respectively. GOC-ISP-Val was found to be a substrate of hPEPT1. Overall, this study indicates that the prodrug, GOC-ISP-Val, seems to be a promising oral anti-influenza agent that has sufficient stability at physiologically relevant pHs before absorption, significantly improved permeability via hPEPT1 and potentially rapid activation in the intestinal cells. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

[Strontium and calcium metabolism. Interaction of strontium and vitamin D].

PubMed

Rousselet, F; El Solh, N; Maurat, J P; Gruson, M; Girard, M L

1975-01-01

Oral administration of strontium to calcium wellfed rats blocks the intestinal absorption of calcium. When high doses of vitamine D are given over long period, the inhibition of calcium intestinal absorption disapears. Under these conditions the absorption of strontium is increased. It is suggested that there is only one absorption mechanism for these two cations. An overdose of the vitamine D increases the renal elimination of strontium but under these conditions the plasma concentration of the strontium is unchanged. Vitamine D brings about the some action on the bone fixation of the strontium as it does on the bone fixation of calcium. The bone fixation is increased with low dosages. The bone fixation is decreased with high dosages.

Avian species differences in the intestinal absorption of xenobiotics (PCB, dieldrin, Hg2+)

USGS Publications Warehouse

Serafin, J.A.

1984-01-01

1. Intestinal absorption of a polychlorinated biphenyl, dieldrin, and mercury (from HgCl2) was measured in adult Northern bobwhites, Eastern screech owls, American kestrels, black-crowned night-herons and mallards in vivo by an in situ luminal perfusion technique.2. Bobwhites, screech owls and kestrels absorbed much more of each xenobiotic than black-crowned night-herons and mallards.3. Mallards absorbed less dieldrin and mercury than black-crowned night-herons.4. Mercury absorption by kestrels was more than twice that in screech owls and eight times that observed in mallards.5. Pronounced differences in xenobiotic absorption rates between bobwhites, screech owls and kestrels on the one hand, and black-crowned night-herons and mallards on the other, raise the possibility that absorptive ability may be associated with the phylogenetic classification of birds.

Immunological demonstration of intestinal absorption and digestion of protein macromolecules in the trout (Salmo gairdneri).

PubMed

Georgopoulou, U; Sire, M F; Vernier, J M

1986-01-01

An immunofluorescence technique using antibodies against the Fc and Fab fragments of human IgG (IgGH) was used to study the absorption of proteins by the intestinal epithelial cells of rainbow trout after oral or anal administration. Cellular absorption of a high molecular weight protein, hepatitis-B surface antigen (HBsAg), was also studied by using two monoclonal antibodies, one specific for the confirmation of the antigen (implying disulfide bridges), and the other that reacts with the constituent polypeptides. Both absorbed IgGH and HBsAg were seen to be segregated in the apical vacuolar system, a characteristic feature of intestinal epithelial cells. The same antibodies were used with an everted sac technique in conjunction with immunofluorescence, to show the intravacuolar degradation of IgGH and HBsAg following absorption. By using an antibody against cathepsin D, it was possible to demonstrate, by immunofluorescence, the localization of this enzyme in the same vacuolar system. After coupling the antibody to peroxidase or to the protein A/colloidalgold complex, the ultrastructural antigenic sites of cathepsin D could be seen to be localized in the interior of the vacuoles. The vacuolar localization of a cathepsin B activity was determined by incubating sections of intestinal mucosa, or isolated epithelial cells, with a specific synthetic substrate (Z-Ala-Arg-Arg-methoxynaphthylamide). The supranuclear hyaloplasmic vacuoles of intestinal epithelial cells may be considered to be phagolysosomes that assure the degradation of absorbed proteins. This function may be of fundamental importance in the in the nutritional processes of this species.

Development and optimization of a self-microemulsifying drug delivery system for atorvastatin calcium by using D-optimal mixture design.

PubMed

Yeom, Dong Woo; Song, Ye Seul; Kim, Sung Rae; Lee, Sang Gon; Kang, Min Hyung; Lee, Sangkil; Choi, Young Wook

2015-01-01

In this study, we developed and optimized a self-microemulsifying drug delivery system (SMEDDS) formulation for improving the dissolution and oral absorption of atorvastatin calcium (ATV), a poorly water-soluble drug. Solubility and emulsification tests were performed to select a suitable combination of oil, surfactant, and cosurfactant. A D-optimal mixture design was used to optimize the concentration of components used in the SMEDDS formulation for achieving excellent physicochemical characteristics, such as small droplet size and high dissolution. The optimized ATV-loaded SMEDDS formulation containing 7.16% Capmul MCM (oil), 48.25% Tween 20 (surfactant), and 44.59% Tetraglycol (cosurfactant) significantly enhanced the dissolution rate of ATV in different types of medium, including simulated intestinal fluid, simulated gastric fluid, and distilled water, compared with ATV suspension. Good agreement was observed between predicted and experimental values for mean droplet size and percentage of the drug released in 15 minutes. Further, pharmacokinetic studies in rats showed that the optimized SMEDDS formulation considerably enhanced the oral absorption of ATV, with 3.4-fold and 4.3-fold increases in the area under the concentration-time curve and time taken to reach peak plasma concentration, respectively, when compared with the ATV suspension. Thus, we successfully developed an optimized ATV-loaded SMEDDS formulation by using the D-optimal mixture design, that could potentially be used for improving the oral absorption of poorly water-soluble drugs.

Development and optimization of a self-microemulsifying drug delivery system for ator vastatin calcium by using d-optimal mixture design

PubMed Central

Yeom, Dong Woo; Song, Ye Seul; Kim, Sung Rae; Lee, Sang Gon; Kang, Min Hyung; Lee, Sangkil; Choi, Young Wook

2015-01-01

In this study, we developed and optimized a self-microemulsifying drug delivery system (SMEDDS) formulation for improving the dissolution and oral absorption of atorvastatin calcium (ATV), a poorly water-soluble drug. Solubility and emulsification tests were performed to select a suitable combination of oil, surfactant, and cosurfactant. A d-optimal mixture design was used to optimize the concentration of components used in the SMEDDS formulation for achieving excellent physicochemical characteristics, such as small droplet size and high dissolution. The optimized ATV-loaded SMEDDS formulation containing 7.16% Capmul MCM (oil), 48.25% Tween 20 (surfactant), and 44.59% Tetraglycol (cosurfactant) significantly enhanced the dissolution rate of ATV in different types of medium, including simulated intestinal fluid, simulated gastric fluid, and distilled water, compared with ATV suspension. Good agreement was observed between predicted and experimental values for mean droplet size and percentage of the drug released in 15 minutes. Further, pharmacokinetic studies in rats showed that the optimized SMEDDS formulation considerably enhanced the oral absorption of ATV, with 3.4-fold and 4.3-fold increases in the area under the concentration-time curve and time taken to reach peak plasma concentration, respectively, when compared with the ATV suspension. Thus, we successfully developed an optimized ATV-loaded SMEDDS formulation by using the d-optimal mixture design, that could potentially be used for improving the oral absorption of poorly water-soluble drugs. PMID:26089663

Potential of Lactobacillus plantarum CCFM639 in Protecting against Aluminum Toxicity Mediated by Intestinal Barrier Function and Oxidative Stress.

PubMed

Yu, Leilei; Zhai, Qixiao; Tian, Fengwei; Liu, Xiaoming; Wang, Gang; Zhao, Jianxin; Zhang, Hao; Narbad, Arjan; Chen, Wei

2016-12-02

Aluminum (Al) is a ubiquitous metal that can seriously harm the health of animals and humans. In our previous study, we demonstrated that Lactobacillus plantarum CCFM639 can decrease Al burden in the tissues of mice by inhibiting intestinal Al absorption. The main aim of the present research was to investigate whether the protection by the strain is also associated with enhancement of the intestinal barrier, alleviation of oxidative stress and modulation of the inflammatory response. In an in vitro cell model, two protection modes (intervention and therapy) were examined and the results indicated that L. plantarum CCFM639 alleviated Al-induced cytotoxicity. In a mouse model, L. plantarum CCFM639 treatment was found to significantly alleviate oxidative stress in the intestinal tract, regulate the function of the intestinal mucosal immune system, restore the integrity of tight junction proteins and maintain intestinal permeability. These results suggest that in addition to Al sequestration, L. plantarum CCFM639 can also inhibit Al absorption by protecting the intestinal barrier, alleviating Al-induced oxidative stress and inflammatory response. Therefore, L. plantarum CCFM639 has the potential to be a dietary supplement ingredient that provides protection against Al-induced gut injury.

[Effect of multicomponent environment on intestinal permeability of puerarin in biopharmaceutics classification system of Chinese materia medica].

PubMed

Liu, Yang; Wang, Gang; Dong, Ling; Tang, Ming-Min; Zhu, Mei-Ling; Dong, Hong-Huant; Hou, Cheng-Bo

2014-12-01

The evaluation of permeability in biopharmaceutics classification system of Chinese materia medica (CMMBCS) requires multicomponent as a whole in order to conduct research, even in the study of a specific component, should also be put in the multicomponent environment. Based on this principle, the high content components in Gegen Qinlian decoction were used as multicomponent environmental impact factors in the experiment, and the relevant parameters of intestinal permeability about puerarin were measured with using in situ single-pass intestinal perfusion model, to investigate and evaluate the intestinal permeability of puerarin with other high content components. The experimental results showed that different proportions of baicalin, glycyrrhizic acid and berberine had certain influence on intestinal permeability of puerarin, and glycyrrhizic acid could significantly inhibit the intestinal absorption of puerarin, moreover, high concentration of berberine could promote the absorption of puerarin. The research results indicated that the important research ideas of permeability evaluation in biopharmaceutics classification system of Chinese materia medica with fully considering the effects of other ingredients in multicomponent environment.

Evaluation of jojoba oil as a low-energy fat. 2. Intestinal transit time, stomach emptying and digestibility in short-term feeding studies in rats.

PubMed

Verschuren, P M; Nugteren, D H

1989-01-01

The influence of jojoba oil (JO) incorporation in the diet on stomach emptying and intestinal transit time, and the digestion and absorption of JO were investigated in short-term feeding studies in rats. The animals were fed purified diets containing 18% (w/w) fat, of which half consisted of a mixture of lard and sunflower seed oil (SF) supplemented with an equivalent amount of JO. The control animals were fed a mixture of lard and SF (18%). No treatment-related differences were observed in the rate of stomach emptying or the intestinal transit time. Comparative lipid analysis of lymph, intestinal content, intestinal mucosa and faeces indicated that most of the ingested JO was degraded and absorbed. Part of the JO was present as wax ester in the lymph. Hydrolysis of JO was much slower than that of triacylglycerols and continued in the alimentary tract beyond the small intestine due to bacterial processes. JO did not influence the absorption of the conventional fat.

Green Tea as Inhibitor of the Intestinal Absorption of Lipids: Potential Mechanism for its Lipid-Lowering Effect1

PubMed Central

Koo, Sung I.; Noh, Sang K.

2007-01-01

Animal and epidemiological studies suggest that green tea catechins may reduce the risk of cardiovascular diseases (CHD). The health benefit of green tea has been attributed to its antioxidant and anti-inflammatory properties; however, considerable evidence suggests that green tea and its catechins may reduce the risk of CHD by lowering the plasma levels of cholesterol and triglyceride. Although the mechanism underlying such effect of green tea is yet to be determined, it is evident from in vitro and in vivo studies that green tea or catechins inhibit the intestinal absorption of dietary lipids. Studies in vitro indicate that green tea catechins, particularly EGCG, interfere with the emulsification, digestion, and micellar solubilization of lipids, critical steps involved in the intestinal absorption of dietary fat, cholesterol, and other lipids. Based on the observations, it is likely that green tea or its catechins lower the absorption and tissue accumulation of other lipophilic organic compounds. The available information strongly suggests that green tea or its catechins may be used as safe and effective lipid-lowering therapeutic agents. PMID:17296491

Physiology of Intestinal Absorption and Secretion

PubMed Central

Kiela, Pawel R.; Ghishan, Fayez K.

2016-01-01

Virtually all nutrients from the diet are absorbed into blood across the highly polarized epithelial cell layer forming the small and large intestinal mucosa. Anatomical, histological, and functional specializations along the gastrointestinal tract are responsible for the effective and regulated nutrient transport via both passive and active mechanisms. In this chapter, we summarize the current state of knowledge regarding the mechanism of intestinal absorption of key nutrients such as sodium, anions (chloride, sulfate, oxalate), carbohydrates, amino acids and peptides, lipids, lipidand water-soluble vitamins, as well as the major minerals and micronutrients. This outline, including the molecular identity, specificity, and coordinated activities of key transport proteins and genes involved, serves as the background for the following chapters focused on the pathophysiology of acquired and congenital intestinal malabsorption, as well as clinical tools to test and treat malabsorptive symptoms. PMID:27086882

Titanium dioxide nanoparticle exposure alters metabolic homeostasis in a cell culture model of the intestinal epithelium and Drosophila melanogaster.

PubMed

Richter, Jonathan W; Shull, Gabriella M; Fountain, John H; Guo, Zhongyuan; Musselman, Laura P; Fiumera, Anthony C; Mahler, Gretchen J

2018-06-01

Nanosized titanium dioxide (TiO 2 ) is a common additive in food and cosmetic products. The goal of this study was to investigate if TiO 2 nanoparticles affect intestinal epithelial tissues, normal intestinal function, or metabolic homeostasis using in vitro and in vivo methods. An in vitro model of intestinal epithelial tissue was created by seeding co-cultures of Caco-2 and HT29-MTX cells on a Transwell permeable support. These experiments were repeated with monolayers that had been cultured with the beneficial commensal bacteria Lactobacillus rhamnosus GG (L. rhamnosus). Glucose uptake and transport in the presence of TiO 2 nanoparticles was assessed using fluorescent glucose analog 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG). When the cell monolayers were exposed to physiologically relevant doses of TiO 2 , a statistically significant reduction in glucose transport was observed. These differences in glucose absorption were eliminated in the presence of beneficial bacteria. The decrease in glucose absorption was caused by damage to intestinal microvilli, which decreased the surface area available for absorption. Damage to microvilli was ameliorated in the presence of L. rhamnosus. Complimentary studies in Drosophila melanogaster showed that TiO 2 ingestion resulted in decreased body size and glucose content. The results suggest that TiO 2 nanoparticles alter glucose transport across the intestinal epithelium, and that TiO 2 nanoparticle ingestion may have physiological consequences.

Distinguishing between the Permeability Relationships with Absorption and Metabolism To Improve BCS and BDDCS Predictions in Early Drug Discovery

PubMed Central

2015-01-01

The biopharmaceutics classification system (BCS) and biopharmaceutics drug distribution classification system (BDDCS) are complementary classification systems that can improve, simplify, and accelerate drug discovery, development, and regulatory processes. Drug permeability has been widely accepted as a screening tool for determining intestinal absorption via the BCS during the drug development and regulatory approval processes. Currently, predicting clinically significant drug interactions during drug development is a known challenge for industry and regulatory agencies. The BDDCS, a modification of BCS that utilizes drug metabolism instead of intestinal permeability, predicts drug disposition and potential drug–drug interactions in the intestine, the liver, and most recently the brain. Although correlations between BCS and BDDCS have been observed with drug permeability rates, discrepancies have been noted in drug classifications between the two systems utilizing different permeability models, which are accepted as surrogate models for demonstrating human intestinal permeability by the FDA. Here, we recommend the most applicable permeability models for improving the prediction of BCS and BDDCS classifications. We demonstrate that the passive transcellular permeability rate, characterized by means of permeability models that are deficient in transporter expression and paracellular junctions (e.g., PAMPA and Caco-2), will most accurately predict BDDCS metabolism. These systems will inaccurately predict BCS classifications for drugs that particularly are substrates of highly expressed intestinal transporters. Moreover, in this latter case, a system more representative of complete human intestinal permeability is needed to accurately predict BCS absorption. PMID:24628254

Activation of rat intestinal mucosal mast cells by fat absorption.

PubMed

Ji, Yong; Sakata, Yasuhisa; Yang, Qing; Li, Xiaoming; Xu, Min; Yoder, Stephanie; Langhans, Wolfgang; Tso, Patrick

2012-06-01

Previous studies have linked certain types of gut mucosal immune cells with fat intake. We determined whether fat absorption activates intestinal mucosal mast cells (MMC), a key component of the gut mucosal immune system. Conscious intestinal lymph fistula rats were used. The mesenteric lymph ducts were cannulated, and the intraduodenal (i.d.) tubes were installed for the infusion of Liposyn II 20% (an intralipid emulsion). Lymphatic concentrations of histamine, rat MMC protease II (RMCPII), a specific marker of rat intestinal MMC degranulation, and prostaglandin D(2) (PGD(2)) were measured by ELISA. Intestinal MMC degranulation was visualized by immunofluorescent microscopy of jejunum sections taken at 1 h after Liposyn II gavage. Intraduodenal bolus infusion of Liposyn II 20% (4.4 kcal/3 ml) induced approximately a onefold increase in lymphatic histamine and PGD(2), ∼20-fold increase in lymphatic RMCPII, but only onefold increase in peripheral serum RMCPII concentrations. Release of RMCPII into lymph increased dose dependently with the amount of lipid fed. In addition, i.d. infusion of long-chain triacylglycerol trilinolein (C18:2 n-6, the major composite in Liposyn II) significantly increased the lymphatic RMCPII concentration, whereas medium-chain triacylglycerol tricaprylin (C8:0) did not alter lymph RMCPII secretion. Immunohistochemistry image revealed the degranulation of MMC into lamina propria after lipid feeding. These novel findings indicate that intestinal MMC are activated and degranulate to release MMC mediators to the circulation during fat absorption. This action of fatty acid is dose and chain length dependent.

Distinguishing between the permeability relationships with absorption and metabolism to improve BCS and BDDCS predictions in early drug discovery.

PubMed

Larregieu, Caroline A; Benet, Leslie Z

2014-04-07

The biopharmaceutics classification system (BCS) and biopharmaceutics drug distribution classification system (BDDCS) are complementary classification systems that can improve, simplify, and accelerate drug discovery, development, and regulatory processes. Drug permeability has been widely accepted as a screening tool for determining intestinal absorption via the BCS during the drug development and regulatory approval processes. Currently, predicting clinically significant drug interactions during drug development is a known challenge for industry and regulatory agencies. The BDDCS, a modification of BCS that utilizes drug metabolism instead of intestinal permeability, predicts drug disposition and potential drug-drug interactions in the intestine, the liver, and most recently the brain. Although correlations between BCS and BDDCS have been observed with drug permeability rates, discrepancies have been noted in drug classifications between the two systems utilizing different permeability models, which are accepted as surrogate models for demonstrating human intestinal permeability by the FDA. Here, we recommend the most applicable permeability models for improving the prediction of BCS and BDDCS classifications. We demonstrate that the passive transcellular permeability rate, characterized by means of permeability models that are deficient in transporter expression and paracellular junctions (e.g., PAMPA and Caco-2), will most accurately predict BDDCS metabolism. These systems will inaccurately predict BCS classifications for drugs that particularly are substrates of highly expressed intestinal transporters. Moreover, in this latter case, a system more representative of complete human intestinal permeability is needed to accurately predict BCS absorption.

Activation of rat intestinal mucosal mast cells by fat absorption

PubMed Central

Sakata, Yasuhisa; Yang, Qing; Li, Xiaoming; Xu, Min; Yoder, Stephanie; Langhans, Wolfgang; Tso, Patrick

2012-01-01

Previous studies have linked certain types of gut mucosal immune cells with fat intake. We determined whether fat absorption activates intestinal mucosal mast cells (MMC), a key component of the gut mucosal immune system. Conscious intestinal lymph fistula rats were used. The mesenteric lymph ducts were cannulated, and the intraduodenal (i.d.) tubes were installed for the infusion of Liposyn II 20% (an intralipid emulsion). Lymphatic concentrations of histamine, rat MMC protease II (RMCPII), a specific marker of rat intestinal MMC degranulation, and prostaglandin D2 (PGD2) were measured by ELISA. Intestinal MMC degranulation was visualized by immunofluorescent microscopy of jejunum sections taken at 1 h after Liposyn II gavage. Intraduodenal bolus infusion of Liposyn II 20% (4.4 kcal/3 ml) induced approximately a onefold increase in lymphatic histamine and PGD2, ∼20-fold increase in lymphatic RMCPII, but only onefold increase in peripheral serum RMCPII concentrations. Release of RMCPII into lymph increased dose dependently with the amount of lipid fed. In addition, i.d. infusion of long-chain triacylglycerol trilinolein (C18:2 n-6, the major composite in Liposyn II) significantly increased the lymphatic RMCPII concentration, whereas medium-chain triacylglycerol tricaprylin (C8:0) did not alter lymph RMCPII secretion. Immunohistochemistry image revealed the degranulation of MMC into lamina propria after lipid feeding. These novel findings indicate that intestinal MMC are activated and degranulate to release MMC mediators to the circulation during fat absorption. This action of fatty acid is dose and chain length dependent. PMID:22461027

Alligators and Crocodiles Have High Paracellular Absorption of Nutrients, But Differ in Digestive Morphology and Physiology.

PubMed

Tracy, Christopher R; McWhorter, Todd J; Gienger, C M; Starck, J Matthias; Medley, Peter; Manolis, S Charlie; Webb, Grahame J W; Christian, Keith A

2015-12-01

Much of what is known about crocodilian nutrition and growth has come from animals propagated in captivity, but captive animals from the families Crocodilidae and Alligatoridae respond differently to similar diets. Since there are few comparative studies of crocodilian digestive physiology to help explain these differences, we investigated young Alligator mississippiensis and Crocodylus porosus in terms of (1) gross and microscopic morphology of the intestine, (2) activity of the membrane-bound digestive enzymes aminopeptidase-N, maltase, and sucrase, and (3) nutrient absorption by carrier-mediated and paracellular pathways. We also measured gut morphology of animals over a larger range of body sizes. The two species showed different allometry of length and mass of the gut, with A. mississippiensis having a steeper increase in intestinal mass with body size, and C. porosus having a steeper increase in intestinal length with body size. Both species showed similar patterns of magnification of the intestinal surface area, with decreasing magnification from the proximal to distal ends of the intestine. Although A. mississippiensis had significantly greater surface-area magnification overall, a compensating significant difference in gut length between species meant that total surface area of the intestine was not significantly different from that of C. porosus. The species differed in enzyme activities, with A. mississippiensis having significantly greater ability to digest carbohydrates relative to protein than did C. porosus. These differences in enzyme activity may help explain the differences in performance between the crocodilian families when on artificial diets. Both A. mississippiensis and C. porosus showed high absorption of 3-O methyl d-glucose (absorbed via both carrier-mediated and paracellular transport), as expected. Both species also showed surprisingly high levels of l-glucose-uptake (absorbed paracellularly), with fractional absorptions as high as those previously seen only in small birds and bats. Analyses of absorption rates suggested a relatively high proportional contribution of paracellular (i.e., non-mediated) uptake to total uptake of nutrients in both species. Because we measured juveniles, and most paracellular studies to date have been on adults, it is unclear whether high paracellular absorption is generally high within crocodilians or whether these high values are specific to juveniles. © The Author 2015. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

RADIOACTIVE IRON ABSORPTION BY GASTRO-INTESTINAL TRACT

PubMed Central

Hahn, P. F.; Bale, W. F.; Ross, J. F.; Balfour, W. M.; Whipple, G. H.

1943-01-01

Iron absorption is a function of the gastro-intestinal mucosal epithelium. The normal non-anemic dog absorbs little iron but chronic anemia due to blood loss brings about considerable absorption—perhaps 5 to 15 times normal. In general the same differences are observed in man (1). Sudden change from normal to severe anemia within 24 hours does not significantly increase iron absorption. As the days pass new hemoglobin is formed. The body iron stores are depleted and within 7 days iron absorption is active, even when the red cell hematocrit is rising. Anoxemia of 50 per cent normal oxygen concentration for 48 hours does not significantly enhance iron absorption. In this respect it resembles acute anemia. Ordinary doses of iron given 1 to 6 hours before radio-iron will cause some "mucosa block"—that is an intake of radio-iron less than anticipated. Many variables which modify peristalsis come into this reaction. Iron given by vein some days before the dose of radio-iron does not appear to inhibit iron absorption. Plasma radio-iron absorption curves vary greatly. The curves may show sharp peaks in 1 to 2 hours when the iron is given in an empty stomach but after 6 hours when the radio-iron is given with food. Duration time of curves also varies widely, the plasma iron returning to normal in 6 to 12 hours. Gastric, duodenal, or jejunal pouches all show very active absorption of iron. The plasma concentration peak may reach a maximum before the solution of iron is removed from the gastric pouch—another example of "mucosa block." Absorption and distribution of radio-iron in the body of growing pups give very suggestive experimental data. The spleen, heart, upper gastro-intestinal tract, marrow, and pancreas show more radio-iron than was expected. The term "physiological saturation" with iron may be applied to the gastro-intestinal mucosal epithelium and explain one phase of acceptance or refusal of ingested iron. Desaturation is a matter of days not hours, whereas saturation may take place within 1 to 2 hours. We believe this change is a part of the complex protein metabolism of the cell. PMID:19871320

Adaptation to different salinities exposes functional specialization in the intestine of the sea bream (Sparus aurata L.).

PubMed

Gregório, Sílvia F; Carvalho, Edison S M; Encarnação, Sandra; Wilson, Jonathan M; Power, Deborah M; Canário, Adelino V M; Fuentes, Juan

2013-02-01

The processing of intestinal fluid, in addition to a high drinking rate, is essential for osmoregulation in marine fish. This study analyzed the long-term response of the sea bream (Sparus aurata L.) to relevant changes of external salinity (12, 35 and 55 p.p.t.), focusing on the anterior intestine and in the less-often studied rectum. Intestinal water absorption, epithelial HCO(3)(-) secretion and gene expression of the main molecular mechanisms (SLC26a6, SLC26a3, SLC4a4, atp6v1b, CFTR, NKCC1 and NKCC2) involved in Cl(-) and HCO(3)(-) movements were examined. The anion transporters SLC26a6 and SLC26a3 are expressed severalfold higher in the anterior intestine, while the expression of Atp6v1b (V-type H(+)-ATPase β-subunit) is severalfold higher in the rectum. Prolonged exposure to altered external salinity was without effect on water absorption but was associated with concomitant changes in intestinal fluid content, epithelial HCO(3)(-) secretion and salinity-dependent expression of SLC26a6, SLC26a3 and SLC4a4 in the anterior intestine. However, the most striking response to external salinity was obtained in the rectum, where a 4- to 5-fold increase in water absorption was paralleled by a 2- to 3-fold increase in HCO(3)(-) secretion in response to a salinity of 55 p.p.t. In addition, the rectum of high salinity-acclimated fish shows a sustained (and enhanced) secretory current (I(sc)), identified in vitro in Ussing chambers and confirmed by the higher expression of CFTR and NKCC1 and by immunohistochemical protein localization. Taken together, the present results suggest a functional anterior-posterior specialization with regard to intestinal fluid processing and subsequently to salinity adaptation of the sea bream. The rectum becomes more active at higher salinities and functions as the final controller of intestinal function in osmoregulation.

Segmental dependent transport of low permeability compounds along the small intestine due to P-glycoprotein: the role of efflux transport in the oral absorption of BCS class III drugs.

PubMed

Dahan, Arik; Amidon, Gordon L

2009-01-01

The purpose of this study was to investigate the role of P-gp efflux in the in vivo intestinal absorption process of BCS class III P-gp substrates, i.e. high-solubility low-permeability drugs. The in vivo permeability of two H (2)-antagonists, cimetidine and famotidine, was determined by the single-pass intestinal perfusion model in different regions of the rat small intestine, in the presence or absence of the P-gp inhibitor verapamil. The apical to basolateral (AP-BL) and the BL-AP transport of the compounds in the presence or absence of various efflux transporters inhibitors (verapamil, erythromycin, quinidine, MK-571 and fumitremorgin C) was investigated across Caco-2 cell monolayers. P-gp expression levels in the different intestinal segments were confirmed by immunoblotting. Cimetidine and famotidine exhibited segmental dependent permeability through the gut wall, with decreased P(eff) in the distal ileum in comparison to the proximal regions of the intestine. Coperfusion of verapamil with the drugs significantly increased the permeability in the ileum, while no significant change in the jejunal permeability was observed. Both drugs exhibited significantly greater BL-AP than AP-BL Caco-2 permeability, indicative of net mucosal secretion. Concentration dependent decrease of this secretion was obtained by the P-gp inhibitors verapamil, erythromycin and quinidine, while no effect was evident by the MRP2 inhibitor MK-571 and the BCRP inhibitor FTC, indicating that P-gp is the transporter mediates the intestinal efflux of cimetidine and famotidine. P-gp levels throughout the intestine were inversely related to the in vivo permeability of the drugs from the different segments. The data demonstrate that for these high-solubility low-permeability P-gp substrates, P-gp limits in vivo intestinal absorption in the distal segments of the small intestine; however P-gp plays a minimal role in the proximal intestinal segments due to significant lower P-gp expression levels in this region.

Dissolution and dissolution/permeation experiments for predicting systemic exposure following oral administration of the BCS class II drug clarithromycin.

PubMed

Kristin, Forner; René, Holm; Boontida, Morakul; Buraphacheep, Junyaprasert Varaporn; Maximilian, Ackermann; Johanna, Mazur; Peter, Langguth

2017-04-01

In order to save time and resources in early drug development, in vitro methods that correctly predict the formulation effect on oral drug absorption are necessary. The aim of this study was to 1) evaluate various BCS class II drug formulations with in vitro methods and in vivo in order to 2) determine which in vitro method best correlates with the in vivo results. Clarithromycin served as model compound in formulations with different particle sizes and content of excipients. The performed in vitro experiments were dissolution and dissolution/permeation experiments across two types of membrane, Caco-2 cells and excised rat intestinal sheets. The in vivo study was performed in rats. The oral absorption was enhanced by downsizing drug particles and by increasing the excipient concentration. This correlated strongly with the flux across Caco-2 cells but not with the other in vitro experiments. The insufficient correlation with the dissolution experiments can be partly explained by excipient caused problems during the filtration step. The very poor correlation of the in vivo data with the flux across excised rat intestinal sheets might be due to an artificially enlarged mucus layer ex vivo. In conclusion, downsizing BCS class II drug particles and the addition of surfactants enhanced the in vivo absorption, which was best depicted by dissolution/permeation experiments across Caco-2 cells. This setup is proposed as best model to predict the in vivo formulation effect. Also, this is the first study to evaluate the impact of the nature of the permeation membrane in dissolution/permeation experiments. Copyright © 2017 Elsevier B.V. All rights reserved.

In vitro investigation of intestinal transport mechanism of silicon, supplied as orthosilicic acid-vanillin complex.

PubMed

Sergent, Thérèse; Croizet, Karine; Schneider, Yves-Jacques

2017-02-01

Silicon (Si) is one of the most abundant trace elements in the body. Although pharmacokinetics data described its absorption from the diet and its body excretion, the mechanisms involved in the uptake and transport of Si across the gut wall have not been established. Caco-2 cells were used as a well-accepted in vitro model of the human intestinal epithelium to investigate the transport, across the intestinal barrier in both the absorption and excretion directions, of Si supplied as orthosilicic acid stabilized by vanillin complex (OSA-VC). The transport of this species was found proportional to the initial concentration and to the duration of incubation, with absorption and excretion mean rates similar to those of Lucifer yellow, a marker of paracellular diffusion, and increasing in the presence of EGTA, a chelator of divalents cations including calcium. A cellular accumulation of Si, polarized from the apical side of cells, was furthermore detected. These results provide evidence that Si, ingested as a food supplement containing OSA-VC, crosses the intestinal mucosa by passive diffusion via the paracellular pathway through the intercellular tight junctions and accumulates intracellularly, probably by an uptake mechanism of facilitated diffusion. This study can help to further understand the kinetic of absorption of Si. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Influence of dietary spices on the in vivo absorption of ingested β-carotene in experimental rats.

PubMed

Veda, Supriya; Srinivasan, Krishnapura

2011-05-01

Animal studies were conducted to evaluate the influence of dietary spice compounds, piperine, capsaicin and ginger, on the absorption of orally administered β-carotene and its conversion to vitamin A. In rats maintained on these spice-containing diets for 8 weeks, concentrations of β-carotene and retinol were determined in the serum, liver and intestine 4 h after a single oral administration of β-carotene. β-Carotene concentration was significantly increased in the serum, liver and intestine of piperine- and ginger-fed rats, suggesting improved absorption of β-carotene. However, retinol concentration was not significantly changed in these animals, suggesting that the bioconversion of β-carotene to vitamin A was not similarly influenced. Between the two enzymes involved in the bioconversion of β-carotene to vitamin A, the activity of intestinal and hepatic β-carotene 15,15'-dioxygenase was either unaffected or lowered by these spice treatments. The activity of intestinal and hepatic retinal reductase was unaffected by the dietary spices. Activities of these two enzymes involved in the bioconversion of β-carotene to retinal were inhibited by the test spices in vitro, thus corroborating with the in vivo observation. Although the bioconversion of β-carotene was not promoted, increased absorption and tissue levels of β-carotene by the dietary spices may contribute to a higher antioxidant protection.

Microvillus-Specific Protein Tyrosine Phosphatase SAP-1 Plays a Role in Regulating the Intestinal Paracellular Transport of Macromolecules.

PubMed

Mori, Shingo; Kamei, Noriyasu; Murata, Yoji; Takayama, Kozo; Matozaki, Takashi; Takeda-Morishita, Mariko

2017-09-01

The stomach cancer-associated protein tyrosine phosphatase 1 (SAP-1) is a receptor-type protein tyrosine phosphatase that is specifically expressed on the apical membrane of the intestinal epithelium. SAP-1 is known to maintain the balance of phosphorylation of proteins together with protein kinases; however, its biological function and impact on pharmacokinetics in the intestine remain unclear. The present study, therefore, aimed at clarifying the relationship between SAP-1 and the intestinal absorption behaviors of typical transporter substrates and macromolecules. The endogenous levels of glucose and total cholesterol in the blood were similar between wild-type and SAP-1-deficient mice (Sap1 -/- ), suggesting no contribution of SAP-1 to biogenic influx. Moreover, in vitro transport study with everted ileal sacs demonstrated that there was no difference in the absorption of breast cancer resistance protein, P-glycoprotein, and peptide transporter substrates between both mice. However, absorptive clearance of macromolecular model dextrans (FD-4 and FD-10) in Sap1 -/- mice was significantly higher than that in wild-type mice, and this was confirmed by the trend of increased FD-4 absorption from colonic loops of Sap1 -/- mice. Therefore, the results of this study suggest the partial contribution of SAP-1 to the regulated transport of hydrophilic macromolecules through paracellular tight junctions. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

[Clinical and pharmacological aspects of rifaximin, local antibiotic therapy in intestinal disorders].

PubMed

Gasztonyi, Beáta; Hunyady, Béla

2004-10-24

The authors report pharmacokinetics and indications of rifaximin and the results of clinical studies. Rifaximin has a large antibacterial spectrum with a good therapeutic effect on both gram positive and gram negative aerob and anaerob bacteria. Practically there is no absorption (< 1%) following oral administration with a high concentration in gastrointestinal mucosa (8000 microg/g). No increase in absorption can be detected in intestinal damage caused by inflammatory bowel disease. The remarkable safety profile of rifaximin is due to its negligible quality of absorption. According to the clinical studies rifaximin could be an adequate therapeutic approach in all gastrointestinal diseases and interventions when antibacterial therapy is needed.

Models of antimicrobial pressure on intestinal bacteria of the treated host populations.

PubMed

Volkova, V V; Cazer, C L; Gröhn, Y T

2017-07-01

Antimicrobial drugs are used to treat pathogenic bacterial infections in animals and humans. The by-stander enteric bacteria of the treated host's intestine can become exposed to the drug or its metabolites reaching the intestine in antimicrobially active form. We consider which processes and variables need to be accounted for to project the antimicrobial concentrations in the host's intestine. Those include: the drug's fraction (inclusive of any active metabolites) excreted in bile; the drug's fractions and intestinal segments of excretion via other mechanisms; the rates and intestinal segments of the drug's absorption and re-absorption; the rates and intestinal segments of the drug's abiotic and biotic degradation in the intestine; the digesta passage time through the intestinal segments; the rates, mechanisms, and reversibility of the drug's sorption to the digesta and enteric microbiome; and the volume of luminal contents in the intestinal segments. For certain antimicrobials, the antimicrobial activity can further depend on the aeration and chemical conditions in the intestine. Model forms that incorporate the inter-individual variation in those relevant variables can support projections of the intestinal antimicrobial concentrations in populations of treated host, such as food animals. To illustrate the proposed modeling framework, we develop two examples of treatments of bovine respiratory disease in beef steers by oral chlortetracycline and injectable third-generation cephalosporin ceftiofur. The host's diet influences the digesta passage time, volume, and digesta and microbiome composition, and may influence the antimicrobial loss due to degradation and sorption in the intestine. We consider two diet compositions in the illustrative simulations. The examples highlight the extent of current ignorance and need for empirical data on the variables influencing the selective pressures imposed by antimicrobial treatments on the host's intestinal bacteria.

Lipid-associated Oral Delivery: Mechanisms and Analysis of Oral Absorption Enhancement

PubMed Central

Rezhdo, Oljora; Speciner, Lauren; Carrier, Rebecca L.

2016-01-01

The majority of newly discovered oral drugs are poorly water soluble, and co-administration with lipids has proven effective in significantly enhancing bioavailability of some compounds with low aqueous solubility. Yet, lipid-based delivery technologies have not been widely employed in commercial oral products. Lipids can impact drug transport and fate in the gastrointestinal (GI) tract through multiple mechanisms including enhancement of solubility and dissolution kinetics, enhancement of permeation through the intestinal mucosa, and triggering drug precipitation upon lipid emulsion depletion (e.g., by digestion). The effect of lipids on drug absorption is currently not quantitatively predictable, in part due to the multiple complex dynamic processes that can be impacted by lipids. Quantitative mechanistic analysis of the processes significant to lipid system function and overall impact on drug absorption can aid understanding of drug-lipid interactions in the GI tract and exploitation of such interactions to achieve optimal lipid-based drug delivery. In this review, we discuss the impact of co-delivered lipids and lipid digestion on drug dissolution, partitioning, and absorption in the context of the experimental tools and associated kinetic expressions used to study and model these processes. The potential benefit of a systems-based consideration of the concurrent multiple dynamic processes occurring upon co-dosing lipids and drugs to predict the impact of lipids on drug absorption and enable rational design of lipid-based delivery systems is presented. PMID:27520734

The effect of ingested lactulose on absorption of L-rhamnose, D-xylose, and 3-O-methyl-D-glucose in subjects with ileostomies.

PubMed

Jenkins, A P; Menzies, I S; Nukajam, W S; Creamer, B

1994-09-01

We have previously shown that small oral doses of poorly absorbed solute can significantly reduce absorption of test sugars in normal volunteers. To confirm these results and investigate the underlying mechanism, the effects of lactulose on absorption of three test sugars in subjects with ileostomies were studied. Ten fasted subjects with ileostomies ingested an isosmolar test solution containing 2.5 g 3-O-methyl-D-glucose, 5.0 g D-xylose, 1.0 g L-rhamnose, and 50 microCi 51Cr-labelled ethylenediaminetetraacetic acid together with a blue dye transit marker. Urine was collected for time periods of 0-5 h and 5-24 h, to measure excretion of absorbed sugars, and ileostomy effluent was saved from 0-5 h and from 5 h until blue dye transit marker was no longer present, to measure small-bowel output of unabsorbed sugars. After 1 week the test was repeated, including 5 g lactulose in the test solution. Inclusion of lactulose in the test solution significantly reduced the 5 h and 24 h urine excretion of L-rhamnose and D-xylose but not that of 3-O-methyl-D-glucose and increased 0- to 5-h and total ileostomy output of L-rhamnose and D-xylose but not of 3-O-methyl-D-glucose. The presence of lactulose also reduced the time for first appearance of the blue dye transit marker in the effluent and increased effluent volume together with output of electrolyte. Poorly absorbed solute reduces intestinal absorption by retention of fluid and electrolyte, with subsequent intraluminal dilution and acceleration of transit.

Augmented cholesterol absorption and sarcolemmal sterol enrichment slow small intestinal transit in mice, contributing to cholesterol cholelithogenesis

PubMed Central

Xie, Meimin; Kotecha, Vijay R; Andrade, Jon David P; Fox, James G; Carey, Martin C

2012-01-01

Cholesterol gallstones are associated with slow intestinal transit in humans as well as in animal models, but the molecular mechanism is unknown. We investigated in C57L/J mice whether the components of a lithogenic diet (LD; 1.0% cholesterol, 0.5% cholic acid and 17% triglycerides), as well as distal intestinal infection with Helicobacter hepaticus, influence small intestinal transit time. By quantifying the distribution of 3H-sitostanol along the length of the small intestine following intraduodenal instillation, we observed that, in both sexes, the geometric centre (dimensionless) was retarded significantly (P < 0.05) by LD but not slowed further by helicobacter infection (males, 9.4 ± 0.5 (uninfected), 9.6 ± 0.5 (infected) on LD compared with 12.5 ± 0.4 and 11.4 ± 0.5 on chow). The effect of the LD was reproduced only by the binary combination of cholesterol and cholic acid. We inferred that the LD-induced cholesterol enrichment of the sarcolemmae of intestinal smooth muscle cells produced hypomotility from signal-transduction decoupling of cholecystokinin (CCK), a physiological agonist for small intestinal propulsion in mice. Treatment with ezetimibe in an amount sufficient to block intestinal cholesterol absorption caused small intestinal transit time to return to normal. In most cholesterol gallstone-prone humans, lithogenic bile carries large quantities of hepatic cholesterol into the upper small intestine continuously, thereby reproducing this dietary effect in mice. Intestinal hypomotility promotes cholelithogenesis by augmenting formation of deoxycholate, a pro-lithogenic secondary bile salt, and increasing the fraction of intestinal cholesterol absorbed. PMID:22331417

Drug gastrointestinal absorption in rat: Strain and gender differences.

PubMed

Oltra-Noguera, Davinia; Mangas-Sanjuan, Victor; González-Álvarez, Isabel; Colon-Useche, Sarin; González-Álvarez, Marta; Bermejo, Marival

2015-10-12

Predictive animal models of intestinal drug absorption are essential tools in drug development to identify compounds with promising biopharmaceutical properties. In situ perfusion absorption studies are routinely used in the preclinical setting to screen drug candidates. The objective of this work is to explore the differences in magnitude and variability on intestinal absorption associated with rat strain and gender. Metoprolol and Verapamil absorption rate coefficients were determined using the in situ closed loop perfusion model in four strains of rats and in both genders. Strains used were Sprague-Dawley, Wistar-Han, Wistar-Unilever, Long-Evans and CD∗IGS. In the case of Metoprolol only CD∗IGS and Wistar Unilever showed differences between males and females. For Verapamil, Wistar Han and Sprague-Dawley strains do not show differences between male and female rats. That means that in these strains permeability data from male and female could be combined. In male rats, which are commonly used for permeability estimation, there were differences for Metoprolol permeability between Sprague-Dawley (with lower permeability values) and the other strains, while for Verapamil Sprague-Dawley and Wistar-Han showed the lower permeability values. In conclusion, the selection of rat's strain and gender for intestinal absorption experiments is a relevant element during study design and data from different strains may not be always comparable. Copyright © 2015 Elsevier B.V. All rights reserved.

Nano-sized water-in-oil-in-water emulsion enhances intestinal absorption of calcein, a high solubility and low permeability compound.

PubMed

Koga, Kenjiro; Takarada, Nobuo; Takada, Kanji

2010-02-01

Our goal was to develop safe and stable multilayer emulsions capable of enhancing intestinal absorption of biopharmaceutics classification system (BCS) class III drugs. First, w/o emulsions were prepared using calcein as a model BCS class III compound and condensed ricinoleic acid tetraglycerin ester as a hydrophobic emulsifier. Then water-in-oil-in-water (w/o/w) emulsions were prepared with shirasu porous glass (SPG) membranes. Particle size analyses and calcein leakage from oil droplets in w/o/w emulsions led us to select stearic acid hexaglycerin esters (HS-11) and Gelucire 44/14 as hydrophilic emulsifiers. Analyses of the absorption-enhancing effects of w/o/w emulsions on intestinal calcein absorption in rats showed that calcein bioavailability after intraduodenal (i.d.) administration of HS-11 or Gelucire 44/14+polyvinyl alcohol (PVA) w/o/w emulsions prepared with 0.1-microm pore-sized SPGs was significantly higher than that of the calcein control. However, serum calcein concentration vs. time profiles after i.d. administration of w/o/w emulsions prepared with 1.1-microm and 30-microm pore-sized SPGs and an emulsion prepared with a calcein-containing outer water phase were comparable to control profiles. These results suggested that HS-11 or Gelucire 44/14+PVA are safe outer water phase additives and that 0.1-microm pore-sized SPGs are important for preparing w/o/w emulsions that enhanced intestinal calcein absorption. Copyright (c) 2009 Elsevier B.V. All rights reserved.

Absorption of Iron from Ferritin Is Independent of Heme Iron and Ferrous Salts in Women and Rat Intestinal Segments123

PubMed Central

Chen, Huijun; Miranda, Constanza; Janser, Heinz; Elsenhans, Bernd; Núñez, Marco T.; Pizarro, Fernando; Schümann, Klaus

2012-01-01

Ferritin iron from food is readily bioavailable to humans and has the potential for treating iron deficiency. Whether ferritin iron absorption is mechanistically different from iron absorption from small iron complexes/salts remains controversial. Here, we studied iron absorption (RBC 59Fe) from radiolabeled ferritin iron (0.5 mg) in healthy women with or without non-ferritin iron competitors, ferrous sulfate, or hemoglobin. A 9-fold excess of non-ferritin iron competitor had no significant effect on ferritin iron absorption. Larger amounts of iron (50 mg and a 99-fold excess of either competitor) inhibited iron absorption. To measure transport rates of iron that was absorbed inside ferritin, rat intestinal segments ex vivo were perfused with radiolabeled ferritin and compared to perfusion with ferric nitrilotriacetic (Fe-NTA), a well-studied form of chelated iron. Intestinal transport of iron absorbed inside exogenous ferritin was 14.8% of the rate measured for iron absorbed from chelated iron. In the steady state, endogenous enterocyte ferritin contained >90% of the iron absorbed from Fe-NTA or ferritin. We found that ferritin is a slow release source of iron, readily available to humans or animals, based on RBC iron incorporation. Ferritin iron is absorbed by a different mechanism than iron salts/chelates or heme iron. Recognition of a second, nonheme iron absorption process, ferritin endocytosis, emphasizes the need for more mechanistic studies on ferritin iron absorption and highlights the potential of ferritin present in foods such as legumes to contribute to solutions for global iron deficiency. PMID:22259191

P-gp, MRP2 and OAT1/OAT3 mediate the drug-drug interaction between resveratrol and methotrexate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jia, Yongming

The purpose of present study was to investigate the effect of resveratrol (Res) on altering methotrexate (MTX) pharmacokinetics and clarify the related molecular mechanism. Res significantly increased rat intestinal absorption of MTX in vivo and in vitro. Simultaneously, Res inhibited MTX efflux transport in MDR1-MDCK and MRP2-MDCK cell monolayers, suggesting that the target of drug interaction was MDR1 and MRP2 in the intestine during the absorption process. Furthermore, there was a significant decrease in renal clearance of MTX after simultaneous intravenous administration. Similarly, MTX uptake was markedly inhibited by Res in rat kidney slices and hOAT1/3-HEK293 cell, indicating that OAT1more » and OAT3 were involved in the drug interaction in the kidney. Additionally, concomitant administration of Res decreased cytotoxic effects of MTX in hOAT1/3-HEK293 cells, and ameliorated nephrotoxicity caused by MTX in rats. Conversely, intestinal damage caused by MTX was not exacerbated after Res treatment. In conclusion, Res enhanced MTX absorption in intestine and decreased MTX renal elimination by inhibiting P-gp, MRP2, OAT1 and OAT3 in vivo and in vitro. Res improved MTX-induced renal damage without increasing intestinal toxicity. - Highlights: • DDI between MTX and Res will occur when they are co-administered. • The first targets of the DDI are P-gp and MRP2 located in intestine. • The second targets of the DDI are OAT1 and OAT3 in kidney. • Res improved MTX-induced renal damage without increasing intestinal toxicity.« less

Bisphenol A promotes cholesterol absorption in Caco-2 cells by up-regulation of NPC1L1 expression.

PubMed

Feng, Dan; Zou, Jun; Zhang, Shanshan; Li, Xuechun; Li, Peiyang; Lu, Minqi

2017-01-06

Bisphenol A (BPA), an commonly exposed environmental chemicals in humans, has been shown to have a hypercholesterolemic effect with molecular mechanism not clear. Since intestinal cholesterol absorption plays a major role in maintaining total body cholesterol homeostasis, the present study is to investigate whether BPA affects cholesterol absorption in the intestinal Caco-2 cells. The Caco-2 cells were pretreated with BPA at different concentrations for 24 h and then incubated with radioactive micellar cholesterol for 2 h. The absorption of radioactive cholesterol was quantified by liquid scintillation. The expression of Niemann-Pick C1-like 1 (NPC1L1) and sterol regulatory element binding protein-2 (SREBP-2) was analyzed by Western blot and qPCR. We found that confluent Caco-2 cells expressed NPC1L1, and the absorption of cholesterol in the cells was inhibited by ezetimibe, a specific inhibitor of NPC1L1. We then pretreated the cells with 0.1-10 nM BPA for 24 h and found that BPA at 1 and 10 nM doses promoted cholesterol absorption. In addition, we found that the BPA-induced promotion of cholesterol absorption was associated with significant increase in the levels of NPC1L1 protein and NPC1L1 mRNA. Moreover, the stimulatory effects of BPA on cholesterol absorption and NPC1L1 expression could be prevented by blockade of the SREBP-2 pathway. This study provides the first evidence that BPA promotes cholesterol absorption in the intestinal cells and the stimulatory effect of BPA is mediated, at least in part, by SREBP-2-NPC1L1 signaling pathway.

Decrease in oral bioavailability of ciclosporin by intravenous pulse of methylprednisolone succinate in rats.

PubMed

Konishi, Hiroki; Sumi, Masaki; Shibata, Nobuhito; Takada, Kanji; Minouchi, Tokuzo; Yamaji, Akira

2004-10-01

We examined the effects of high-dose methylprednisolone on the bioavailability of orally administered ciclosporin in rats. To emulate the clinical protocol of methylprednisolone pulse therapy, methylprednisolone sodium succinate (MPS), a prodrug of methylprednisolone, was intravenously administered as repeated doses (66.3 mg kg(-1)) for 3 days. The area under the blood ciclosporin concentration versus time curve after oral administration was significantly reduced by 60% by pulse treatment with MPS. Based on our previous finding that the total body clearance of ciclosporin was reduced by about 20% by the same methylprednisolone pulse protocol, the extent of reduction in the oral bioavailability of ciclosporin was estimated to be approximately 50%, indicating a drug interaction between high-dose methylprednisolone and orally administered ciclosporin, which affected the absorption process. In rats treated with MPS, an in-situ efflux experiment using rhodamine-123 demonstrated that the reverse transport function of P-glycoprotein (P-gp) in the small intestine was significantly enhanced, although there was no significant increase in the intestinal microsomal activity of triazolam alpha- and 4-hydroxylation, metabolic probes for CYP3A. In addition, a significant decrease was observed in the amount of secreted bile acids serving as an enhancer of gastrointestinal absorption of ciclosporin in MPS treatment. To directly estimate the absorptive capacity, an in-situ absorption test was conducted using a closed-loop of small intestine in control and MPS-treated rats. Intestinal absorption of ciclosporin was significantly decreased, not only in the absence of bile flow but also by treatment with MPS, which well reflected the change in the in-vivo pharmacokinetic behaviour of ciclosporin after methylprednisolone pulsing. These results demonstrate that bioavailability of ciclosporin is markedly reduced by MPS pulse treatment, and the mechanism of this interaction was confirmed to involve enhancement of small-intestinal P-gp function and decrease in bile secretion.

The effect of amino acids on the intestinal absorption of immunoglobulins in the neonatal rat

PubMed Central

Bamford, D. R.; Donnelly, H.

1974-01-01

An in vitro preparation of 10-day-old rat intestine was used to examine the absorption of a number of amino acids and immunoglobulins. Evidence was obtained for the active absorption of alanine, leucine, methionine, histidine and lysine, but not for aspartic acid. A selective absorption of the homologous molecule was found in experiments where 131I-labelled rat and bovine IgG were presented to the ileum in 10-minute incubations. The greater uptake of rat IgG was unrelated to the relative rates of catabolism of the two molecules. Although the uptake of rat IgG was unaffected by 100 mM concentrations of neutral and acidic amino acids, the basic amino acids arginine and lysine significantly stimulated uptake. PMID:4854740

Effects of quercetin and menadione on intestinal calcium absorption and the underlying mechanisms.

PubMed

Marchionatti, Ana M; Pacciaroni, Adriana; Tolosa de Talamoni, Nori G

2013-01-01

Quercetin (QT) could be considered as a potential therapeutic agent for different diseases due to its antioxidant, anti-inflammatory, antiviral and anticancer properties. This study was designed to investigate the ability of QT to protect the chick intestine against menadione (MEN) induced injury in vivo and in vitro. Four-week old chicks (Gallus gallus) were treated i.p. with 2.5μmol of MEN/kg b.w. or with i.l. 50μM QT or both. QT protected the intestinal Ca(2+) absorption against the inhibition caused by MEN, but QT alone did not modify. Glutathione (GSH) depletion provoked by MEN in chick enterocytes was abolished by QT treatment, whereas QT alone did not modify the intestinal GSH content. The enhancement of GSH peroxidase activity produced by MEN was blocked by QT treatment. In contrast, superoxide dismutase activity remained high after simultaneous treatment of enterocytes with MEN and QT. The flavonol also avoided changes in the mitochondrial membrane permeability (swelling) produced by MEN. The FasL/Fas/caspase-3 pathway was activated by MEN, effect that was abrogated by QT. In conclusion, QT may be useful in preventing inhibition of chick intestinal Ca(2+) absorption caused by MEN or other substances that deplete GSH, by blocking the oxidative stress and the FasL/Fas/caspase-3 pathway activation. Copyright © 2012 Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoadley, J.E.; Leinart, A.S.; Cousins, R.J.

Intestinal 65Zn transport and metallothionein levels were examined in rats fed zinc-adequate and zinc-deficient diets and in rats subjected to an overnight fast. 65Zn uptake by intestines perfused with 1.5 microM 65Zn was greater in both zinc-deficient and fasted groups than in the control group. Mucosal retention of 65Zn was also greater in the zinc-deficient group but not in the fasted group. The greater 65Zn uptake in the fasted group was associated with a compartment that readily released 65Zn back into the lumen. Kinetic analysis of the rate of 65Zn transfer to the vascular space (absorption) showed that 65Zn absorptionmore » involved approximately 3% of mucosal 65Zn in a 40-min perfusion period. The half-life (t1/2) of this mucosal 65Zn rapid transport pool corresponded directly to changes in intestinal metallothionein levels. Both metallothionein and t1/2 were higher in the fasted group and lower in the zinc-deficient group than in controls. While the rate of 65Zn transport from this rapid transport pool decreased with increasing metallothionein level, the predicted pool size increased when the metallothionein level was elevated by fasting. These results indicate that the rate of zinc absorption is inversely related to intestinal metallothionein levels, but the portion of mucosal 65Zn available for absorption is directly related to intestinal metallothionein.« less

Improvement of intestinal absorption of forsythoside A in weeping forsythia extract by various absorption enhancers based on tight junctions.

PubMed

Zhou, Wei; Qin, Kun Ming; Shan, Jin Jun; Ju, Wen Zheng; Liu, Shi Jia; Cai, Bao Chang; Di, Liu Qing

2012-12-15

Forsythoside A (FTA), one of the main active ingredients in weeping forsythia extract, possesses strong antibacterial, antioxidant and antiviral effects, and its content was about 8% of totally, higher largely than that of other ingredients, but the absolute bioavailability orally was approximately 0.5%, which is significant low influencing clinical efficacies of its oral preparations. In the present study, in vitro Caco-2 cell, in situ single-pass intestinal perfusion and in vivo pharmacokinetics study were performed to investigate the effects of absorption enhancers based on tight junctions: sodium caprate and water-soluble chitosan on the intestinal absorption of FTA, and the eventual mucosal epithelial damage resulted from absorption enhancers was evaluated by MTT test, measurement of total amount of protein and the activity of LDH and morphology observation, respectively. The pharmacological effects such as antioxidant activity improvement by absorption enhancers were verified by PC12 cell damage inhibition rate after H₂O₂ insults. The observations from in vitro Caco-2 cell showed that the absorption of FTA in weeping forsythia extract could be improved by absorption enhancers. Meanwhile, the absorption enhancing effect of water-soluble chitosan may be almost saturable up to 0.0032% (w/v), and sodium caprate at concentrations up to 0.64 mg/ml was safe for the Caco-2 cells, but water-soluble chitosan at different concentrations was all safe for these cells. The observations from single-pass intestinal perfusion in situ model showed that duodenum, jejunum, ileum and colon showed significantly concentration-dependent increase in P(eff)-value, and that P(eff)-value in the ileum and colon groups, where sodium caprate was added, was higher than that of duodenum and jejunum groups, but P(eff)-value in the jejunum group was higher than that of duodenum, ileum and colon groups where water-soluble chitosan was added. Intestinal mucosal toxicity studies showed no significant toxicity below 800 μg/ml sodium caprate and water-soluble chitosan at different concentrations. In pharmacokinetics study, water-soluble chitosan at dosage of 50mg/kg improved the bioavailability of FTA in weeping forsythia extract to the greatest extent, and was safe for gastrointestine from morphological observation. Besides, treatment with weeping forsythia extract with water-soluble chitosan at dosage of 50 mg/kg prevented PC12 cell damage upon H₂O₂ stimulation better than that of control. All findings above suggested that water-soluble chitosan at dosage of 50 mg/kg might be safe and effective absorption enhancer for improving the bioavailability of FTA and the antioxidant activity in vivo in weeping forsythia extract. Copyright © 2012 Elsevier GmbH. All rights reserved.

Intestinal absorption of triglyceride and vitamin D3 in aged and young rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Holt, P.R.; Dominguez, A.A.

1981-12-01

(3H)Trioleyl glycerol (TO) and (14C)vitamin D3 were perfused intraduodenally for 5 hr in aged (19-21 months) and young adult (4-5 months) Sprague-Dawley rats. The rate of intestinal uptake from the gastrointestinal lumen and transport into the body of these lipids were decreased in the aged animals. Since the distribution of TO lipolytic products in the lumen was unchanged, reduced intestinal uptake rate probably occurred at the mucosal membrane. Furthermore, in the aged rats, the rate of transintestinal transport of both trioleyl glycerol and vitamin D3 was impaired. No evidence for impaired mucosal TO reesterification or for accumulation of vitamin D3more » metabolites was found, suggesting that intestinal lipid accumulation resulted from a defect in lipoprotein assembly or in discharge from the mucosal cell. Impaired absorption of lipids may contribute to malnutrition and osteopenia of advancing age.« less

Pinolenic Acid in Structured Triacylglycerols Exhibits Superior Intestinal Lymphatic Absorption As Compared to Pinolenic Acid in Natural Pine Nut Oil.

PubMed

Chung, Min-Yu; Woo, Hyunjoon; Kim, Juyeon; Kong, Daecheol; Choi, Hee-Don; Choi, In-Wook; Kim, In-Hwan; Noh, Sang K; Kim, Byung Hee

2017-03-01

The positional distribution pattern of fatty acids (FAs) in the triacylglycerols (TAGs) affects intestinal absorption of these FAs. The aim of this study was to compare lymphatic absorption of pinolenic acid (PLA) present in structured pinolenic TAG (SPT) where PLA was evenly distributed on the glycerol backbone, with absorption of pine nut oil (PNO) where PLA was predominantly positioned at the sn-3 position. SPT was prepared via the nonspecific lipase-catalyzed esterification of glycerol with free FA obtained from PNO. Lymphatic absorption of PLA from PNO and from SPT was compared in a rat model of lymphatic cannulation. Significantly (P < 0.05) greater amounts of PLA were detected in lymph collected for 8 h from an emulsion containing SPT (28.5 ± 0.7% dose) than from an emulsion containing PNO (26.2 ± 0.6% dose), thereby indicating that PLA present in SPT has a greater capacity for lymphatic absorption than PLA from PNO.

Ezetimibe Promotes Brush Border Membrane-to-Lumen Cholesterol Efflux in the Small Intestine

PubMed Central

Nakano, Takanari; Inoue, Ikuo; Takenaka, Yasuhiro; Ono, Hiraku; Katayama, Shigehiro; Awata, Takuya; Murakoshi, Takayuki

2016-01-01

Ezetimibe inhibits Niemann-Pick C1-like 1 (NPC1L1), an apical membrane cholesterol transporter of enterocytes, thereby reduces intestinal cholesterol absorption. This treatment also increases extrahepatic reverse cholesterol transport via an undefined mechanism. To explore this, we employed a trans-intestinal cholesterol efflux (TICE) assay, which directly detects circulation-to-intestinal lumen 3H-cholesterol transit in a cannulated jejunal segment, and found an increase of TICE by 45%. To examine whether such increase in efflux occurs at the intestinal brush border membrane(BBM)-level, we performed luminal perfusion assays, similar to TICE but the jejunal wall was labelled with orally-given 3H-cholesterol, and determined elevated BBM-to-lumen cholesterol efflux by 3.5-fold with ezetimibe. Such increased efflux probably promotes circulation-to-lumen cholesterol transit eventually; thus increases TICE. Next, we wondered how inhibition of NPC1L1, an influx transporter, resulted in increased efflux. When we traced orally-given 3H-cholesterol in mice, we found that lumen-to-BBM 3H-cholesterol transit was rapid and less sensitive to ezetimibe treatment. Comparison of the efflux and fractional cholesterol absorption revealed an inverse correlation, indicating the efflux as an opposite-regulatory factor for cholesterol absorption efficiency and counteracting to the naturally-occurring rapid cholesterol influx to the BBM. These suggest that the ezetimibe-stimulated increased efflux is crucial in reducing cholesterol absorption. Ezetimibe-induced increase in cholesterol efflux was approximately 2.5-fold greater in mice having endogenous ATP-binding cassette G5/G8 heterodimer, the major sterol efflux transporter of enterocytes, than the knockout counterparts, suggesting that the heterodimer confers additional rapid BBM-to-lumen cholesterol efflux in response to NPC1L1 inhibition. The observed framework for intestinal cholesterol fluxes may provide ways to modulate the flux to dispose of endogenous cholesterol efficiently for therapeutic purposes. PMID:27023132

Effects of fasting and refeeding on gene expression of slc15a1a, a gene encoding an oligopeptide transporter (PepT1), in the intestine of Mozambique tilapia.

PubMed

Orozco, Zenith Gaye A; Soma, Satoshi; Kaneko, Toyoji; Watanabe, Soichi

2017-01-01

The tissue distribution of slc15a1a, a gene that encodes an oligopeptide transporter, PepT1, and its response to fasting and refeeding were investigated in the intestinal epithelium of Mozambique tilapia for a better understanding of its role on nutrient absorption. The slc15a1a was predominantly expressed in the absorptive epithelia of the anterior part of the intestine, suggesting that digested oligopeptides are primarily absorbed in the anterior intestine. The response of slc15a1a to fasting was evaluated at 1, 2, 4, 7 and 14days after the last feeding. Fasting revealed a biphasic effect, where short-term fasting significantly upregulated slc15a1a expression and long-term fasting resulted in downregulation. The expression level continued to decrease and fell below the pre-fasted level from day 4 to 14. Proximal (the hepatic loop, HL) and distal parts (the proximal major coil, PMC) of the anterior intestine showed different magnitudes of responses to fasting; slc15a1a expression in the PMC showed greater upregulation and downregulation than that in the HL. Refeeding significantly stimulated slc15a1a expression at day 3, although the expression did not exceed the pre-fasted level. Observed responses of slc15a1a to fasting and refeeding suggest that the expression level of this gene can serve as a sensitive indicator of the changes that may occur in altering nutritional conditions. These findings contribute to a better understanding of the role of PepT1 in nutrition and of the complex mechanisms underlying the absorption of oligopeptides and amino acids in the intestine, and may lead to development of possible means to manipulate the absorption processes for the improvement of growth and other metabolic and physiological conditions in fish. Copyright © 2016. Published by Elsevier Inc.

Ezetimibe Promotes Brush Border Membrane-to-Lumen Cholesterol Efflux in the Small Intestine.

PubMed

Nakano, Takanari; Inoue, Ikuo; Takenaka, Yasuhiro; Ono, Hiraku; Katayama, Shigehiro; Awata, Takuya; Murakoshi, Takayuki

2016-01-01

Ezetimibe inhibits Niemann-Pick C1-like 1 (NPC1L1), an apical membrane cholesterol transporter of enterocytes, thereby reduces intestinal cholesterol absorption. This treatment also increases extrahepatic reverse cholesterol transport via an undefined mechanism. To explore this, we employed a trans-intestinal cholesterol efflux (TICE) assay, which directly detects circulation-to-intestinal lumen 3H-cholesterol transit in a cannulated jejunal segment, and found an increase of TICE by 45%. To examine whether such increase in efflux occurs at the intestinal brush border membrane(BBM)-level, we performed luminal perfusion assays, similar to TICE but the jejunal wall was labelled with orally-given 3H-cholesterol, and determined elevated BBM-to-lumen cholesterol efflux by 3.5-fold with ezetimibe. Such increased efflux probably promotes circulation-to-lumen cholesterol transit eventually; thus increases TICE. Next, we wondered how inhibition of NPC1L1, an influx transporter, resulted in increased efflux. When we traced orally-given 3H-cholesterol in mice, we found that lumen-to-BBM 3H-cholesterol transit was rapid and less sensitive to ezetimibe treatment. Comparison of the efflux and fractional cholesterol absorption revealed an inverse correlation, indicating the efflux as an opposite-regulatory factor for cholesterol absorption efficiency and counteracting to the naturally-occurring rapid cholesterol influx to the BBM. These suggest that the ezetimibe-stimulated increased efflux is crucial in reducing cholesterol absorption. Ezetimibe-induced increase in cholesterol efflux was approximately 2.5-fold greater in mice having endogenous ATP-binding cassette G5/G8 heterodimer, the major sterol efflux transporter of enterocytes, than the knockout counterparts, suggesting that the heterodimer confers additional rapid BBM-to-lumen cholesterol efflux in response to NPC1L1 inhibition. The observed framework for intestinal cholesterol fluxes may provide ways to modulate the flux to dispose of endogenous cholesterol efficiently for therapeutic purposes.

Early childhood growth failure and the developmental origins of adult disease: Do enteric infections and malnutrition increase risk for the metabolic syndrome?

PubMed Central

DeBoer, Mark D.; Lima, Aldo A. M.; Oría, Reinaldo B.; Scharf, Rebecca J.; Moore, Sean R.; Luna, Max A.; Guerrant, Richard L.

2012-01-01

Hypotheses regarding the developmental origins of health and disease postulate that developing fetuses–and potentially young children—undergo adaptive epigenetic changes with longstanding effects on metabolism and other processes. Ongoing research explores whether these adaptations occur during early life following malnutrition. In the developing world there remains a high degree of nutritional stunting—linear growth failure due to inadequate calories that may be exacerbated by inflammation from ongoing infections. In areas with poor sanitation children experience vicious cycles of enteric infections and malnutrition, resulting in poor nutrient absorption from intestinal mucosa changes now termed “environmental enteropathy.” Emerging evidence links early childhood diarrhea and/or growth failure with increased CVD risk factors in later life, including dyslipidemia, hypertension and glucose intolerance. The mechanisms for these associations remain poorly understood and may relate to epigenetic responses to poor nutrition, increased inflammation or both. Given increases in CVD in developing areas of the world, associations between childhood malnutrition, early life infections and increased CVD risk factors underscore further reasons to improve nutrition and infection-related outcomes for young children worldwide. PMID:23110643

Short bowel syndrome: highlights of patient management, quality of life, and survival.

PubMed

Kelly, Darlene G; Tappenden, Kelly A; Winkler, Marion F

2014-05-01

Short bowel syndrome (SBS) occurs as a result of intestinal resection, and in many patients is associated with complications, such as diarrhea, dehydration, weight loss, and nutrition deficiencies. Many individuals with SBS develop intestinal failure and require parenteral nutrition (PN) and/or intravenous (IV) fluids (PN/IV). Although PN is essential for survival, some patients with SBS who require long-term PN experience significant complications that contribute to morbidity and mortality. Consequently, therapies that decrease reliance on PN are of considerable importance. Intestinal adaptation, which results in morphologic and functional changes that increase performance of the remnant bowel, occurs spontaneously after intestinal resection. These effects can be enhanced with nutrition and pharmaceutical approaches. For example, oral or tube-fed nutrients stimulate growth and adaptation of intestinal tissues. In addition, prebiotics support growth of beneficial intestinal microbiota that produce short-chain fatty acids, which have been shown in preclinical studies to enhance intestinal structure and function. Finally, glucagon-like peptide 2 (GLP-2) is an endogenous peptide that promotes intestinal rehabilitation and improves intestinal absorption. Teduglutide, a recombinant human GLP-2 analog, has recently been approved in the United States for the treatment of adults with SBS who are dependent on PN. In pharmacodynamic and clinical studies, teduglutide has been shown to promote changes in intestinal structure, such as increases in villus height and crypt depth, and to improve intestinal absorption, as indicated by reduced PN/IV dependence. This article presents a brief overview of SBS, including effects on survival and quality of life and current treatment options.

Improvement of Intestinal Absorption of Forsythoside A and Chlorogenic Acid by Different Carboxymethyl Chitosan and Chito-oligosaccharide, Application to Flos Lonicerae - Fructus Forsythiae Herb Couple Preparations

PubMed Central

Zhou, Wei; Wang, Haidan; Zhu, Xuanxuan; Shan, Jinjun; Yin, Ailing; Cai, Baochang; Di, Liuqing

2013-01-01

The current study aims to investigate the effect of chitosan derivatives on the intestinal absorption and bioavailabilities of forsythoside A (FTA) and Chlorogenic acid (CHA), the major active components in Flos Lonicerae - Fructus Forsythiae herb couple. Biopharmaceutics and pharmacokinetics properties of the two compounds have been characterized in vitro, in situ as well as in rats. Based on the identified biopharmaceutics characteristics of the two compounds, the effect of chitosan derivatives as an absorption enhancer on the intestinal absorption and pharmacokinetics of FTA and CHA in pure compound form as well as extract form were investigated in vitro, in situ and in vivo. Both FTA and CHA demonstrated very limited intestinal permeabilities, leading to oral bioavailabilities being only 0.50% and 0.13% in rats, respectively. Results from both in vitro, in situ as well as in vivo studies consistently indicated that Chito-oligosaccharide (COS) at dosage of 25 mg/kg could enhance intestinal permeabilities significantly as well as the in vivo bioavailabilities of both FTA and CHA than CMCs in Flos Lonicerae - Fructus Forsythiae herb couple preparations, and was safe for gastrointestine from morphological observation. Besides, treatment with Flos Lonicerae - Fructus Forsythiae herb couple preparations with COS at the dosage of 25 mg/kg prevented MDCK damage after influenza virus propagation, which was significantly better than control. The current findings not only identified the usefulness of COS for the improved delivery of Flos Lonicerae - Fructus Forsythiae preparations but also demonstrated the importance of biopharmaceutical characterization in the dosage form development of traditional Chinese medicine. PMID:23675483

Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption.

PubMed

Fox, Raymond G; Magness, Scott; Kujoth, Gregory C; Prolla, Tomas A; Maeda, Nobuyo

2012-05-01

Changes in intestinal absorption of nutrients are important aspects of the aging process. To address this issue, we investigated the impact of accelerated mitochondrial DNA mutations on the stem/progenitor cells in the crypts of Lieberkühn in mice homozygous for a mitochondrial DNA polymerase gamma mutation, Polg(D257A), that exhibit accelerated aging phenotype. As early as 3-7 mo of age, the small intestine was significantly enlarged in the PolgD257A mice. The crypts of the PolgD257A mice contained 20% more cells than those of their wild-type littermates and exhibited a 10-fold increase in cellular apoptosis primarily in the stem/progenitor cell zones. Actively dividing cells were proportionally increased, yet a significantly smaller proportion of cells was in the S phase of the cell cycle. Stem cell-derived organoids from PolgD257A mice failed to develop fully in culture and exhibited fewer crypt units, indicating an impact of the mutation on the intestinal epithelial stem/progenitor cell maintenance. In addition, epithelial cell migration along the crypt-villus axis was slowed and less organized, and the ATP content in the villi was significantly reduced. On a high-fat, high-carbohydrate diet, PolgD257A mice showed significantly restricted absorption of excess lipids accompanied by an increase in fecal steatocrits. We conclude that the PolgD257A mutation causes cell cycle dysregulation in the crypts leading to the age-associated changes in the morphology of the small intestine and contributes to the restricted absorption of dietary lipids.

A pilot study examining the relationship among Crohn disease activity, glucagon-like peptide-2 signalling and intestinal function in pediatric patients

PubMed Central

Sigalet, David L; Kravarusic, Dragan; Butzner, Decker; Hartmann, Bolette; Holst, Jens J; Meddings, Jon

2013-01-01

BACKGROUND/OBJECTIVES: The relationship between the enteroendocrine hormone glucagon-like peptide 2 (GLP-2) and intestinal inflammation is unclear. GLP-2 promotes mucosal growth, decreases permeability and reduces inflammation in the intestine; physiological stimulation of GLP-2 release is triggered by nutrient contact. The authors hypothesized that ileal Crohn disease (CD) affects GLP-2 release. METHODS: With ethics board approval, pediatric patients hospitalized with CD were studied; controls were recruited from local schools. Inclusion criteria were endoscopy-confirmed CD (primarily of the small intestine) with a disease activity index >150. Fasting and post-prandial GLP-2 levels and quantitative urinary recovery of orally administered 3-O-methyl-glucose (active transport) and lactulose/mannitol (passive) were quantified during the acute and remission phases. RESULTS: Seven patients (mean [± SD] age 15.3±1.3 years) and 10 controls (10.3±1.6 years) were studied. In patients with active disease, fasting levels of GLP-2 remained stable but postprandial levels were reduced. Patients with active disease exhibited reduced glucose absorption and increased lactulose/mannitol recovery; all normalized with disease remission. The change in the lactulose/mannitol ratio was due to both reduced lactulose and increased mannitol absorption. CONCLUSIONS: These findings suggest that pediatric patients with acute ileal CD have decreased postprandial GLP-2 release, reduced glucose absorption and increased intestinal permeability. Healing of CD resulted in normalization of postprandial GLP-2 release and mucosal functioning (nutrient absorption and permeability), the latter due to an increase in mucosal surface area. These findings have implications for the use of GLP-2 and feeding strategies as a therapy in CD patients; further studies of the effects of inflammation and the GLP-2 axis are recommended. PMID:24106731

Species differences in the pharmacokinetics of cefadroxil as determined in wildtype and humanized PepT1 mice.

PubMed

Hu, Yongjun; Smith, David E

2016-05-01

PepT1 (SLC15A1) is a high-capacity low-affinity transporter that is important in the absorption of digested di/tripeptides from dietary protein in the small intestine. PepT1 is also crucial for the intestinal uptake and absorption of therapeutic agents such as the β-lactam aminocephalosporins and antiviral prodrugs. Species differences, however, have been observed in PepT1-mediated intestinal absorption and pharmacokinetics, thereby, making it more difficult to predict systemic drug exposure. In the present study, we evaluated the in situ intestinal permeability of the PepT1 substrate cefadroxil in wildtype and humanized PepT1 (huPepT1) mice, and the in vivo absorption and disposition of drug after escalating oral doses. The in situ perfusions indicated that cefadroxil had a twofold higher affinity (i.e., twofold lower Km) for jejunal PepT1 in huPepT1 mice, lower but substantial permeability in all regions of the small intestine, and low but measureable permeability in the colon as compared to wildtype animals. The in vivo experiments indicated almost superimposable pharmacokinetic profiles between the two genotypes after intravenous bolus dosing of cefadroxil. In contrast, after oral dose escalation, the systemic exposure of cefadroxil was reduced in huPepT1 mice as compared to wildtype animals. Moreover, the AUC and Cmax versus dose relationships were nonlinear for huPepT1 but not wildtype mice, and similar to that observed from human subjects. In conclusion, our findings indicate that huPepT1 mice may provide a valuable tool in the drug discovery process by better predicting the oral pharmacokinetic profiles of PepT1 substrates in humans. Copyright © 2016 Elsevier Inc. All rights reserved.

Gastrointestinal assimilation of Cu during digestion of a single meal in the freshwater rainbow trout (Oncorhynchus mykiss).

PubMed

Nadella, Sunita R; Bucking, Carol; Grosell, Martin; Wood, Chris M

2006-08-01

Gastrointestinal processing and assimilation of Cu in vivo was investigated by sequential chyme analysis over a 72 h period following ingestion of a single satiation meal (3% body weight) of commercial trout food (Cu content=0.42 micromol g(-1)) by adult rainbow trout. Leaded glass ballotini beads incorporated into the food and detected by X-ray radiography were employed as an inert marker in order to quantify net Cu absorption or secretion in various parts of the tract. Cu concentrations in the supernatant (fluid phase) fell from about 0.06 micromol mL(-1) (63 microM) in the stomach at 2 h to about 0.003 micromol mL(-1) (3 microM) in the posterior intestine at 72 h. Cu concentrations in the solid phase were 10 to 30-fold higher than in the fluid phase, and increased about 4-fold from the stomach at 2 h to the posterior intestine at 72 h. By reference to the inert marker, overall net Cu absorption from the ingested food by 72 h was about 50%. The mid-intestine, and posterior intestine emerged as important sites of net Cu and water absorption and a potential role for the stomach in this process was also indicated. The anterior intestine was a site of large net Cu addition to the chyme, probably due to large net additions of Cu-containing fluids in the form of bile and other secretions in this segment. The results provide valuable information about sites of Cu absorption and realistic concentrations of Cu in chyme fluid for future in vitro mechanistic studies on Cu transport in the trout gastrointestinal tract.

Capsaicin pretreatment enhanced the bioavailability of fexofenadine in rats by P-glycoprotein modulation: in vitro, in situ and in vivo evaluation.

PubMed

Bedada, Satish Kumar; Appani, Ramgopal; Boga, Praveen Kumar

2017-06-01

Capsaicin is the main pungent principle present in chili peppers has been found to possess P-glycoprotein (P-gp) inhibition activity in vitro, which may have the potential to modulate bioavailability of P-gp substrates. Therefore, purpose of this study was to evaluate the effect of capsaicin on intestinal absorption and bioavailability of fexofenadine, a P-gp substrate in rats. The mechanistic evaluation was determined by non-everted sac and intestinal perfusion studies to explore the intestinal absorption of fexofenadine. These results were confirmed by an in vivo pharmacokinetic study of oral administered fexofenadine in rats. The intestinal transport and apparent permeability (P app ) of fexofenadine were increased significantly by 2.8 and 2.6 fold, respectively, in ileum of capsaicin treated rats when compared to control group. Similarly, absorption rate constant (K a ), fraction absorbed (F ab ) and effective permeability (P eff ) of fexofenadine were increased significantly by 2.8, 2.9 and 3.4 fold, respectively, in ileum of rats pretreated with capsaicin when compared to control group. In addition, maximum plasma concentration (C max ) and area under the concentration-time curve (AUC) were increased significantly by 2.3 and 2.4 fold, respectively, in rats pretreated with capsaicin as compared to control group. Furthermore, obtained results in rats pretreated with capsaicin were comparable to verapamil (positive control) treated rats. Capsaicin pretreatment significantly enhanced the intestinal absorption and bioavailability of fexofenadine in rats likely by inhibition of P-gp mediated cellular efflux, suggesting that the combined use of capsaicin with P-gp substrates may require close monitoring for potential drug interactions.

Severe changes in colon epithelium in the Mecp2-null mouse model of Rett syndrome.

PubMed

Millar-Büchner, Pamela; Philp, Amber R; Gutierrez, Noemí; Villanueva, Sandra; Kerr, Bredford; Flores, Carlos A

2016-12-01

Rett syndrome is best known due to its severe and devastating symptoms in the central nervous system. It is produced by mutations affecting the Mecp2 gene that codes for a transcription factor. Nevertheless, evidence for MECP2 activity has been reported for tissues other than those of the central nervous system. Patients affected by Rett presented with intestinal affections whose origin is still not known. We have observed that the Mecp2-null mice presented with episodes of diarrhea, and decided to study the intestinal phenotype in these mice. Mecp2-null mice or bearing the conditional intestinal deletion of MECP2 were used. Morphometirc and histologic analysis of intestine, and RT-PCR, western blot and immunodetection were perfomed on intestinal samples of the animals. Electrical parameters of the intestine were determined by Ussing chamber experiments in freshly isolated colon samples. First we determined that MECP2 protein is mainly expressed in cells of the lower part of the colonic crypts and not in the small intestine. The colon of the Mecp2-null mice was shorter than that of the wild-type. Histological analysis showed that epithelial cells of the surface have abnormal localization of key membrane proteins like ClC-2 and NHE-3 that participate in the electroneutral NaCl absorption; nevertheless, electrogenic secretion and absorption remain unaltered. We also detected an increase in a proliferation marker in the crypts of the colon samples of the Mecp2-null mice, but the specific silencing of Mecp2 from intestinal epithelium was not able to recapitulate the intestinal phenotype of the Mecp2-null mice. In summary, we showed that the colon is severely affected by Mecp2 silencing in mice. Changes in colon length and epithelial histology are similar to those observed in colitis. Changes in the localization of proteins that participate in fluid absorption can explain watery stools, but the exclusive deletion of Mecp2 from the intestine did not reproduce colon changes observed in the Mecp2-null mice, indicating the participation of other cells in this phenotype and the complex interaction between different cell types in this disease.

Potential of Lactobacillus plantarum CCFM639 in Protecting against Aluminum Toxicity Mediated by Intestinal Barrier Function and Oxidative Stress

PubMed Central

Yu, Leilei; Zhai, Qixiao; Tian, Fengwei; Liu, Xiaoming; Wang, Gang; Zhao, Jianxin; Zhang, Hao; Narbad, Arjan; Chen, Wei

2016-01-01

Aluminum (Al) is a ubiquitous metal that can seriously harm the health of animals and humans. In our previous study, we demonstrated that Lactobacillus plantarum CCFM639 can decrease Al burden in the tissues of mice by inhibiting intestinal Al absorption. The main aim of the present research was to investigate whether the protection by the strain is also associated with enhancement of the intestinal barrier, alleviation of oxidative stress and modulation of the inflammatory response. In an in vitro cell model, two protection modes (intervention and therapy) were examined and the results indicated that L. plantarum CCFM639 alleviated Al-induced cytotoxicity. In a mouse model, L. plantarum CCFM639 treatment was found to significantly alleviate oxidative stress in the intestinal tract, regulate the function of the intestinal mucosal immune system, restore the integrity of tight junction proteins and maintain intestinal permeability. These results suggest that in addition to Al sequestration, L. plantarum CCFM639 can also inhibit Al absorption by protecting the intestinal barrier, alleviating Al-induced oxidative stress and inflammatory response. Therefore, L. plantarum CCFM639 has the potential to be a dietary supplement ingredient that provides protection against Al-induced gut injury. PMID:27918411

The absorption, distribution, excretion and toxicity of mesoporous silica nanoparticles in mice following different exposure routes.

PubMed

Fu, Changhui; Liu, Tianlong; Li, Linlin; Liu, Huiyu; Chen, Dong; Tang, Fangqiong

2013-03-01

Mesoporous silica nanoparticles (MSNs) are emerging as one of the promising nanomaterials for biomedical applications, but the nanomaterials-body interaction exposed by different administration routes remained poorly understood. In the present study, a systematic investigation of the absorption, distribution, excretion and toxicity of silica nanoparticles (SNs) with the average size of 110 nm after four different exposure routes including intravenous, hypodermic, intramuscular injection and oral administration to mice were achieved. The results showed that a fraction of the SNs administrated by the intramuscular and hypodermic injection could cross different biological barriers into the liver but with a low absorption rate. Exposing by oral administration, SNs were absorbed into the intestinal tract and persisted in the liver. And SNs administrated by intravenous injection were mainly present in the liver and spleen. In addition, SNs could cause inflammatory response around the injection sites after intramuscular and hypodermic injection. It was also found that SNs were mainly excreted through urine and feces after different exposure routes. This study will be helpful for selecting the appropriate exposed routes for the development of nanomaterials-based drug delivery system for biomedical applications. Copyright © 2013 Elsevier Ltd. All rights reserved.

Evidence that low plasma 1,25-dihydroxyvitamin D causes intestinal malabsorption of calcium and phosphate in juvenile X-linked hypophosphatemic mice.

PubMed

Meyer, R A; Meyer, M H; Gray, R W; Bruns, M E

1987-02-01

X-linked hypophosphatemic (Hyp) mice are a model for human sex-linked vitamin D-resistant rickets. We have reported intestinal malabsorption of calcium in young Hyp mice, and in this report we have explored the mechanism for it. To test for resistance of the intestine to 1,25(OH)2 vitamin D3, this hormone was continually infused via osmotic minipumps into 4-week-old normal and Hyp mice at 0, 17, 50 or 150 ng/kg/day. After 3 days, 45Ca and inorganic 32P were administered by gavage, and the mice were sacrificed on the fifth day. The Hyp mice showed responses to the hormone equivalent to the normal mice in terms of increased intestinal absorption of both 45Ca and 32P, increased plasma isotope levels, increased femoral isotope content, and increased duodenal and renal 9 kD vitamin D-dependent calcium-binding protein (calbindin-D9K; CaBP). Plasma 1,25(OH)2D was measured in these mice. There were significant correlations of plasma 1,25(OH)2D to the intestinal absorption of 45Ca and 32P and to duodenal and renal CaBP. Plasma 1,25(OH)2D was also measured in stock normal and Hyp mice and was found to be lower in 4-week-old Hyp mice than in 4-week-old normal mice (113 +/- 10 pM (n = 18) vs. 67 +/- 10 (n = 20), normal vs. Hyp, p less than .01), but unchanged at 13 weeks of age (77 +/- 13 (n = 13) vs. 70 +/- 15 (n = 15), NS). This observed difference in plasma 1,25(OH)2D between normal and Hyp mice at 4 weeks of age was sufficient to explain the observed normal-to-Hyp differences in intestinal absorption of 45Ca and duodenal and renal CaBP. It also explained 72 +/- 18% of the observed difference in 32P absorption. We conclude that Hyp mouse intestine is not resistant to 1,25(OH)2D and that the lower plasma 1,25(OH)2D of 4-week-old Hyp mice causes intestinal malabsorption of calcium and phosphate.

The imaging and modelling of the physical processes involved in digestion and absorption.

PubMed

Schulze, K S

2015-02-01

The mechanical activity of the gastro-intestinal tract serves to store, propel and digest food. Contractions disperse particles and transform solids and secretions into the two-phase slurry called chyme; movements of the intestine deliver nutrients to mucosal sites of absorption, and from the submucosa into the lymphatic and portal venous circulation. Colonic motor activity helps to extract fluid and electrolytes from chyme and to compound and compact luminal debris into faeces for elimination. We outline how dynamic imaging by ultrasound and magnetic resonance can demonstrate intestinal flow processes critical to digestion like mixing, dilution, swelling, dispersion and elution. Computational fluid mechanics enables a numerical rendition of the forces promoting digestion: pressure and flow fields, the shear stresses dispersing particles or the effectiveness of bolus mixing can be calculated. These technologies provide new insights into the mechanical processes that promote digestion and absorption. © 2014 This article is a U.S. Government work and is in the public domain in the USA.

Pharmacokinetics and Bioavailability of the Isoflavones Formononetin and Ononin and Their in Vitro Absorption in Ussing Chamber and Caco-2 Cell Models.

PubMed

Luo, Li-Yu; Fan, Miao-Xuan; Zhao, Hai-Yu; Li, Ming-Xing; Wu, Xu; Gao, Wen-Yuan

2018-03-21

Formononetin and its glycoside ononin are bioactive isoflavones widely present in legumes. The present study investigated the pharmacokinetics, bioavailability, and in vitro absorption of formononetin and ononin. After an oral administration to rats, formononetin showed a higher systemic exposure over ononin. The oral bioavailability of formononetin and ononin were 21.8% and 7.3%, respectively. Ononin was more bioavailable than perceived, and its bioavailability reached 21.7% when its metabolite formononetin was taken into account. Both formononetin and ononin exhibited better absorption in large intestine segments than that in small intestine segments. Formononetin displayed a better permeability in all intestinal segments over ononin. Transport of formononetin across Caco-2 cell monolayer was mainly through passive diffusion, while ononin was actively pumped out by MRP2 but not P-gp. The results provide evidence for better understanding of the pharmacological actions of formononetin and ononin, which advocates more in vivo evaluations or human trials.

Energy absorption as a measure of intestinal failure in the short bowel syndrome.

PubMed Central

Rodrigues, C A; Lennard-Jones, J E; Thompson, D G; Farthing, M J

1989-01-01

Energy absorption from a liquid test meal, intestinal transit rate and water and sodium output over a six hour period were measured in five patients with an ileostomy and 12 patients with the short bowel syndrome, five of whom were on longterm parenteral nutrition. The proportion of total energy absorbed was greatest in the ileostomists (median 87%, range 82-92%), less in short bowel patients not on parenteral nutrition (median 67%, range 59-78%, p less than 0.01) and least in the short bowel group who needed it (median 27%, range 2-63%, p less than 0.01). Transit rate was more rapid in the short bowel patients compared with the ileostomists. A close correlation was observed between percentage energy absorption and the dry weight of the stools/stoma effluent collected during the six hour test period (r = -0.99, p less than 0.001). This simple non-invasive test quantitates the degree of intestinal failure and may be of practical help in management. PMID:2495238

Energy absorption as a measure of intestinal failure in the short bowel syndrome.

PubMed

Rodrigues, C A; Lennard-Jones, J E; Thompson, D G; Farthing, M J

1989-02-01

Energy absorption from a liquid test meal, intestinal transit rate and water and sodium output over a six hour period were measured in five patients with an ileostomy and 12 patients with the short bowel syndrome, five of whom were on longterm parenteral nutrition. The proportion of total energy absorbed was greatest in the ileostomists (median 87%, range 82-92%), less in short bowel patients not on parenteral nutrition (median 67%, range 59-78%, p less than 0.01) and least in the short bowel group who needed it (median 27%, range 2-63%, p less than 0.01). Transit rate was more rapid in the short bowel patients compared with the ileostomists. A close correlation was observed between percentage energy absorption and the dry weight of the stools/stoma effluent collected during the six hour test period (r = -0.99, p less than 0.001). This simple non-invasive test quantitates the degree of intestinal failure and may be of practical help in management.

Vitamin D and intestinal calcium transport after bariatric surgery.

PubMed

Schafer, Anne L

2017-10-01

Bariatric surgery is a highly effective treatment for obesity, but it may have detrimental effects on the skeleton. Skeletal effects are multifactorial but mediated in part by nutrient malabsorption. While there is increasing interest in non-nutritional mechanisms such as changes in fat-derived and gut-derived hormones, nutritional factors are modifiable and thus represent potential opportunities to prevent and treat skeletal complications. This review begins with a discussion of normal intestinal calcium transport, including recent advances in our understanding of its regulation by vitamin D, and areas of continued uncertainty. Human and animal studies of vitamin D and intestinal calcium transport after bariatric surgery are then summarized. In humans, even with optimized 25-hydroxyvitamin D levels and recommended calcium intake, fractional calcium absorption decreased dramatically after Roux-en-Y gastric bypass (RYGB). In rats, intestinal calcium absorption was lower after RYGB than after sham surgery, despite elevated 1,25-dihyroxyvitamin D levels and intestinal gene expression evidence of vitamin D responsiveness. Such studies have the potential to shed new light on the physiology of vitamin D and intestinal calcium transport. Moreover, understanding the effects of bariatric surgery on these processes may improve the clinical care of bariatric surgery patients. Published by Elsevier Ltd.

Choline deficiency impairs intestinal lipid metabolism in the lactating rat.

PubMed

da Silva, Robin P; Kelly, Karen B; Lewis, Erin D; Leonard, Kelly-Ann; Goruk, Sue; Curtis, Jonathan M; Vine, Donna F; Proctor, Spencer D; Field, Catherine J; Jacobs, René L

2015-10-01

Choline is a precursor to phosphatidylcholine (PC), a structural molecule in cellular membranes that is crucial for cell growth and function. PC is also required for the secretion of lipoprotein particles from liver and intestine. Choline requirements are increased during lactation when maternal choline is supplied to the offspring through breast milk. To investigate the effect of dietary choline on intestinal lipid metabolism during lactation, choline-supplemented (CS), phosphatidylcholine-supplemented (PCS) or choline-deficient (CD) diets were fed to dams during the suckling period. CD dams had lower plasma triacylglycerol, cholesterol and apoB in the fasted state and following a fat-challenge (P < .05). There was a higher content of neutral lipids and lower content of PC in the intestine of CD dams, compared with CS and PCS fed animals (P < .05). In addition, there was lower (P < .05) villus height in CD dams, which indicated a reduced absorptive surface area in the intestine. Choline is critical for the absorption of fat in lactating rats and choline deficiency alters intestinal morphology and impairs chylomicron secretion by limiting the supply of PC. Copyright © 2015 Elsevier Inc. All rights reserved.

Influence of Physiological Gastrointestinal Surfactant Ratio on the Equilibrium Solubility of BCS Class II Drugs Investigated Using a Four Component Mixture Design

PubMed Central

2017-01-01

The absorption of poorly water-soluble drugs is influenced by the luminal gastrointestinal fluid content and composition, which control solubility. Simulated intestinal fluids have been introduced into dissolution testing including endogenous amphiphiles and digested lipids at physiological levels; however, in vivo individual variation exists in the concentrations of these components, which will alter drug absorption through an effect on solubility. The use of a factorial design of experiment and varying media by introducing different levels of bile, lecithin, and digested lipids has been previously reported, but here we investigate the solubility variation of poorly soluble drugs through more complex biorelevant amphiphile interactions. A four-component mixture design was conducted to understand the solubilization capacity and interactions of bile salt, lecithin, oleate, and monoglyceride with a constant total concentration (11.7 mM) but varying molar ratios. The equilibrium solubility of seven low solubility acidic (zafirlukast), basic (aprepitant, carvedilol), and neutral (fenofibrate, felodipine, griseofulvin, and spironolactone) drugs was investigated. Solubility results are comparable with literature values and also our own previously published design of experiment studies. Results indicate that solubilization is not a sum accumulation of individual amphiphile concentrations, but a drug specific effect through interactions of mixed amphiphile compositions with the drug. This is probably due to a combined interaction of drug characteristics; for example, lipophilicity, molecular shape, and ionization with amphiphile components, which can generate specific drug–micelle affinities. The proportion of each component can have a remarkable influence on solubility with, in some cases, the highest and lowest points close to each other. A single-point solubility measurement in a fixed composition simulated media or human intestinal fluid sample will therefore provide a value without knowledge of the surrounding solubility topography meaning that variability may be overlooked. This study has demonstrated how the amphiphile ratios influence drug solubility and highlights the importance of the envelope of physiological variation when simulating in vivo drug behavior. PMID:28749696

Sodium Cromoglycate Prevents Exacerbation of IgE-Mediated Food-Allergic Reaction Induced by Aspirin in a Rat Model of Egg Allergy.

PubMed

Yokooji, Tomoharu; Matsuo, Hiroaki

2015-01-01

Aspirin (ASP)-facilitated absorption of ingested allergens is considered an exacerbating factor in the development of food allergy. Sodium cromoglycate (SCG) is used for the treatment of atopic dermatitis with food allergy, but the efficacy of SCG in ASP-exacerbated food-allergy reactions is unclear. In this study, we evaluated the effect of SCG on ASP-exacerbated food-allergic reactions, as well as allergen absorption, in egg-allergic model rats. Plasma concentrations of ovalbumin (OVA) and fluorescein isothiocyanate-labeled dextran (FD-40), a marker for nonspecific-absorption pathways, were measured after oral administration of mixtures of OVA and FD-40 in OVA-unsensitized and OVA-sensitized rats. IgE-mediated allergic reactions were evaluated by measuring changes in rectal temperature and Evans blue dye (EBD) extravasation in the intestine and liver after oral challenge with OVA. The effects of ASP and SCG on such absorption and allergic reactions were also evaluated kinetically. In OVA-sensitized rats, plasma concentrations of OVA and FD-40 were significantly higher than those in unsensitized rats after oral administration. ASP increased the intestinal absorption of OVA and FD-40 via the paracellular pathway, and a lower rectal temperature and higher EBD extravasation were detected in the intestine and liver of OVA-sensitized rats. SCG ameliorated these ASP-facilitated absorptions and allergic reactions in a dose-dependent manner. In particular, high-dose SCG (195.2 μmol/kg) completely inhibited these absorptions and reactions. SCG can prevent ASP-exacerbated allergic reactions in patients with food allergy resulting from inhibition of increases in allergen absorption. © 2015 S. Karger AG, Basel.

Influence of intestinal efflux pumps on the absorption and transport of furosemide

PubMed Central

Al-Mohizea, Abdullah M.

2010-01-01

Purpose Furosemide is a commonly used diuretic which is used in the treatment of edema, congestive heart failure, hypertension and renal failure. Its absorption exhibits inter- and intra-subject variability that can be attributed to many factors including the intestinal efflux pumps such as the P-glycoprotein (P-gp). This study was done due to the great disagreement between what is published in the literature regarding the influence of P-gp on furosemide and at the same time due to the importance of this drug in the treatment of different conditions as described above. In addition, an investigation of the effect of two of the commonly used pharmaceutical excipients (hydroxypropyl β-cyclodextrin [HPβCD] and Tween 80) and also a P-gp inhibitor (verapamil hydrochloride) on the intestinal absorption of this drug were also done. Methods The study utilized the everted intestinal sacs technique to investigate both the effect of the efflux transporter (P-gp) on furosemide absorption and also the effect of the chosen excipients. Results The absorption of furosemide was significantly influenced by the P-gp as confirmed by the everted vis the non-everted sacs together with the verapamil study in which the transport of furosemide was inhibited by verapamil. In addition, Tween 80 was also shown to inhibit the P-gp pump whereas the HPβCD did not significantly influence the efflux of furosemide in this study. Conclusions P-glycoprotein and some of the used excipients in the formulation play a very important role in the transport of furosemide and other drugs. Thus excipients that affect the activity of P-gp should be avoided when formulating drugs that are substrate for the P-gp or other efflux pumps. PMID:23960725

Erythritol reduces small intestinal glucose absorption, increases muscle glucose uptake, improves glucose metabolic enzymes activities and increases expression of Glut-4 and IRS-1 in type 2 diabetic rats.

PubMed

Chukwuma, Chika Ifeanyi; Mopuri, Ramgopal; Nagiah, Savania; Chuturgoon, Anil Amichund; Islam, Md Shahidul

2017-08-02

Studies have reported that erythritol, a low or non-glycemic sugar alcohol possesses anti-hyperglycemic and anti-diabetic potentials but the underlying mode of actions is not clear. This study investigated the underlying mode of actions behind the anti-hyperglycemic and anti-diabetic potentials of erythritol using different experimental models (experiment 1, 2 and 3). Experiment 1 examined the effects of increasing concentrations (2.5-20%) of erythritol on glucose absorption and uptake in isolated rat jejunum and psoas muscle, respectively. Experiments 2 and 3 examined the effects of a single oral dose of erythritol (1 g/kg bw) on intestinal glucose absorption, gastric emptying and postprandial blood glucose increase, glucose tolerance, serum insulin level, muscle/liver hexokinase and liver glucose-6 phosphatase activities, liver and muscle glycogen contents and mRNA and protein expression of muscle Glut-4 and IRS-1 in normal and type 2 diabetic animals. Experiment 1 revealed that erythritol dose dependently enhanced muscle glucose ex vivo. Experiment 2 demonstrated that erythritol feeding delayed gastric emptying and reduced small intestinal glucose absorption as well as postprandial blood glucose rise, especially in diabetic animals. Experiment 3 showed that erythritol feeding improved glucose tolerance, muscle/liver hexokinase and liver glucose-6 phosphatase activities, glycogen storage and also modulated expression of muscle Glut-4 and IRS-1 in diabetic animals. Data suggest that erythritol may exert anti-hyperglycemic effects not only via reducing small intestinal glucose absorption, but also by increasing muscle glucose uptake, improving glucose metabolic enzymes activity and modulating muscle Glut-4 and IRS-1 mRNA and protein expression. Hence, erythritol may be a useful dietary supplement for managing hyperglycemia, particularly for T2D.

Physiological barriers to the oral delivery of curcumin.

PubMed

Berginc, K; Trontelj, J; Basnet, N Skalko; Kristl, A

2012-06-01

Curcumin, a principal component from Curcuma longa, with antioxidant and anti-inflammatory activities was proposed as a potential candidate for the preventation and/or treatment of cancer and chronic diseases. However, curcumin could not achieve its expected therapeutic outcome in clinical trials due to its low solubility and poor bioavailability. The actual intestinal physiological barriers limiting curcumin absorption after oral administration have not been fully investigated. To identify the main barriers curtailing its absorption, in vitro permeability of curcumin and flux of its glucuronide were monitored in rat jejunum and Transwell grown Caco-2 cells. Curcumin was more permeable under acidic conditions, but the permeability was substantially below the permeability of highly permeable standards. Its efflux could not be inhibited by specific Pgp and MRP inhibitors. BCRP was found to participate in curcumin transport, but the Organic Anion Transporting Polypeptide (OATP) did not. The permeability of curcumin significantly increased when the structure of mucus was compromised. The inhibitor of curcumin metabolism, piperin, failed to act as a permeability enhancer. Piperin inhibited Pgp and MRP transporters and decreased the amount of glucuronide transported back into the intestine. Inclusion of piperin in curcumin-containing formulations is highly recommended as to inhibit curcumin glucuronidation and to increase the transport of formed glucuronides into the plasma, therefore increasing the probability of glucuronide distribution into target tissue and inter-convertion to curcumin. It would also be beneficial, if curcumin delivery systems could reversibly compromise the mucous integrity to minimize the non-specific binding of curcumin to its constituents.

Vitamin D-mediated calcium absorption in patients with clinically stable Crohn's disease: a pilot study

USDA-ARS?s Scientific Manuscript database

Vitamin D is the critical hormone for intestinal absorption of calcium. Optimal calcium absorption is important for proper mineralization of bone in the prevention of osteoporosis and osteoporotic fractures, among other important functions. Diseases associated with gut inflammation, such as Crohn's ...

Glucose Plus Fructose Ingestion for Post-Exercise Recovery-Greater than the Sum of Its Parts?

PubMed

Gonzalez, Javier T; Fuchs, Cas J; Betts, James A; van Loon, Luc J C

2017-03-30

Carbohydrate availability in the form of muscle and liver glycogen is an important determinant of performance during prolonged bouts of moderate- to high-intensity exercise. Therefore, when effective endurance performance is an objective on multiple occasions within a 24-h period, the restoration of endogenous glycogen stores is the principal factor determining recovery. This review considers the role of glucose-fructose co-ingestion on liver and muscle glycogen repletion following prolonged exercise. Glucose and fructose are primarily absorbed by different intestinal transport proteins; by combining the ingestion of glucose with fructose, both transport pathways are utilised, which increases the total capacity for carbohydrate absorption. Moreover, the addition of glucose to fructose ingestion facilitates intestinal fructose absorption via a currently unidentified mechanism. The co-ingestion of glucose and fructose therefore provides faster rates of carbohydrate absorption than the sum of glucose and fructose absorption rates alone. Similar metabolic effects can be achieved via the ingestion of sucrose (a disaccharide of glucose and fructose) because intestinal absorption is unlikely to be limited by sucrose hydrolysis. Carbohydrate ingestion at a rate of ≥1.2 g carbohydrate per kg body mass per hour appears to maximise post-exercise muscle glycogen repletion rates. Providing these carbohydrates in the form of glucose-fructose (sucrose) mixtures does not further enhance muscle glycogen repletion rates over glucose (polymer) ingestion alone. In contrast, liver glycogen repletion rates are approximately doubled with ingestion of glucose-fructose (sucrose) mixtures over isocaloric ingestion of glucose (polymers) alone. Furthermore, glucose plus fructose (sucrose) ingestion alleviates gastrointestinal distress when the ingestion rate approaches or exceeds the capacity for intestinal glucose absorption (~1.2 g/min). Accordingly, when rapid recovery of endogenous glycogen stores is a priority, ingesting glucose-fructose mixtures (or sucrose) at a rate of ≥1.2 g·kg body mass -1 ·h -1 can enhance glycogen repletion rates whilst also minimising gastrointestinal distress.

Glucose Plus Fructose Ingestion for Post-Exercise Recovery—Greater than the Sum of Its Parts?

PubMed Central

Gonzalez, Javier T.; Fuchs, Cas J.; Betts, James A.; van Loon, Luc J. C.

2017-01-01

Carbohydrate availability in the form of muscle and liver glycogen is an important determinant of performance during prolonged bouts of moderate- to high-intensity exercise. Therefore, when effective endurance performance is an objective on multiple occasions within a 24-h period, the restoration of endogenous glycogen stores is the principal factor determining recovery. This review considers the role of glucose–fructose co-ingestion on liver and muscle glycogen repletion following prolonged exercise. Glucose and fructose are primarily absorbed by different intestinal transport proteins; by combining the ingestion of glucose with fructose, both transport pathways are utilised, which increases the total capacity for carbohydrate absorption. Moreover, the addition of glucose to fructose ingestion facilitates intestinal fructose absorption via a currently unidentified mechanism. The co-ingestion of glucose and fructose therefore provides faster rates of carbohydrate absorption than the sum of glucose and fructose absorption rates alone. Similar metabolic effects can be achieved via the ingestion of sucrose (a disaccharide of glucose and fructose) because intestinal absorption is unlikely to be limited by sucrose hydrolysis. Carbohydrate ingestion at a rate of ≥1.2 g carbohydrate per kg body mass per hour appears to maximise post-exercise muscle glycogen repletion rates. Providing these carbohydrates in the form of glucose–fructose (sucrose) mixtures does not further enhance muscle glycogen repletion rates over glucose (polymer) ingestion alone. In contrast, liver glycogen repletion rates are approximately doubled with ingestion of glucose–fructose (sucrose) mixtures over isocaloric ingestion of glucose (polymers) alone. Furthermore, glucose plus fructose (sucrose) ingestion alleviates gastrointestinal distress when the ingestion rate approaches or exceeds the capacity for intestinal glucose absorption (~1.2 g/min). Accordingly, when rapid recovery of endogenous glycogen stores is a priority, ingesting glucose–fructose mixtures (or sucrose) at a rate of ≥1.2 g·kg body mass−1·h−1 can enhance glycogen repletion rates whilst also minimising gastrointestinal distress. PMID:28358334

Glucagon-like peptide-2 induces rapid digestive adaptation following intestinal resection in preterm neonates

PubMed Central

Vegge, Andreas; Thymann, Thomas; Lund, Pernille; Stoll, Barbara; Bering, Stine B.; Hartmann, Bolette; Jelsing, Jacob; Qvist, Niels; Burrin, Douglas G.; Jeppesen, Palle B.; Holst, Jens J.

2013-01-01

Short bowel syndrome (SBS) is a frequent complication after intestinal resection in infants suffering from intestinal disease. We tested whether treatment with the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) increases intestinal volume and function in the period immediately following intestinal resection in preterm pigs. Preterm pigs were fed enterally for 48 h before undergoing resection of 50% of the small intestine and establishment of a jejunostomy. Following resection, pigs were maintained on total parenteral nutrition (TPN) without (SBS, n = 8) or with GLP-2 treatment (3.5 μg/kg body wt per h, SBS+GLP-2, n = 7) and compared with a group of unresected preterm pigs (control, n = 5). After 5 days of TPN, all piglets were fed enterally for 24 h, and a nutrient balance study was performed. Intestinal resection was associated with markedly reduced endogenous GLP-2 levels. GLP-2 increased the relative absorption of wet weight (46 vs. 22%), energy (79 vs. 64%), and all macronutrients (all parameters P < 0.05). These findings were supported by a 200% increase in sucrase and maltase activities, a 50% increase in small intestinal epithelial volume (P < 0.05), as well as increased DNA and protein contents and increased total protein synthesis rate in SBS+GLP-2 vs. SBS pigs (+100%, P < 0.05). Following intestinal resection in preterm pigs, GLP-2 induced structural and functional adaptation, resulting in a higher relative absorption of fluid and macronutrients. GLP-2 treatment may be a promising therapy to enhance intestinal adaptation and improve digestive function in preterm infants with jejunostomy following intestinal resection. PMID:23764891

Digestion of fatty acids in ruminants: a meta-analysis of flows and variation factors: 2. C18 fatty acids.

PubMed

Glasser, F; Schmidely, P; Sauvant, D; Doreau, M

2008-05-01

In ruminants, dietary lipids are extensively hydrogenated by rumen micro-organisms, and the extent of this biohydrogenation is a major determinant of long-chain fatty acid profiles of animal products (milk, meat). This paper reports on the duodenal flows of C18 fatty acids and their absorption in the small intestine, using a meta-analysis of a database of 77 experiments (294 treatments). We established equations for the prediction of duodenal flows of various 18-carbon (C18) fatty acids as a function of the intakes of their precursors and other dietary factors (source and/or technological treatment of dietary lipids). We also quantified the influence of several factors modifying rumen metabolism (pH, forage : concentrate ratio, level of intake, fish oil supplementation). We established equations for the apparent absorption of these fatty acids in the small intestine as a function of their duodenal flows. For all C18 unsaturated fatty acids, apparent absorption was a linear function of duodenal flow. For 18:0, apparent absorption levelled off for high duodenal flows. From this database, with fatty acid flows expressed in g/kg dry matter intake, we could not find any significant differences between animal categories (lactating cows, other cattle or sheep) in terms of rumen metabolism or intestinal absorption of C18 fatty acids.

The role of intestinal oxalate transport in hyperoxaluria and the formation of kidney stones in animals and man

PubMed Central

Whittamore, Jonathan M.; Hatch, Marguerite

2016-01-01

The intestine exerts a considerable influence over urinary oxalate in two ways, through the absorption of dietary oxalate and by serving as an adaptive extra-renal pathway for elimination of this waste metabolite. Knowledge of the mechanisms responsible for oxalate absorption and secretion by the intestine therefore have significant implications for understanding the etiology of hyperoxaluria, as well as offering potential targets for future treatment strategies for calcium oxalate kidney stone disease. In this review, we present the recent developments and advances in this area over the past 10 years, and put to the test some of the new ideas that have emerged during this time, using human and mouse models. A key focus for our discussion are the membrane-bound anion exchangers, belonging to the SLC26 gene family, some of which have been shown to participate in transcellular oxalate absorption and secretion. This has offered the opportunity to not only examine the roles of these specific transporters, revealing their importance to oxalate homeostasis, but to also probe the relative contributions made by the active transcellular and passive paracellular components of oxalate transport across the intestine. We also discuss some of the various physiological stimuli and signaling pathways which have been suggested to participate in the adaptation and regulation of intestinal oxalate transport. Finally, we offer an update on research into Oxalobacter formigenes, alongside recent investigations of other oxalate-degrading gut bacteria, in both laboratory animals and humans. PMID:27913853

Effect of Npt2b deletion on intestinal and renal inorganic phosphate (Pi) handling.

PubMed

Ikuta, Kayo; Segawa, Hiroko; Sasaki, Shohei; Hanazaki, Ai; Fujii, Toru; Kushi, Aoi; Kawabata, Yuka; Kirino, Ruri; Sasaki, Sumire; Noguchi, Miwa; Kaneko, Ichiro; Tatsumi, Sawako; Ueda, Otoya; Wada, Naoko A; Tateishi, Hiromi; Kakefuda, Mami; Kawase, Yosuke; Ohtomo, Shuichi; Ichida, Yasuhiro; Maeda, Akira; Jishage, Kou-Ichi; Horiba, Naoshi; Miyamoto, Ken-Ichi

2018-06-01

Hyperphosphatemia is common in chronic kidney disease and is associated with morbidity and mortality. The intestinal Na + -dependent phosphate transporter Npt2b is thought to be an important molecular target for the prevention of hyperphosphatemia. The role of Npt2b in the net absorption of inorganic phosphate (Pi), however, is controversial. In the present study, we made tamoxifen-inducible Npt2b conditional knockout (CKO) mice to analyze systemic Pi metabolism, including intestinal Pi absorption. Although the Na + -dependent Pi transport in brush-border membrane vesicle uptake levels was significantly decreased in the distal intestine of Npt2b CKO mice compared with control mice, plasma Pi and fecal Pi excretion levels were not significantly different. Data obtained using the intestinal loop technique showed that Pi uptake in Npt2b CKO mice was not affected at a Pi concentration of 4 mM, which is considered the typical luminal Pi concentration after meals in mice. Claudin, which may be involved in paracellular pathways, as well as claudin-2, 12, and 15 protein levels were significantly decreased in the Npt2b CKO mice. Thus, Npt2b deficiency did not affect Pi absorption within the range of Pi concentrations that normally occurs after meals. These findings indicate that abnormal Pi metabolism may also be involved in tight junction molecules such as Cldns that are affected by Npt2b deficiency.

Intestinal transport of gentamicin with a novel, glycosteroid drug transport agent

NASA Technical Reports Server (NTRS)

Axelrod, H. R.; Kim, J. S.; Longley, C. B.; Lipka, E.; Amidon, G. L.; Kakarla, R.; Hui, Y. W.; Weber, S. J.; Choe, S.; Sofia, M. J.

1998-01-01

PURPOSE: The objective was to investigate the ability of a glycosteroid (TC002) to increase the oral bioavailability of gentamicin. METHODS: Admixtures of gentamicin and TC002 were administered to the rat ileum by injection and to dogs by ileal or jejunal externalized ports, or PO. Bioavailability of gentamicin was determined by HPLC. 3H-TC002 was injected via externalized cannulas into rat ileum or jejunum, or PO and its distribution and elimination was determined. The metabolism of TC002 in rats was evaluated by solid phase extraction and HPLC analysis of plasma, urine and feces following oral or intestinal administration. RESULTS: The bioavailability of gentamicin was substantially increased in the presence of TC002 in both rats and dogs. The level of absorption was dependent on the concentration of TC002 and site of administration. Greatest absorption occurred following ileal orjejunal administration. TC002 was significantly more efficacious than sodium taurocholate, but similar in cytotoxicity. TC002 remained primarily in the GI tract following oral or intestinal administration and cleared rapidly from the body. It was only partly metabolized in the GI tract, but was rapidly and completely converted to its metabolite in plasma and urine. CONCLUSIONS: TC002 shows promise as a new drug transport agent for promoting intestinal absorption of polar molecules such as gentamicin.

Effects of vasoactive intestinal peptide and pancreatic polypeptide in rabbit intestine.

PubMed Central

Camilleri, M; Cooper, B T; Adrian, T E; Bloom, S R; Chadwick, V S

1981-01-01

The effects of porcine vasoactive intestinal peptide (VIP) and bovine pancreatic polypeptide (PP) on jejunal, ileal, and colonic fluid transport were studied in the rabbit. VIP produced secretion in the small intestine (jejunum greater than ileum) but did not affect absorption in the colon. PP had no secretory effects in jejunum, ileum, or colon. The small intestinal secretion induced by VIP was not associated with raised cAMP concentrations in the mucosa; this suggests that the secretory effects of VIP in vivo are mediated by a mechanism other than stimulation of adenylate cyclase. PMID:6257593

Lipid-associated oral delivery: Mechanisms and analysis of oral absorption enhancement.

PubMed

Rezhdo, Oljora; Speciner, Lauren; Carrier, Rebecca

2016-10-28

The majority of newly discovered oral drugs are poorly water soluble, and co-administration with lipids has proven effective in significantly enhancing bioavailability of some compounds with low aqueous solubility. Yet, lipid-based delivery technologies have not been widely employed in commercial oral products. Lipids can impact drug transport and fate in the gastrointestinal (GI) tract through multiple mechanisms including enhancement of solubility and dissolution kinetics, enhancement of permeation through the intestinal mucosa, and triggering drug precipitation upon lipid emulsion depletion (e.g., by digestion). The effect of lipids on drug absorption is currently not quantitatively predictable, in part due to the multiple complex dynamic processes that can be impacted by lipids. Quantitative mechanistic analysis of the processes significant to lipid system function and overall impact on drug absorption can aid in the understanding of drug-lipid interactions in the GI tract and exploitation of such interactions to achieve optimal lipid-based drug delivery. In this review, we discuss the impact of co-delivered lipids and lipid digestion on drug dissolution, partitioning, and absorption in the context of the experimental tools and associated kinetic expressions used to study and model these processes. The potential benefit of a systems-based consideration of the concurrent multiple dynamic processes occurring upon co-dosing lipids and drugs to predict the impact of lipids on drug absorption and enable rational design of lipid-based delivery systems is presented. Copyright © 2016 Elsevier B.V. All rights reserved.

The absorption and first-pass metabolism of [14C]-1,3-dinitrobenzene in the isolated vascularly perfused rat small intestine.

PubMed

Adams, P C; Rickert, D E

1996-11-01

We tested the hypothesis that the small intestine is capable of the first-pass, reductive metabolism of xenobiotics. A simplified version of the isolated vascularly perfused rat small intestine was developed to test this hypothesis with 1,3-dinitrobenzene (1,3-DNB) as a model xenobiotic. Both 3-nitroaniline (3-NA) and 3-nitroacetanilide (3-NAA) were formed and absorbed following intralumenal doses of 1,3-DNB (1.8 or 4.2 mumol) to isolated vascularly perfused rat small intestine. Dose, fasting, or antibiotic pretreatment had no effect on the absorption and metabolism of 1,3-DNB in this model system. The failure of antibiotic pretreatment to alter the metabolism of 1,3-DNA indicated that 1,3-DNB metabolism was mammalian rather than microfloral in origin. All data from experiments initiated with lumenal 1,3-DNB were fit to a pharmacokinetic model (model A). ANOVA analysis revealed that dose, fasting, or antibiotic pretreatment had no statistically significant effect on the model-dependent parameters. 3-NA (1.5 mumol) was administered to the lumen of isolated vascularly perfused rat small intestine to evaluate model A predictions for the absorption and metabolism of this metabolite. All data from experiments initiated with 3-NA were fit to a pharmacokinetic model (model B). Comparison of corresponding model-dependent pharmacokinetic parameters (i.e. those parameters which describe the same processes in models A and B) revealed quantitative differences. Evidence for significant quantitative differences in the pharmacokinetics or metabolism of formed versus preformed 3-NA in rat small intestine may require better definition of the rate constants used to describe tissue and lumenal processes or identification and incorporation of the remaining unidentified metabolites into the models.

Role of nutrient-sensing taste 1 receptor (T1R) family members in gastrointestinal chemosensing.

PubMed

Shirazi-Beechey, Soraya P; Daly, Kristian; Al-Rammahi, Miran; Moran, Andrew W; Bravo, David

2014-06-01

Luminal nutrient sensing by G-protein-coupled receptors (GPCR) expressed on the apical domain of enteroendocrine cells activates intracellular pathways leading to secretion of gut hormones that control vital physiological processes such as digestion, absorption, food intake and glucose homeostasis. The taste 1 receptor (T1R) family of GPCR consists of three members: T1R1; T1R2; T1R3. Expression of T1R1, T1R2 and T1R3 at mRNA and protein levels has been demonstrated in the intestinal tissue of various species. It has been shown that T1R2-T1R3, in association with G-protein gustducin, is expressed in intestinal K and L endocrine cells, where it acts as the intestinal glucose (sweet) sensor. A number of studies have demonstrated that activation of T1R2-T1R3 by natural sugars and artificial sweeteners leads to secretion of glucagon-like peptides 1&2 (GLP-1 and GLP-2) and glucose dependent insulinotropic peptide (GIP). GLP-1 and GIP enhance insulin secretion; GLP-2 increases intestinal growth and glucose absorption. T1R1-T1R3 combination co-expressed on the apical domain of cholecystokinin (CCK) expressing cells is a luminal sensor for a number of L-amino acids; with amino acid-activation of the receptor eliciting CCK secretion. This article focuses on the role of the gut-expressed T1R1, T1R2 and T1R3 in intestinal sweet and L-amino acid sensing. The impact of exploiting T1R2-T1R3 as a nutritional target for enhancing intestinal glucose absorption and gut structural maturity in young animals is also highlighted.

Soybean β-conglycinin induces inflammation and oxidation and causes dysfunction of intestinal digestion and absorption in fish.

PubMed

Zhang, Jin-Xiu; Guo, Lin-Ying; Feng, Lin; Jiang, Wei-Dan; Kuang, Sheng-Yao; Liu, Yang; Hu, Kai; Jiang, Jun; Li, Shu-Hong; Tang, Ling; Zhou, Xiao-Qiu

2013-01-01

β-Conglycinin has been identified as one of the major feed allergens. However, studies of β-conglycinin on fish are scarce. This study investigated the effects of β-conglycinin on the growth, digestive and absorptive ability, inflammatory response, oxidative status and gene expression of juvenile Jian carp (Cyprinus carpio var. Jian) in vivo and their enterocytes in vitro. The results indicated that the specific growth rate (SGR), feed intake, and feed efficiency were reduced by β-conglycinin. In addition, activities of trypsin, chymotrypsin, lipase, creatine kinase, Na(+),K(+)-ATPase and alkaline phosphatase in the intestine showed similar tendencies. The protein content of the hepatopancreas and intestines, and the weight and length of the intestines were all reduced by β-conglycinin. β-Conglycinin increased lipid and protein oxidation in the detected tissues and cells. However, β-conglycinin decreased superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), glutathione peroxidase (GPx) and glutathione reductase (GR) activities and glutathione (GSH) content in the intestine and enterocytes. Similar antioxidant activity in the hepatopancreas was observed, except for GST. The expression of target of rapamycin (TOR) gene was reduced by β-conglycinin. Furthermore, mRNA levels of interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β) genes were increased by β-conglycinin. However, β-conglycinin increased CuZnSOD, MnSOD, CAT, and GPx1b gene expression. In conclusion, this study indicates that β-conglycinin induces inflammation and oxidation, and causes dysfunction of intestinal digestion and absorption in fish, and finally reduces fish growth. The results of this study provide some information to the mechanism of β-conglycinin-induced negative effects.

The proton-coupled oligopeptide transporter 1 plays a major role in the intestinal permeability and absorption of 5-aminolevulinic acid.

PubMed

Xie, Yehua; Hu, Yongjun; Smith, David E

2016-01-01

5-Aminolevulinic acid (5-ALA) has been widely used in photodynamic therapy and immunofluorescence of tumours. In the present study, the intestinal permeability and oral pharmacokinetics of 5-ALA were evaluated to probe the contribution of the proton-coupled oligopeptide transporter 1 (PEPT1) to the oral absorption and systemic exposure of this substrate. In situ single-pass intestinal perfusions and in vivo oral pharmacokinetic studies were performed in wildtype and Pept1 knockout mice. Perfusion studies were performed as a function of concentration dependence, specificity and permeability of 5-ALA in different intestinal segments. Pharmacokinetic studies were performed after 0.2 and 2.0 μmoL·g(-1) doses of 5-ALA. The permeability of 5-ALA was substantial in duodenal, jejunal and ileal regions of wildtype mice, but the residual permeability of 5-ALA in the small intestine from Pept1 knockout mice was only about 10% of that in wildtype animals. The permeability of 5-ALA in jejunum was specific for PEPT1 with no apparent contribution of other transporters, including the proton-coupled amino acid transporter 1 (PAT1). After oral dosing, the systemic exposure of 5-ALA was reduced by about twofold during PEPT1 ablation, and the pharmacokinetics were dose-proportional after the 0.2 and 2.0 µmol·g(-1) doses. PEPT1 had a minor effect on the disposition and peripheral tissue distribution of 5-ALA. Our findings suggested a major role of PEPT1 in the intestinal permeability and oral absorption of 5-ALA. In contrast, another proton-coupled transporter, PAT1, appeared to play a limited role, at best. © 2015 The British Pharmacological Society.

Body composition measured by dual-energy X-ray absorptiometry in patients who have undergone small-intestinal resection.

PubMed

Haderslev, Kent Valentin; Jeppesen, Paller Bekker; Sorensen, Henrik Ancher; Mortensen, Per Brobech; Staun, Michael

2003-07-01

Patients who have undergone resection of the small intestine have lower body weight than do healthy persons. It remains unclear whether it is the body fat mass or the lean tissue mass that is reduced. We compared body-composition values in patients who had undergone small-intestinal resection with reference values obtained in healthy volunteers, and we studied the relation between body-composition estimates and the net intestinal absorption of energy. In a cross-sectional study, we included 20 men and 24 women who had undergone small-intestinal resection and had malabsorption of energy > 2000 kJ/d. Diagnoses were Crohn disease (n = 37) and other conditions (n = 7). Body composition was estimated by dual-energy X-ray absorptiometry, and data were compared with those from a reference group of 173 healthy volunteers. Energy absorption was measured during 48-h balance studies by using bomb calorimetry, and individual values were expressed relative to the basal metabolic rate. Body weight and body mass index in patients were significantly (P < 0.05) lower than the reference values. Fat mass was 6.4 kg (30%) lower (95% CI: -8.8, -3.9 kg), but lean tissue mass was only slightly and insignificantly lower (1.5 kg, or 3.3%; 95% CI: -3.7, 0.60 kg). Weight, body mass index, and body-composition estimates by dual-energy X-ray absorptiometry did not correlate significantly with the net energy absorption relative to the basal metabolic rate, expressed as a percentage. Patients who had undergone small-intestinal resection had significantly lower body weights and body mass indexes than did healthy persons, and they had significant changes in body composition, mainly decreased body fat mass.

The effect of administration of copper nanoparticles to chickens in drinking water on estimated intestinal absorption of iron, zinc, and calcium.

PubMed

Ognik, Katarzyna; Stępniowska, Anna; Cholewińska, Ewelina; Kozłowski, Krzysztof

2016-09-01

Copper nanoparticles used as a dietary supplement for poultry could affect the absorption of mineral elements. Hence the aim of the study was to determine the effect of administration of copper nanoparticles to chickens in drinking water on intestinal absorption of iron, zinc, and calcium. The experiment was carried out on 126 chicks assigned to seven experimental groups of 18 birds each (3 replications of 6 individuals each). The control group (G-C) did not receive copper nanoparticles. Groups: Cu-5(7), Cu-10(7), and Cu-15(7) received gold nanoparticles in their drinking water in the amounts of 5 mg/L for group Cu-5(7), 10 mg/L for group Cu-10(7), and 15 mg/L for group Cu-15(7) during 8 to 14, 22 to 28, and 36 of 42 days of the life of the chicks. The birds in groups Cu-5(3), Cu-10(3), and Cu-15(3) received copper nanoparticles in the same amounts, but only during 8 to 10, 22 to 24, and 36 to 38 days of life. Blood for analysis was collected from the wing vein of all chicks at the age of 42 days. After the rearing period (day 42), six birds from each experimental group with body weight similar to the group average were slaughtered. The carcasses were dissected and samples of the jejunum were collected for analysis of absorption of selected minerals. Mineral absorption was tested using the in vitro gastrointestinal sac technique. Oral administration of copper nanoparticles to chickens in the amount of 5, 10, and 15 mg/L led to accumulation of this element in the intestinal walls. The highest level of copper nanoparticles applied increased Cu content in the blood plasma of the birds. The in vitro study suggests that copper accumulated in the intestines reduces absorption of calcium and zinc, but does not affect iron absorption. © 2016 Poultry Science Association Inc.

Serum studies in man after administration of vitamin A acetate and vitamin A alcohol

PubMed Central

Fitzgerald, Oliver; Fennelly, James J.; Hingerty, Daniel J.

1962-01-01

Vitamin A acetate and vitamin A alcohol, triolein I131, oleic acid I131, and fat balance tests have been assessed in studies on cases of coeliac disease, pancreatic insufficiency, and some disorders of the small intestinal wall. In coeliac disease a very low serum carotene and flat vitamin A absorption curves have been noted. The contrast between vitamin A acetate and alcohol curves has been clearly shown in cases of pancreatic disorder showing maldigestion. The correlation between vitamin A and triolein I131 absorption (0·89) is closer than that between vitamin A and fat balance. In assessing intestinal absorption serum carotene figures are of value only if very low figures are found. PMID:13893355

Three-dimensional mechanisms of macro-to-micro-scale transport and absorption enhancement by gut villi motions

NASA Astrophysics Data System (ADS)

Wang, Yanxing; Brasseur, James G.

2017-06-01

We evaluate the potential for physiological control of intestinal absorption by the generation of "micromixing layers" (MMLs) induced by coordinated motions of mucosal villi coupled with lumen-scale "macro" eddying motions generated by gut motility. To this end, we apply a three-dimensional (3D) multigrid lattice-Boltzmann model of a lid-driven macroscale cavity flow with microscale fingerlike protuberances at the lower surface. Integrated with a previous 2D study of leaflike villi, we generalize to 3D the 2D mechanisms found there to enhance nutrient absorption by controlled villi motility. In three dimensions, increased lateral spacing within villi within groups that move axially with the macroeddy reduces MML strength and absorptive enhancement relative to two dimensions. However, lateral villi motions create helical 3D particle trajectories that enhance absorption rate to the level of axially moving 2D leaflike villi. The 3D enhancements are associated with interesting fundamental adjustments to 2D micro-macro-motility coordination mechanisms and imply a refined potential for physiological or pharmaceutical control of intestinal absorption.

Expression, Distribution and Role of Aquaporin Water Channels in Human and Animal Stomach and Intestines

PubMed Central

Zhu, Cui; Chen, Zhuang; Jiang, Zongyong

2016-01-01

Stomach and intestines are involved in the secretion of gastrointestinal fluids and the absorption of nutrients and fluids, which ensure normal gut functions. Aquaporin water channels (AQPs) represent a major transcellular route for water transport in the gastrointestinal tract. Until now, at least 11 AQPs (AQP1–11) have been found to be present in the stomach, small and large intestines. These AQPs are distributed in different cell types in the stomach and intestines, including gastric epithelial cells, gastric glands cells, absorptive epithelial cells (enterocytes), goblet cells and Paneth cells. AQP1 is abundantly distributed in the endothelial cells of the gastrointestinal tract. AQP3 and AQP4 are mainly distributed in the basolateral membrane of epithelial cells in the stomach and intestines. AQP7, AQP8, AQP10 and AQP11 are distributed in the apical of enterocytes in the small and large intestines. Although AQP-null mice displayed almost no phenotypes in gastrointestinal tracts, the alterations of the expression and localization of these AQPs have been shown to be associated with the pathology of gastrointestinal disorders, which suggests that AQPs play important roles serving as potential therapeutic targets. Therefore, this review provides an overview of the expression, localization and distribution of AQPs in the stomach, small and large intestine of human and animals. Furthermore, this review emphasizes the potential roles of AQPs in the physiology and pathophysiology of stomach and intestines. PMID:27589719

Expression, Distribution and Role of Aquaporin Water Channels in Human and Animal Stomach and Intestines.

PubMed

Zhu, Cui; Chen, Zhuang; Jiang, Zongyong

2016-08-29

Stomach and intestines are involved in the secretion of gastrointestinal fluids and the absorption of nutrients and fluids, which ensure normal gut functions. Aquaporin water channels (AQPs) represent a major transcellular route for water transport in the gastrointestinal tract. Until now, at least 11 AQPs (AQP1-11) have been found to be present in the stomach, small and large intestines. These AQPs are distributed in different cell types in the stomach and intestines, including gastric epithelial cells, gastric glands cells, absorptive epithelial cells (enterocytes), goblet cells and Paneth cells. AQP1 is abundantly distributed in the endothelial cells of the gastrointestinal tract. AQP3 and AQP4 are mainly distributed in the basolateral membrane of epithelial cells in the stomach and intestines. AQP7, AQP8, AQP10 and AQP11 are distributed in the apical of enterocytes in the small and large intestines. Although AQP-null mice displayed almost no phenotypes in gastrointestinal tracts, the alterations of the expression and localization of these AQPs have been shown to be associated with the pathology of gastrointestinal disorders, which suggests that AQPs play important roles serving as potential therapeutic targets. Therefore, this review provides an overview of the expression, localization and distribution of AQPs in the stomach, small and large intestine of human and animals. Furthermore, this review emphasizes the potential roles of AQPs in the physiology and pathophysiology of stomach and intestines.

Loss of intestinal GATA4 prevents diet-induced obesity and promotes insulin sensitivity in mice

PubMed Central

Patankar, Jay V.; Chandak, Prakash G.; Obrowsky, Sascha; Pfeifer, Thomas; Diwoky, Clemens; Uellen, Andreas; Sattler, Wolfgang; Stollberger, Rudolf; Hoefler, Gerald; Heinemann, Akos; Battle, Michele; Duncan, Stephen; Kratky, Dagmar

2011-01-01

Transcriptional regulation of small intestinal gene expression controls plasma total cholesterol (TC) and triglyceride (TG) levels, which are major determinants of metabolic diseases. GATA4, a zinc finger domain transcription factor, is critical for jejunal identity, and intestinal GATA4 deficiency leads to a jejunoileal transition. Although intestinal GATA4 ablation is known to misregulate jejunal gene expression, its pathophysiological impact on various components of metabolic syndrome remains unknown. Here, we used intestine-specific GATA4 knockout (GATA4iKO) mice to dissect the contribution of GATA4 on obesity development. We challenged adult GATA4iKO mice and control littermates with a Western-type diet (WTD) for 20 wk. Our findings show that WTD-fed GATA4iKO mice are resistant to diet-induced obesity. Accordingly, plasma TG and TC levels are markedly decreased. Intestinal lipid absorption in GATA4iKO mice was strongly reduced, whereas luminal lipolysis was unaffected. GATA4iKO mice displayed a greater glucagon-like peptide-1 (GLP-1) release on normal chow and even after long-term challenge with WTD remained glucose sensitive. In summary, our findings show that the absence of intestinal GATA4 has a beneficial effect on decreasing intestinal lipid absorption causing resistance to hyperlipidemia and obesity. In addition, we show that increased GLP-1 release in GATA4iKO mice decreases the risk for development of insulin resistance. PMID:21177287

Insights into the protective role of solid lipid nanoparticles on rosmarinic acid bioactivity during exposure to simulated gastrointestinal conditions.

PubMed

Madureira, Ana Raquel; Campos, Débora A; Oliveira, Ana; Sarmento, Bruno; Pintado, Maria Manuela; Gomes, Ana Maria

2016-03-01

The evaluation of the digestion effects on bioactive solid lipid nanoparticles (SLN) was performed. For this purpose, witepsol and carnauba SLN loaded with rosmarinic acid (RA) were exposed to the simulated gastrointestinal tract (GIT) conditions prevailing in stomach and small intestine. The simulation of intestinal epithelium was made with a dialysis bag and intestinal cell culture lines. Changes on SLN physical properties, RA release and absorption profiles were followed at each step. Combination of digestion pH and enzymes showed a significant effect upon SLN physical properties. Zeta potential values increased at stomach conditions and decreased at small intestine simulation. Also, at intestine, SLN increased their sizes and released 40-60% of RA, maintaining its initial antioxidant activity values. Sustained release of 40% of RA from SLN was also observed in dialysis tube. At CaCo-2 cell line, both types of SLN showed similar absorbed RA % (ca. 30%). Nevertheless, in CaCo-2/HT29x mix cell lines, for carnauba SLN a lower adsorption RA % was observed than for witepsol SLN. Solid lipid nanoparticles protected RA bioactivity (in terms of antioxidant activity) until reaching the intestine. A controlled release of RA from SLN was achieved and a significant absorption was observed at intestinal cells. Overall, SLN produced with witepsol showed a higher stability than carnauba SLN. Copyright © 2015 Elsevier B.V. All rights reserved.

Acid and alkaline phosphatase localization in the digestive tract mucosa of the Hemisorubim platyrhynchos.

PubMed

Faccioli, Claudemir Kuhn; Chedid, Renata Alari; Mori, Ricardo Hideo; Amaral, Antônio Carlos do; Franceschini-Vicentini, Irene Bastos; Vicentini, Carlos Alberto

2016-09-01

This cytochemical study investigated the acid and alkaline phosphatase of the digestive tract of Hemisorubim platyrhynchos. Acid phosphatase was detected in the lining epithelium throughout the digestive tract, whereas alkaline phosphatase was only observed in the intestine. In the esophagus, an acid phosphatase reaction occurred in the apical cytoplasm of the epithelial cells and was related to epithelial protection and freeing of superficial cells for sloughing. Similar results were also observed in epithelial cells of gastric epithelium. In the gastric glands, acid phosphatase occurred in lysosomes of the oxynticopeptic cells acting in the macromolecule degradation for use as an energy source, whereas in the vesiculotubular system, its presence could be related to secretion processes. Furthermore, acid phosphatase in the intestine occurred in microvilli and lysosomes of the enterocytes and was correlated to absorption and intracellular digestion. However, no difference was reported among the regions of the intestine. However, alkaline phosphatase reaction revealed a large number of reaction dots in the anterior intestine, with the number decreasing toward the posterior intestine. This enzyme has been related to several functions, highlighting its role in the nutrient absorption primarily in the anterior intestine but also being essential in pH regulation because this is a carnivorous species with many gastric glands with secretions that could damage the intestine. Copyright © 2016 Elsevier GmbH. All rights reserved.

Factors influencing growth and intestinal parasitic infections in preschoolers attending philanthropic daycare centers in Salvador, Northeast Region of Brazil.

PubMed

Lander, Rebecca L; Lander, Alastair G; Houghton, Lisa; Williams, Sheila M; Costa-Ribeiro, Hugo; Barreto, Daniel L; Mattos, Angela P; Gibson, Rosalind S

2012-11-01

Poor growth and intestinal parasitic infections are widespread in disadvantaged urban children. This cross-sectional study assessed factors influencing poor growth and intestinal parasites in 376 children aged three to six years in daycare centers in Salvador, in the Northeast Region of Brazil. Data was obtained from seven daycare centers on child weight, height, socio-economic status, health and intestinal parasites in stool samples. Prevalence of moderate underweight (< -1SD > -2SD), wasting and stunting was 12%, 16% and 6% respectively. Socioeconomic status, birth order, and maternal weight were predictors of poor anthropometric status. Almost 30% of children were infected with more than one intestinal parasite. Helminths (17.8%), notably Trichuris trichiura (12%) and Ascaris lumbricoides (10.5%), and protozoan Giardia duodenalis (13%) were the most common types of parasites detected. One percent of children had hookworm and Cryptosporidium sp. and 25% had non-pathogenic protozoan cysts. Boys from families with very low socio-economic status had lower linear growth and presented a greater risk of helminth infection. Deworming is considered an alternative for reducing the prevalence of intestinal parasitic infections in this age group.

Effects of turpentine-induced inflammation on the hypoxic stimulation of intestinal Fe3+ absorption in mice.

PubMed Central

Raja, K. B.; Duane, P.; Peters, T. J.

1990-01-01

Chronic subcutaneous turpentine administration (weekly for 6 weeks) induced a mild normocytic anaemia in mice. In-vitro and in-vivo intestinal Fe3+ absorption parameters were, however, not significantly altered from values in saline-treated or untreated mice. Normal mice, when exposed to 3 days hypoxia demonstrated a 2-3-fold increase in iron absorption in vivo, mainly due to changes in the amount of iron transferred from the mucosa to the plasma and thence to the carcass. A 2-3-fold increase in Vmax was also observed in in-vitro uptake experiments using isolated duodenal fragments. In contrast, turpentine-treated animals, though demonstrating an enhanced in-vitro maximal uptake capacity, failed to elicit an adaptive response in vivo following hypoxic exposure. These findings suggest that a circulating (humoral) factor may be responsible for the inhibition in absorption in vivo in this turpentine-induced inflammatory model. PMID:2278822

Pluronic-Functionalized Silica-Lipid Hybrid Microparticles: Improving the Oral Delivery of Poorly Water-Soluble Weak Bases.

PubMed

Rao, Shasha; Richter, Katharina; Nguyen, Tri-Hung; Boyd, Ben J; Porter, Christopher J H; Tan, Angel; Prestidge, Clive A

2015-12-07

A Pluronic-functionalized silica-lipid hybrid (Plu-SLH) microparticle system for the oral delivery of poorly water-soluble, weak base drugs is reported for the first time. A highly effective Plu-SLH microparticle system was composed of Labrasol as the lipid phase, Pluronic F127 as the polymeric precipitation inhibitor (PPI), and silica nanoparticles as the solid carrier. For the model drug cinnarizine (CIN), the Plu-SLH delivery system was shown to offer significant biopharmaceutical advantages in comparison with unformulated drug and drug in the silica-lipid hybrid (SLH) system. In vitro two-phase dissolution studies illustrated significantly reduced pH provoked CIN precipitation and an 8- to 14-fold improvement in the extent of dissolution in intestinal conditions. In addition, under simulated intestinal digesting conditions, the Plu-SLH provided approximately three times more drug solubilization than the SLH. Oral administration in rats resulted in superior bioavailability for Plu-SLH microparticles, i.e., 1.6- and 2.1-fold greater than the SLH and the unformulated CIN, respectively. A physical mixture of Pluronic and SLH (Plu&SLH), having the same composition as Plu-SLH, was also evaluated, but showed no significant increase in CIN absorption when compared to unmodified CIN or SLH. This work represents the first study where different methods of incorporating PPI to formulate solid-state lipid-based formulations were compared for the impact on the biopharmaceutical performance. The data suggest that the novel physicochemical properties and structure of the fabricated Plu-SLH microparticle delivery system play an important role in facilitating the synergistic advantage of Labrasol and Pluronic F127 in preventing drug precipitation, and the Plu-SLH provides efficient oral delivery of poorly water-soluble weak bases.

Inulin and oligofructose and mineral metabolism: the evidence from animal trials.

PubMed

Scholz-Ahrens, Katharina E; Schrezenmeir, Jürgen

2007-11-01

Nondigestible oligosaccharides have been shown to increase the absorption of several minerals (calcium, magnesium, in some cases phosphorus) and trace elements (mainly copper, iron, zinc). Inulin-type fructans including oligofructose and fructooligosaccharides derived from sucrose by enzymatic transfructosylation are the best investigated food ingredients in this respect. The stimulation of absorption was more pronounced when the demand for calcium was high, i.e., in animals in the rapid growing stage and in animals with impaired calcium absorption because of either ovariectomy or gastrectomy. Even a small stimulation of calcium absorption increased the mineral accumulation in the skeleton because of its persisting effect over months. Inulin-type fructans stimulated mineral absorption and bone mineral accretion when combined with probiotic lactobacilli and in the presence of antibiotics. Direct comparison of different inulin-type fructans revealed a more pronounced effect by inulin or a mixture of long-chain inulin and oligofructose than by oligofructose alone. Mechanisms on how inulin-type fructans mediate this effect include acidification of the intestinal lumen by short-chain fatty acids increasing solubility of minerals in the gut, enlargement of the absorption surface, increased expression of calcium-binding proteins mainly in the large intestine, modulated expression of bone-relevant cytokines, suppression of bone resorption, increased bioavailability of phytoestrogens, and, via stimulation of beneficial commensal microorganisms, increase of calcium uptake by enterocytes. Under certain conditions, inulin-type fructans may improve mineral absorption by their impact on the amelioration of gut health including stabilization of the intestinal flora and reduction of inflammation. The abundance of reports indicate that inulin-type fructans are promising substances that could help to improve the supply with available calcium in human nutrition and by this contribute to bone health.

Glucose transporters and enzymes related to glucose synthesis in small intestinal mucosa of mid-lactation dairy cows fed 2 levels of starch.

PubMed

Lohrenz, A-K; Duske, K; Schönhusen, U; Losand, B; Seyfert, H M; Metges, C C; Hammon, H M

2011-09-01

Diets containing corn starch may improve glucose supply by providing significant amounts of intestinal starch and increasing intestinal glucose absorption in dairy cows. Glucose absorption in the small intestine requires specific glucose transporters; that is, sodium-dependent glucose co-transporter-1 (SGLT1) and facilitated glucose transporter (GLUT2), which are usually downregulated in the small intestine of functional ruminants but are upregulated when luminal glucose is available. We tested the hypothesis that mRNA and protein expression of intestinal glucose transporters and mRNA expression of enzymes related to gluconeogenesis are affected by variable starch supply. Dairy cows (n=9/group) were fed for 4 wk total mixed rations (TMR) containing either high (HS) or low (LS) starch levels in the diet. Feed intake and milk yield were measured daily. After slaughter, tissue samples of the small intestinal mucosa (mid-duodenum and mid-jejunum) were taken for determination of mRNA concentrations of SGLT1 and GLUT2 as well as pyruvate carboxylase, cytosolic phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase by real-time reverse transcription PCR relative to a housekeeping gene. Protein expression of GLUT2 in crude mucosal membranes and of SGLT1 and GLUT2 in brush-border membrane vesicles was quantified by sodium dodecyl sulfate-PAGE and immunoblot. A mixed model was used to examine feeding and time-related changes on feed intake and milk yield and to test feeding and gut site effects on gene or protein expression of glucose transporters and enzymes in the intestinal mucosa. Dry matter intake, but not energy intake, was higher in cows fed HS compared with LS. Abundance of SGLT1 mRNA tended to be higher in duodenal than in jejunal mucosa, and mRNA abundances of pyruvate carboxylase tended to be higher in jejunal than in duodenal mucosa. In brush-border membrane vesicles, SGLT1 and GLUT2 protein expression could be demonstrated. No diet-dependent differences were found concerning mRNA and protein contents of glucose transporter or mRNA level of gluconeogenic enzymes. In conclusion, our investigations on glucose transporters and gluconeogenic enzymes in the small intestinal mucosa of dairy cows did not show significant diet regulation when TMR with different amounts of intestinal starch were fed. Therefore, predicted intestinal glucose absorption after enhanced starch feeding is probably not supported by changes of intestinal glucose transporters in dairy cows. Copyright © 2011 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Intestinal absorption of miltefosine: contribution of passive paracellular transport.

PubMed

Ménez, Cécile; Buyse, Marion; Dugave, Christophe; Farinotti, Robert; Barratt, Gillian

2007-03-01

This study aimed to characterize the transepithelial transport of miltefosine (HePC), the first orally effective drug against visceral leishmaniasis, across the intestinal barrier to further understand its oral absorption mechanism. Caco-2 cell monolayers were used as an in vitro model of the human intestinal barrier. The roles of active and passive mechanisms in HePC intestinal transport were investigated and the relative contributions of the transcellular and paracellular routes were estimated. HePC transport was observed to be pH-independent, partially temperature-dependent, linear as a function of time and non-saturable as a function of concentration. The magnitude of HePC transport was quite similar to that of the paracellular marker mannitol, and EDTA treatment led to an increase in HePC transport. Furthermore, HePC transport was found to be similar in the apical-to-basolateral and basolateral-to-apical directions, strongly suggesting that HePC exhibits non-polarized transport and that no MDR-mediated efflux was involved. These results demonstrate that HePC crosses the intestinal epithelium by a non-specific passive pathway and provide evidence supporting a concentration-dependent paracellular transport mechanism, although some transcellular diffusion cannot be ruled out. Considering that HePC opens epithelial tight junctions, this study shows that HePC may promote its own permeation across the intestinal barrier.

A combination of complexation and self-nanoemulsifying drug delivery system for enhancing oral bioavailability and anticancer efficacy of curcumin.

PubMed

Shukla, Mahendra; Jaiswal, Swati; Sharma, Abhisheak; Srivastava, Pradeep Kumar; Arya, Abhishek; Dwivedi, Anil Kumar; Lal, Jawahar

2017-05-01

Curcumin, the golden spice from Indian saffron, has shown chemoprotective action against many types of cancer including breast cancer. However, poor oral bioavailability is the major hurdle in its clinical application. In the recent years, self-nanoemulsifying drug delivery system (SNEDDS) has emerged as a promising tool to improve the oral absorption and enhancing the bioavailability of poorly water-soluble drugs. In this context, complexation with lipid carriers like phospholipid has also shown the tremendous potential to improve the solubility and therapeutic efficacy of certain drugs with poor oral bioavailability. In the present investigation, a systematic combination of both the approaches is utilized to prepare the phospholipid complex of curcumin and facilitate its incorporation into SNEDDS. The combined use of both the approaches has been explored for the first time to enhance the oral bioavailability and in turn increase the anticancer activity of curcumin. As evident from the pharmacokinetic studies and in situ single pass intestinal perfusion studies in Sprague-Dawley rats, the optimized SNEDDS of curcumin-phospholipid complex has shown enhanced oral absorption and bioavailability of curcumin. The cytotoxicity study in metastatic breast carcinoma cell line has shown the enhancement of cytotoxic action by 38.7%. The primary tumor growth reduction by 58.9% as compared with the control group in 4T1 tumor-bearing BALB/c mice further supported the theory of enhancement of anticancer activity of curcumin in SNEDDS. The developed formulation can be a potential and safe carrier for the oral delivery of curcumin.

Identification of cells expressing OLFM4 and LGR5 mRNA by in situ hybridization in the yolk sac and small intestine of embryonic and early post-hatch chicks.

PubMed

Zhang, H; Wong, E A

2018-02-01

The chicken yolk sac (YS) and small intestine are essential for nutrient absorption during the pre-hatch and post-hatch periods, respectively. Absorptive enterocytes and secretory cells line the intestinal villi and originate from stem cells located in the intestinal crypts. Similarly, in the YS, there are absorptive and secretory cells that presumably originate from a stem cell population. Leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5) and olfactomedin 4 (Olfm4) are 2 widely used markers for intestinal stem cells. The objective of this study was to map the distribution of putative stem cells expressing LGR5 and OLFM4 mRNA in the chicken small intestine from the late embryonic period to early post hatch and the YS during embryogenesis. At embryonic d 11, 13, 15, 17, and 19, the YS was collected (n = 3), and small intestine was collected at embryonic d 19, d of hatch (doh), and d 1, 4, and 7 post hatch (n = 3). Cells expressing OLFM4 and LGR5 mRNA were identified by in situ hybridization. In the YS, cells expressing only LGR5 and not OLFM4 mRNA were localized to the vascular endothelial cells lining the blood vessels. In the small intestine, cells in the intestinal crypt expressed both LGR5 and OLFM4 mRNA. Staining for OLFM4 mRNA was more intense than LGR5 mRNA, demonstrating that Olfm4 is a more robust marker for stem cells than Lgr5. At embryonic d 19 and doh, cells staining for OLFM4 mRNA were already present in the rudimentary crypts, with the greatest staining in the duodenal crypts. The intensity of OLFM4 mRNA staining increased from doh to d 7 post hatch. Dual label staining at doh for the peptide transporter PepT1 and Olfm4 revealed a population of cells above the crypts that did not express Olfm4 or PepT1 mRNA. These cells are likely progenitor transit amplifying cells. Thus, avians and mammals share similarity in the ontogeny of stem cells in the intestinal crypts. © 2017 Poultry Science Association Inc.

Dietary protein, calcium metabolism, and skeletal homeostasis revisited.

PubMed

Kerstetter, Jane E; O'Brien, Kimberly O; Insogna, Karl L

2003-09-01

High dietary protein intakes are known to increase urinary calcium excretion and, if maintained, will result in sustained hypercalciuria. To date, the majority of calcium balance studies in humans have not detected an effect of dietary protein on intestinal calcium absorption or serum parathyroid hormone. Therefore, it is commonly concluded that the source of the excess urinary calcium is increased bone resorption. Recent studies from our laboratory indicate that alterations in dietary protein can, in fact, profoundly affect intestinal calcium absorption. In short-term dietary trials in healthy adults, we fixed calcium intake at 20 mmol/d while dietary protein was increased from 0.7 to 2.1 g/kg. Increasing dietary protein induced hypercalciuria in 20 women [from 3.4 +/- 0.3 ( +/- SE) during the low-protein to 5.4 +/- 0.4 mmol/d during the high-protein diet]. The increased dietary protein was accompanied by a significant increase in intestinal calcium absorption from 18.4 +/- 1.3% to 26.3 +/- 1.5% (as determined by dual stable isotopic methodology). Dietary protein intakes at and below 0.8 g/kg were associated with a probable reduction in intestinal calcium absorption sufficient to cause secondary hyperparathyroidism. The long-term consequences of these low-protein diet-induced changes in mineral metabolism are not known, but the diet could be detrimental to skeletal health. Of concern are several recent epidemiologic studies that demonstrate reduced bone density and increased rates of bone loss in individuals habitually consuming low-protein diets. Studies are needed to determine whether low protein intakes directly affect rates of bone resorption, bone formation, or both.

Supplementing a low-protein diet with dibasic amino acids increases urinary calcium excretion in young women.

PubMed

Bihuniak, Jessica D; Sullivan, Rebecca R; Simpson, Christine A; Caseria, Donna M; Huedo-Medina, Tania B; O'Brien, Kimberly O; Kerstetter, Jane E; Insogna, Karl L

2014-03-01

Increasing dietary protein within a physiologic range stimulates intestinal calcium absorption, but it is not known if specific amino acids or dietary protein as a whole are responsible for this effect. Therefore, we selectively supplemented a low-protein (0.7 g/kg) diet with either the calcium-sensing receptor-activating amino acids (CaSR-AAAs) L-tryptophan, L-phenylalanine, and L-histidine, or the dibasic amino acids (DAAs) L-arginine and L-lysine, to achieve intakes comparable to the content of a high-protein diet (2.1 g/kg) and measured intestinal calcium absorption. Fourteen young women took part in a placebo-controlled, double-blind, crossover feeding trial in which each participant ingested a 6-d low-protein diet supplemented with CaSR-AAAs, DAAs, or methylcellulose capsules (control) after an 11-d adjustment period. All participants ingested all 3 diets in random order. Intestinal calcium absorption was measured between days 5 and 6 using dual-stable calcium isotopes ((42)Ca, (43)Ca, and (44)Ca). There was no difference in calcium absorption between the diet supplemented with CaSR-AAAs (22.9 ± 2.0%) and the control diet (22.3 ± 1.4%) (P = 0.64). However, calcium absorption tended to be greater during the DAA supplementation period (25.2 ± 1.4%) compared with the control diet period (22.3 ± 1.4%) (P < 0.10). Larger and longer clinical trials are needed to clarify the possible benefit of arginine and lysine on calcium absorption.

Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition to Increasing Urinary Glucose Excretion

PubMed Central

Polidori, David; Sha, Sue; Mudaliar, Sunder; Ciaraldi, Theodore P.; Ghosh, Atalanta; Vaccaro, Nicole; Farrell, Kristin; Rothenberg, Paul; Henry, Robert R.

2013-01-01

OBJECTIVE Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor, is also a low-potency SGLT1 inhibitor. This study tested the hypothesis that intestinal canagliflozin levels postdose are sufficiently high to transiently inhibit intestinal SGLT1, thereby delaying intestinal glucose absorption. RESEARCH DESIGN AND METHODS This two-period, crossover study evaluated effects of canagliflozin on intestinal glucose absorption in 20 healthy subjects using a dual-tracer method. Placebo or canagliflozin 300 mg was given 20 min before a 600-kcal mixed-meal tolerance test. Plasma glucose, 3H-glucose, 14C-glucose, and insulin were measured frequently for 6 h to calculate rates of appearance of oral glucose (RaO) in plasma, endogenous glucose production, and glucose disposal. RESULTS Compared with placebo, canagliflozin treatment reduced postprandial plasma glucose and insulin excursions (incremental 0- to 2-h area under the curve [AUC0–2h] reductions of 35% and 43%, respectively; P < 0.001 for both), increased 0- to 6-h urinary glucose excretion (UGE0–6h, 18.2 ± 5.6 vs. <0.2 g; P < 0.001), and delayed RaO. Canagliflozin reduced AUC RaO by 31% over 0 to 1 h (geometric means, 264 vs. 381 mg/kg; P < 0.001) and by 20% over 0 to 2 h (576 vs. 723 mg/kg; P = 0.002). Over 2 to 6 h, canagliflozin increased RaO such that total AUC RaO over 0 to 6 h was <6% lower versus placebo (960 vs. 1,018 mg/kg; P = 0.003). A modest (∼10%) reduction in acetaminophen absorption was observed over the first 2 h, but this difference was not sufficient to explain the reduction in RaO. Total glucose disposal over 0 to 6 h was similar across groups. CONCLUSIONS Canagliflozin reduces postprandial plasma glucose and insulin by increasing UGE (via renal SGLT2 inhibition) and delaying RaO, likely due to intestinal SGLT1 inhibition. PMID:23412078

Carrier-mediated transport of riboflavin in the rat colon.

PubMed

Yuasa, H; Hirobe, M; Tomei, S; Watanabe, J

2000-03-01

Carriers involved in riboflavin transport have generally been presumed to be localized in the upper small intestine. However, using a closed loop technique, we found that in the rat colon the absorption of riboflavin could be significantly reduced by raising the concentration from 0.1 to 200 microM and by adding lumiflavin, an analogue of riboflavin. These results suggest that saturable transport by the carrier that is specific for riboflavin and analogues may also be involved in riboflavin absorption in the colon. At the lower concentration of 0.1 microM, carrier-mediated transport was suggested to prevail, compared with passive transport, both in the colon and the small intestine. Furthermore, carrier-mediated transport in the colon was comparable with that in the small intestine. This study is the first to suggest carrier-mediated riboflavin transport in the colon. Although the riboflavin transport system in the colon needs to be subjected to more detailed investigation of its transport functions and role in riboflavin absorption after oral administration, it would be of interest to explore potential use of this carrier as a system for drug delivery.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kramer, L.

The effect of drugs such as glucocorticoids and thyroid extract on calcium metabolism is unknown. However, several other medications affect the excretion and intestinal absorption of calcium. A controlled study was carried out to investigate these aspects. Urinary calcium was determined for 3 months during the long-term intake of the antituberculous drug isoniazid (INH) and of the antibiotic tetracycline. The effect of the diuretics furosemide and hydrochlorothiazide, of several aluminum-containing antacids, of thyroid extract and of corticosteroids was also studied. Metabolic balances of calcium, phosphorus, magnesium and zinc were determined, as well as the intestinal absorption of calcium using Camore » 47. Plasma levels, urinary and fecal excretions of Ca 47 were determined. All drugs tested increased urinary calcium except for the diuretic hydrochlorothiazide. Regarding the effect of corticosteroids: the intestinal absorption of calcium was unchanged after the short-term use and was very high after long-term use. The studies have shown that several commonly used drugs induce an increase in urinary calcium excretion which may contribute to calcium loss, if this increase persists for prolonged periods of time. Urinary excretions of phosphorus, magnesium and zinc increased in some of the studies.« less

Mechanisms of digestion and absorption of dietary vitamin A.

PubMed

Harrison, Earl H

2005-01-01

Mechanisms involved in the digestion and absorption of dietary vitamin A require the participation of several proteins. Dietary retinyl esters are hydrolyzed in the intestine by the pancreatic enzyme, pancreatic triglyceride lipase, and intestinal brush border enzyme, phospholipase B. Unesterified retinol taken up by the enterocyte is complexed with cellular retinol-binding protein type 2 and the complex serves as a substrate for reesterification of the retinol by the enzyme lecithin:retinol acyltransferase (LRAT). The retinyl esters are then incorporated into chylomicrons, intestinal lipoproteins containing other dietary lipids, such as triglycerides, phospholipids, and free and esterified cholesterol, and apolipoprotein B. Chylomicrons containing newly absorbed retinyl esters are then secreted into the lymph. Although under normal dietary conditions much of the dietary vitamin A is absorbed via the chylomicron/lymphatic route, it is also clear that under some circumstances there is substantial absorption of unesterified retinol via the portal route. Evidence supports the idea that the cellular uptake and efflux of unesterified retinol by enterocytes is mediated by lipid transporters, but the exact number, identity, and role of these proteins is not known and is an active area of research.

The association of pagophagia with Helicobacter pylori infection in patients with iron-deficiency anemia.

PubMed

Asma, Suheyl; Boga, Can; Ozdogu, Hakan; Serin, Ender

2009-07-01

This study aimed to determine the relationship between pagophagia (compulsive ice eating) and H. pylori infection in patients with iron-deficiency anemia. We identified H. pylori infection using the (13)C-urea breath test in 45 patients with iron-deficiency anemia (group 1) and 55 patients with iron-deficiency anemia and pagophagia (group 2). Subgroups for testing oral intestinal iron absorption were randomly assigned from both groups. These subgroups consisted of (a) 10 patients with iron-deficiency anemia, (b) 10 patients with iron-deficiency anemia and pagophagia, (c) 10 patients with iron-deficiency anemia, pagophagia, and H. pylori infection before the eradication of H. pylori and (d) subgroup c after eradication therapy. There was no difference in the rate of H. pylori infection in the iron-deficiency anemia groups, with or without pagophagia. Furthermore, oral intestinal iron absorption was not influenced by pagophagia and/or H. pylori infection. Pagophagia did not increase the risk of H. pylori infection in patients with iron-deficiency anemia. Pagophagia and H. pylori infection do not synergistically affect the development of intestinal iron absorption abnormalities.

Perturbed zinc homeostasis in rural 3-5-y-old Malawian children is associated with abnormalities in intestinal permeability attributed to tropical enteropathy

USDA-ARS?s Scientific Manuscript database

Tropical enteropathy and zinc deficiency are major public health problems worldwide. Tropical enteropathy is characterized by reduced mannitol absorption with normal or increased lactulose absorption when a dual sugar absorption test is administered, the results of which are reported as the lactulos...

Non-invasive, Multimodal Functional Imaging of the Intestine with Frozen Micellar Naphthalocyanines

PubMed Central

Zhang, Yumiao; Jeon, Mansik; Rich, Laurie J.; Hong, Hao; Geng, Jumin; Zhang, Yin; Shi, Sixiang; Barnhart, Todd E.; Alexandridis, Paschalis; Huizinga, Jan D.; Seshadri, Mukund; Cai, Weibo; Kim, Chulhong; Lovell, Jonathan F.

2014-01-01

Overview There is a need for safer and improved methods for non-invasive imaging of the gastrointestinal tract. Modalities based on X-ray radiation, magnetic resonance and ultrasound suffer from limitations with respect to safety, accessibility or lack of adequate contrast. Functional intestinal imaging of dynamic gut processes has not been practical using existing approaches. Here, we report the development of a family of nanoparticles that can withstand the harsh conditions of the stomach and intestine, avoid systemic absorption, and give rise to good optical contrast for photoacoustic imaging. The hydrophobicity of naphthalocyanine dyes was exploited to generate purified ~20 nm frozen micelles, which we call nanonaps, with tunable and large near-infrared absorption values (>1000). Unlike conventional chromophores, nanonaps exhibited non-shifting spectra at ultrahigh optical densities and, following oral administration in mice, passed safely through the gastrointestinal tract. Non-invasive, non-ionizing photoacoustic techniques were used to visualize nanonap intestinal distribution with low background and remarkable resolution with 0.5 cm depth, and enabled real-time intestinal functional imaging with ultrasound co-registration. Positron emission tomography following seamless nanonap radiolabelling allowed complementary whole body imaging. PMID:24997526

Facilitated Bioaccumulation of Perfluorooctanesulfonate in Common Carp (Cyprinus carpio) by Graphene Oxide and Remission Mechanism of Fulvic Acid.

PubMed

Qiang, Liwen; Chen, Meng; Zhu, Lingyan; Wu, Wei; Wang, Qiang

2016-11-01

As one of the most popular carbon-based nanomaterials, graphene oxide (GO) has the potential to be released in aquatic environment and interact with some coexistent organic pollutants, such as perfluorooctanesulfonate (PFOS), which is an emerging persistent organic pollutant. In this study, the adsorption of PFOS on GO in the presence of fulvic acid (FA), the impacts of GO and FA on PFOS toxicokinetics in carp (Cyprinus carpio), and in vitro digestion behaviors were examined. The results indicated that PFOS could be strongly adsorbed on GO with a Freundlich affinity coefficient K F of 580 ± 205 (mg/g)/(mg/L) n , while the adsorption was suppressed by FA due to competitive adsorption. GO significantly enhanced the bioaccumulation of PFOS in blood, kidney, liver, gill, intestine, and muscle of carp, and the corresponding bioaccumulation factor (BAF) was in the range of 2026-53513 L/kg. The enhancement was greatest for liver and intestine, which was 10.3 and 9.33 times of that without GO, respectively. In vivo toxicokinetic and in vitro digestion-absorption experiments indicated that GO could carry PFOS to penetrate the intestine cells. There herein, PFOS absorption, especially via intestine, and the uptake rate coefficient (k u ) were greatly enhanced, leading to distinctly promoted bioaccumulation of PFOS in fish. However, FA could facilitate the flocculation of GO in the intestine and also accelerate excretion of GO-PFOS complex. Thus, in the presence of FA, PFOS absorption was reduced and the promotion effect of GO on PFOS accumulation was remitted.

Biokinetics of food additive silica nanoparticles and their interactions with food components.

PubMed

Lee, Jeong-A; Kim, Mi-Kyung; Song, Jae Ho; Jo, Mi-Rae; Yu, Jin; Kim, Kyoung-Min; Kim, Young-Rok; Oh, Jae-Min; Choi, Soo-Jin

2017-02-01

Nanomaterials have been widely utilized in the food industry in production, packaging, sensors, nutrient delivery systems, and food additives. However, research on the interactions between food-grade nanoparticles and biomolecules as well as their potential toxicity is limited. In the present study, the in vivo solubility, oral absorption, tissue distribution, and excretion kinetics of one of the most extensively used food additives, silica (SiO 2 ) were evaluated with respect to particle size (nano vs bulk) following single-dose oral administration to rats. Intestinal transport mechanism was investigated using a 3D culture system, in vitro model of human intestinal follicle-associated epithelium (FAE). The effect of the presence of food components, such as sugar and protein, on the oral absorption of nanoparticles was also evaluated with focus on their interactions. The results obtained demonstrated that the oral absorption of nanoparticles (3.94±0.38%) was greater than that of bulk materials (2.95±0.37%), possibly due to intestinal transport by microfold (M) cells. On the other hand, particle size was found to have no significant effect on in vivo dissolution property, biodistribution, or excretion kinetics. Oral absorption profile of silica nanoparticles was highly dependent on the presence of sugar or protein, showing rapid absorption rate in glucose, presumably due to their surface interaction on nanoparticles. These findings will be useful for predicting the potential toxicity of food-grade nanoparticles and for understanding biological interactions. Copyright © 2016 Elsevier B.V. All rights reserved.

Influence of a low- and a high-oxalate vegetarian diet on intestinal oxalate absorption and urinary excretion.

PubMed

Thomas, E; von Unruh, G E; Hesse, A

2008-09-01

To compare quantitatively the effect of a low- and a high-oxalate vegetarian diet on intestinal oxalate absorption and urinary excretion. Eight healthy volunteers (three men and five women, mean age 28.6+/-6.3) were studied. Each volunteer performed the [(13)C(2)]oxalate absorption test thrice on a low-oxalate mixed diet, thrice on a low-oxalate vegetarian diet and thrice on a high-oxalate vegetarian diet. For each test, the volunteers had to adhere to an identical diet and collect their 24-h urines. In the morning of the second day, a capsule containing [(13)C(2)]oxalate was ingested. On the low-oxalate vegetarian diet, mean intestinal oxalate absorption and urinary oxalate excretion increased significantly to 15.8+/-2.9% (P=0.012) and 0.414+/-0.126 mmol/day (P=0.012), compared to the mixed diet. On the high-oxalate vegetarian diet, oxalate absorption (12.5+/-4.6%, P=0.161) and urinary excretion (0.340+/-0.077 mmol/day, P=0.093) did not change significantly, compared to the mixed diet. A vegetarian diet can only be recommended for calcium oxalate stone patients, if the diet (1) contains the recommended amounts of divalent cations such as calcium and its timing of ingestion to a meal rich in oxalate is considered and (2) excludes foodstuffs with a high content of nutritional factors, such as phytic acid, which are able to chelate calcium.

[Effects of nandrolone decanoate on bone mineral content and intestinal absorption of calcium].

PubMed

Nuti, R; Righi, G A; Turchetti, V; Vattimo, A

1984-01-28

To evaluate the effects of a long-term treatment with nandrolone decanoate on metabolism of the skeleton, a double-blind randomized study was carried out in women with joint diseases without metabolic bone derangement. Ten patients were treated with 50 mg of nandrolone decanoate every three weeks for two years; in six subjects a treatment with placebo was performed. As it concerns plasma calcium and phosphate, serum alkaline phosphatase, urinary excretion of calcium, phosphate, hydroxyproline and cAMP, as parathyroid index, it was not observed significant differences in the two examined groups. While in placebo group at the end of the study the intestinal radiocalcium remained unchanged and bone mineral content showed a slight decrease, on the contrary nandrolone decanoate treatment promoted a significant improvement in intestinal calcium absorption and an increase in bone mineral content.

Origin of Urinary Oxalate

NASA Astrophysics Data System (ADS)

Holmes, Ross P.; Knight, John; Assimos, Dean G.

2007-04-01

Urinary oxalate is mostly derived from the absorption of ingested oxalate and endogenous synthesis. The breakdown of vitamin C may also contribute small amounts to the urinary oxalate pool. The amount of oxalate absorbed is influenced by the oxalate content of the diet, the concentrations of divalent cations in the gut, the presence of oxalate-degrading organisms, transport characteristics of the intestinal epithelium, and other factors associated with the intestinal environment. Knowledge of pathways associated with endogenous oxalate synthesis is limited. Urinary oxalate excretion can be modified using strategies that limit dietary oxalate absorption and the ingestion of oxalogenic substrates such as hydroxyproline.

Enabling the intestinal absorption of highly polar antiviral agents: ion-pair facilitated membrane permeation of zanamivir heptyl ester and guanidino oseltamivir.

PubMed

Miller, Jonathan M; Dahan, Arik; Gupta, Deepak; Varghese, Sheeba; Amidon, Gordon L

2010-08-02

Antiviral drugs often suffer from poor intestinal permeability, preventing their delivery via the oral route. The goal of this work was to enhance the intestinal absorption of the low-permeability antiviral agents zanamivir heptyl ester (ZHE) and guanidino oseltamivir (GO) utilizing an ion-pairing approach, as a critical step toward making them oral drugs. The counterion 1-hydroxy-2-naphthoic acid (HNAP) was utilized to enhance the lipophilicity and permeability of the highly polar drugs. HNAP substantially increased the log P of the drugs by up to 3.7 log units. Binding constants (K(11(aq))) of 388 M(-1) for ZHE-HNAP and 2.91 M(-1) for GO-HNAP were obtained by applying a quasi-equilibrium transport model to double-reciprocal plots of apparent octanol-buffer distribution coefficients versus HNAP concentration. HNAP enhanced the apparent permeability (P(app)) of both compounds across Caco-2 cell monolayers in a concentration-dependent manner, as substantial P(app) (0.8-3.0 x 10(-6) cm/s) was observed in the presence of 6-24 mM HNAP, whereas no detectable transport was observed without counterion. Consistent with a quasi-equilibrium transport model, a linear relationship with slope near 1 was obtained from a log-log plot of Caco-2 P(app) versus HNAP concentration, supporting the ion-pair mechanism behind the permeability enhancement. In the rat jejunal perfusion assay, the addition of HNAP failed to increase the effective permeability (P(eff)) of GO. However, the rat jejunal permeability of ZHE was significantly enhanced by the addition of HNAP in a concentration-dependent manner, from essentially zero without HNAP to 4.0 x 10(-5) cm/s with 10 mM HNAP, matching the P(eff) of the high-permeability standard metoprolol. The success of ZHE-HNAP was explained by its >100-fold stronger K(11(aq)) versus GO-HNAP, making ZHE-HNAP less prone to dissociation and ion-exchange with competing endogenous anions and able to remain intact during membrane permeation. Overall, this work presents a novel approach to enable the oral delivery of highly polar antiviral drugs, and provides new insights into the underlying mechanisms governing the success or failure of the ion-pairing strategy to increase oral absorption.

Drug therapies for reducing gastric acidity in people with cystic fibrosis.

PubMed

Ng, Sze May; Francini, Angelo J

2012-04-18

Malabsorption of fat and protein contributes to poor nutritional status in people with cystic fibrosis. Impaired pancreatic function may also result in increased gastric acidity, leading in turn to heartburn, peptic ulcers and the impairment of oral pancreatic enzyme replacement therapy. The administration of gastric acid-reducing agents has been used as an adjunct to pancreatic enzyme therapy to improve absorption of fat and gastro-intestinal symptoms in people with cystic fibrosis. It is important to establish the evidence regarding potential benefits of drugs that reduce gastric acidity in people with cystic fibrosis. To assess the effect of drug therapies for reducing gastric acidity for: nutritional status; symptoms associated with increased gastric acidity; fat absorption; lung function; quality of life and survival; and to determine if any adverse effects are associated with their use. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals, abstract books and conference proceedings.Most recent search of the Group's Trials Register: 15 February 2012. All randomised and quasi-randomised trials involving agents that reduce gastric acidity compared to placebo or a comparator treatment. Both authors independently selected trials, assessed trial quality and extracted data. Thirty-eight trials were identified from the searches. Sixteen trials, with 256 participants, were suitable for inclusion. Seven trials were limited to children and three trials enrolled only adults. Meta-analysis was not performed. However, one trial found that drug therapies that reduce gastric acidity improved gastro-intestinal symptoms such as abdominal pain; seven trials reported significant improvement in measures of fat malabsorption; and two trials reported no significant improvement in nutritional status. Only one trial reported measures of respiratory function and one trial reported an adverse effect with prostaglandin E2 analogue misoprostol. No trials have been identified assessing the effectiveness of these agents in improving quality of life, the complications of increased gastric acidity, or survival. Trials have shown limited evidence that agents that reduce gastric acidity are associated with improvement in gastro-intestinal symptoms and fat absorption. Currently, there is insufficient evidence to indicate whether there is an improvement in nutritional status, lung function, quality of life, or survival. We therefore recommend that large, multicentre, randomised controlled clinical trials are undertaken to evaluate these interventions.

Chamomile (Matricaria recutita L.) decoction extract inhibits in vitro intestinal glucose absorption and attenuates high fat diet-induced lipotoxicity and oxidative stress.

PubMed

Jabri, Mohamed-Amine; Sakly, Mohsen; Marzouki, Lamjed; Sebai, Hichem

2017-03-01

The present study aimed to investigate the inhibitory effect of chamomile decoction extract (CDE) on intestinal glucose absorption as well as its protective role against high fat diet (HFD)-induced obesity and lipotoxicity in rats. We used the Ussing chamber system to investigate the effect of CDE on intestinal transport of glucose. Male Wistar rats were fed HFD for six weeks to provoke obesity. CDE (100mg/kg, b.w. p.o.) has been per orally administered to HFD fed rats. Ex vivo, we found that CDE significantly and dose-dependently increased intestinal absorption of glucose. In vivo, HFD increased the body, liver and kidney weights, while CDE treatment showed a significant protective effects. High fat diet induced also a lipid profiles disorder and a disturbances in kidney and liver function parameters. Moreover liver and kidney lipotoxicity is accompanied by an oxidative stress status characterized by increased lipoperoxidation, depletion of antioxidant enzymes activity and non-enzymatic antioxidant (-SH groups and GSH) levels as well as increased levels of free iron, hydrogen peroxide (H 2 O 2 ) and calcium. However, treatment with CDE alleviated all the deleterious effects of HFD feed. These findings suggest that chamomile decoction extract can be used as functional beverage against obesity, hyperglycemia and hyperlipidemia. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

H(+)/solute-induced intracellular acidification leads to selective activation of apical Na(+)/H(+) exchange in human intestinal epithelial cells.

PubMed

Thwaites, D T; Ford, D; Glanville, M; Simmons, N L

1999-09-01

The intestinal absorption of many nutrients and drug molecules is mediated by ion-driven transport mechanisms in the intestinal enterocyte plasma membrane. Clearly, the establishment and maintenance of the driving forces - transepithelial ion gradients - are vital for maximum nutrient absorption. The purpose of this study was to determine the nature of intracellular pH (pH(i)) regulation in response to H(+)-coupled transport at the apical membrane of human intestinal epithelial Caco-2 cells. Using isoform-specific primers, mRNA transcripts of the Na(+)/H(+) exchangers NHE1, NHE2, and NHE3 were detected by RT-PCR, and identities were confirmed by sequencing. The functional profile of Na(+)/H(+) exchange was determined by a combination of pH(i), (22)Na(+) influx, and EIPA inhibition experiments. Functional NHE1 and NHE3 activities were identified at the basolateral and apical membranes, respectively. H(+)/solute-induced acidification (using glycylsarcosine or beta-alanine) led to Na(+)-dependent, EIPA-inhibitable pH(i) recovery or EIPA-inhibitable (22)Na(+) influx at the apical membrane only. Selective activation of apical (but not basolateral) Na(+)/H(+) exchange by H(+)/solute cotransport demonstrates that coordinated activity of H(+)/solute symport with apical Na(+)/H(+) exchange optimizes the efficient absorption of nutrients and Na(+), while maintaining pH(i) and the ion gradients involved in driving transport.

An evaluation of in vitro intestinal absorption of iron, calcium and potassium in chickens receiving gold nanoparticles.

PubMed

Sembratowicz, I; Ognik, K; Stępniowska, A

2016-08-01

This study evaluated the effect of oral administration of colloidal gold nanoparticles on accumulation of gold in the small intestine and intestinal absorption of iron, calcium and potassium under in vitro conditions. The gold nanoparticles are non-ionic, nanocrystalline, chemically pure particles 5 nm in size, produced in a physical process. In total, 126 one day-old Ross 308 chicks were assigned to 7 experimental groups of 18 birds each (3 replications of 6 individuals each). The control group (G-C) did not receive gold nanoparticles. Groups: Au-5(7), Au-10(7) and Au-15(7) received gold nanoparticles in their drinking water in the amounts of 5 mg l(-1) for group Au-5(7), 10 mg l(-1) for group Au-10(7) and 15 mg l(-1) for group Au-15(7) in 8-14, 22-28 and 36-42 d of life. The birds in groups Au-5(3), Au-10(3) and Au-15(3) received gold nanoparticles in the same amounts, but only in 8-10, 22-24 and 36-38 d of life. The study revealed that nanogold supplied via ingestion leads to dose- and time-dependent accumulation of gold in the intestinal walls. Nanogold present in the jejunum has a negative impact on the absorption of calcium, iron and potassium under in vitro conditions.

Crystal-liquid Fugacity Ratio as a Surrogate Parameter for Intestinal Permeability.

PubMed

Zakeri-Milani, Parvin; Fasihi, Zohreh; Akbari, Jafar; Jannatabadi, Ensieh; Barzegar-Jalali, Mohammad; Loebenberg, Raimar; Valizadeh, Hadi

We assessed the feasibility of using crystal-liquid fugacity ratio (CLFR) as an alternative parameter for intestinal permeability in the biopharmaceutical classification (BCS) of passively absorbed drugs. Dose number, fraction of dose absorbed, intestinal permeability, and intrinsic dissolution rate were used as the input parameters. CLFR was determined using thermodynamic parameters i.e., melting point, molar fusion enthalpy, and entropy of drug molecules obtained using differential scanning calorimetry. The CLFR values were in the range of 0.06-41.76 mole percent. There was a close relationship between CLFR and in vivo intestinal permeability (r > 0.8). CLFR values of greater than 2 mole percent corresponded to complete intestinal absorption. Applying CLFR versus dose number or intrinsic dissolution rate, more than 92% of tested drugs were correctly classified with respect to the reported classification system on the basis of human intestinal permeability and solubility. This investigation revealed that the CLFR might be an appropriate parameter for quantitative biopharmaceutical classification. This could be attributed to the fact that CLFR could be a measure of solubility of compounds in lipid bilayer which was found in this study to be directly proportional to the intestinal permeability of compounds. This classification enables researchers to define characteristics for intestinal absorption of all four BCS drug classes using suitable cutoff points for both intrinsic dissolution rate and crystal-liquid fugacity ratio. Therefore, it may be used as a surrogate for permeability studies. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Effects of nucleotide supplementation in milk replacer on small intestinal absorptive capacity in dairy calves.

PubMed

Kehoe, S I; Heinrichs, A J; Baumrucker, C R; Greger, D L

2008-07-01

Milk replacer was supplemented with nucleotides and fed to dairy calves from birth through weaning to examine the potential for enhancing recovery of small intestinal function after enteric infection. Three treatments of 23 calves each were fed milk replacer (10% body weight/d) supplemented with no nucleotides (C), purified nucleotides (N), or nucleotides from an extract of Saccharomyces cerevisiae (S). Average daily gain, health scores, fecal dry matter, and fecal bacteria were monitored, and blood was analyzed for packed cell volume, glucose, blood urea nitrogen (BUN), and creatinine. Calves were monitored twice daily for fecal score, and 48 h after increased fecal fluidity was recorded, intestinal function was evaluated by measuring absorption of orally administered xylose (0.5 g/kg of body weight). Packed cell volume of blood was greater for treatment N for wk 2 and 5 compared with other treatment groups. Four calves per treatment were killed, and intestinal tissue was evaluated for morphology, enzyme activities, and nucleoside transporter mRNA expression. Treatment S calves had increased abundance of nucleoside transporter mRNA, numerically longer villi, and lower alkaline phosphatase than other groups. Growth measurements and plasma concentrations of glucose, BUN, creatinine, and IgG were not different between treatments; however, BUN-to-creatinine ratio was higher for treatment N, possibly indicating decreased kidney function. There were also no treatment effects on fecal dry matter and fecal bacteria population. However, N-treated calves had the highest detrimental and lowest beneficial bacteria overall, indicating an unfavorable intestinal environment. Supplementation of purified nucleotides did not improve intestinal morphology or function and resulted in higher fecal water loss and calf dehydration. Supplementation of nucleotides derived from yeast tended to increase calf intestinal function, provide a more beneficial intestinal environment, and improve intestinal morphology.

Significance of Ca-soap formation for calcium absorption in the rat.

PubMed Central

Gacs, G; Barltrop, D

1977-01-01

The significance of calcium soap formation in the inhibition of calcium absorption has been studied in rats. 47Ca labelled soaps of fatty acids were introduced into the duodenum and the absorption of calcium measured after four hours in a whole body counter. The absorption of calcium was inversely correlated with the chain length of the fatty acid varying from 1% for Ca-stearate to 60% for Ca-hexanoate. Increasing the degree of unsaturation of the fatty acid was accompanied by increased calcium absorption. The availability of calcium for absorption from the soaps was correlated with their solubility in 1% aqueous Na-tauroglycocholate. The percentages of calcium as soap in the small intestine and the faeces after intragastric administration of calcium and fats were similar, which suggests that the faecal content of calcium soaps is an index of intestinal soap formation. Soap formation was negligible when CaCl2 was given with tristearate, triolaeate, or tridecanoate and no depression of calcium absorption was observed. Calcium absorption was markedly impaired by the addition of phosphates at a Ca/P ratio of 1:1 irrespective of the presence of neutral fats. Stearic acid resulted in significant soap formation and reduced calcium absorption. The degree of Ca-soap formation and the inhibition of calcium absorption were well correlated. The results suggest that, although calcium soap formation may markedly depress calcium absorption in the rat, no significant soap formation takes place when fats are given in the form of triglycerides. PMID:838405

The utility of rat jejunal permeability for biopharmaceutics classification system.

PubMed

Zakeri-Milani, Parvin; Valizadeh, Hadi; Tajerzadeh, Hosnieh; Islambulchilar, Ziba

2009-12-01

The biopharmaceutical classification system has been developed to provide a scientific approach for classifying drug compounds based on their dose/solubility ratio and human intestinal permeability. Therefore in this study a new classification is presented, which is based on a correlation between rat and human intestinal permeability values. In situ technique in rat jejunum was used to determine the effective intestinal permeability of tested drugs. Then three dimensionless parameters--dose number, absorption number, and dissolution number (D(o), A(n), and D(n))--were calculated for each drug. Four classes of drugs were defined, that is, class I, D(0) < 0.5, P(eff(rat)) > 5.09 x 10(-5) cm/s; class II, D(o) > 1, P(eff(rat)) > 5.09 x 10( -5) cm/s; class III, D(0) < 0.5, P(eff(rat)) < 4.2 x 10(-5) cm/s; and class IV, D(o) > 1, P(eff(rat)) < 4.2 x 10(-5) cm/s. A region of borderline drugs (0.5 < D(o) < 1, 4.2 x 10(-5) < P(eff(rat)) < 5.09 x 10(-5) cm/s) was also defined. According to obtained results and proposed classification for drugs, it is concluded that drugs could be categorized correctly based on dose number and their intestinal permeability values in rat model using single-pass intestinal perfusion technique. This classification enables us to remark defined characteristics for intestinal absorption of all four classes using suitable cutoff points for both dose number and rat effective intestinal permeability values.

The influence of guar gum on intestinal cholesterol transport in the rat.

PubMed

Gee, J M; Blackburn, N A; Johnson, I T

1983-09-01

Everted sacs of rat proximal small intestine were used to determine the effect of guar gum (5 g/l) on the uptake of cholesterol (0.1 mM) from a solution of micelles. The uptake of cholesterol was found to be linear both in the presence and absence of guar gum. When guar was present throughout the whole of the incubation medium, the uptake of cholesterol was reduced to approximately 40% of control values. Sacs which had been pre-incubated in guar gum before exposure to cholesterol in a guar-free medium also showed a reduction in cholesterol uptake but this was less pronounced. A two-stage perfusion technique, previously described (Blackburn & Johnson, 1981), was used to determine the effect of a guar layer adsorbed to the mucosal surface on cholesterol absorption in vivo. Such a layer leads to a reduction of approximately 36%; it was concluded that guar slows the absorption of cholesterol from micelles by a mechanism, or mechanisms, involving an increased resistance to diffusion in the aqueous medium. Groups of rats were meal-fed for at least 30 d on semi-synthetic diets with or without the inclusion of guar gum (20 g/kg). Rates of intestinal absorption of cholesterol, glucose and fluid were then determined by the perfusion technique in vivo. There was no reduction in absorption in the test animals compared with the controls. It is proposed that guar gum is able to slow the intestinal transport of cholesterol from a suspension of pre-formed micelles, but only when both are present in the lumen together. No evidence was obtained to suggest that the consumption by rats of a diet containing guar gum, at a level similar to that used in human studies, leads to any adaptive reduction in their rates of cholesterol or glucose absorption.

Intestinal absorption and activation of decitabine amino acid ester prodrugs mediated by peptide transporter PEPT1 and enterocyte enzymes.

PubMed

Tao, Wenhui; Zhao, Dongyang; Sun, Mengchi; Wang, Ziyu; Lin, Bin; Bao, Yu; Li, Yingying; He, Zhonggui; Sun, Yinghua; Sun, Jin

2018-04-25

Decitabine (DAC), a potent DNA methyltransferase (DNMT) inhibitor, has a limited oral bioavailability. Its 5'-amino acid ester prodrugs could improve its oral delivery but the specific absorption mechanism is not yet fully understood. The aim of this present study was to investigate the in vivo absorption and activation mechanism of these prodrugs using in situ intestinal perfusion and pharmacokinetics studies in rats. Although PEPT1 transporter is pH dependent, there appeared to be no proton cotransport in the perfusion experiment with a preferable transport at pH 7.4 rather than pH 6.5. This suggested that the transport was mostly dependent on the dissociated state of the prodrugs and the proton gradient might play only a limited role. In pH 7.4 HEPES buffer, an increase in P eff was observed for L-val-DAC, D-val-DAC, L-phe-DAC and L-trp-DAC (2.89-fold, 1.2-fold, 2.73-fold, and 1.90-fold, respectively), compared with the parent drug. When co-perfusing the prodrug with Glysar, a known substrate of PEPT1, the permeabilities of the prodrugs were significantly inhibited compared with the control. To further investigate the absorption of the prodrugs, L-val-DAC was selected and found to be concentration-dependent and saturable, suggesting a carrier-mediated process (intrinsic K m : 7.80 ± 2.61 mM) along with passive transport. Determination of drug in intestinal homogenate after perfusion further confirmed that the metabolic activation mainly involved an intestinal first-pass effect. In a pharmacokinetic evaluation, the oral bioavailability of L-val-DAC, L-phe-DAC and L-trp-DAC were nearly 1.74-fold, 1.69-fold and 1.49-fold greater than that of DAC. The differences in membrane permeability and oral bioavailability might be due to the different stability in the intestinal lumen and the distinct PEPT1 affinity which is mainly caused by the stereochemistry, hydrophobicity and steric hindrance of the side chains. In summary, the detailed investigation of the absorption mechanism by in vivo intestinal perfusion and pharmacokinetic studies showed that the prodrugs of DAC exhibited excellent permeability and oral bioavailability, which might be attributed to a hybrid (partly PEPT1-mediated and partly passive) transport mode and a rapid activation process in enterocytes. Copyright © 2018 Elsevier B.V. All rights reserved.

An alternative explanation for the occurrence of short circuit current increases in the small intestine following challenge by bacterial enterotoxins.

PubMed

Lucas, M L

2013-10-01

Secretory diarrhoeal disease due to enterotoxins is thought to arise from the enhancement to pathologically high rates of normally occurring chloride ion and therefore fluid secretion from enterocytes. In support of this concept, many enterotoxins increase intestinal short-circuit current, regarded now as faithfully reflecting the increased chloride ion secretion. Contradicting this assumption, STa reduces absorption but does not cause secretion in vivo although short-circuit current is increased in vitro. There is therefore a mismatch between an assumed enterocyte mediated secretory event that should but does not cause net fluid secretion and an undoubtedly increased short-circuit current. It is proposed here that short-circuit current increases are not themselves secretory events but result from interrupted fluid absorption. A noteworthy feature of compounds that inhibit the increase in short-circuit current is that the majority are vasoactive, neuroactive or both. In general, vasodilator substances increase current. An alternative hypothesis for the origin of short-circuit current increases is that these result from reflex induction of electrogenic fluid absorption. This reflex enhances a compensatory response that is also present at a cellular level. An intestinal reflex is therefore proposed by which decreases in interstitial and intravascular volume or pressure within the intestine initiate an electrogenic fluid absorption mechanism that compensates for the loss of electrically neutral fluid absorption. This hypothesis would explain the apparently complex pharmacology of short-circuit current increases since many depressor substances have receptors in common with enterocytes and enteric nerves. The proposed alternative view of the origin of short-circuit current increases assumes that these do not represent chloride secretion from the enterocytes. This view may therefore aid the successful development of anti-diarrhoeal drugs to overcome a major cause of infant mortality worldwide, if short-circuit current data are being persistently misinterpreted. The putative but testable link between interstitial volume or pressure and fluid absorption also provides support for the alternative view of secretion; namely, that enhanced capillary and epithelial cell tight junctional permeability together with increased intracapillary pressure may cause secretion and not chloride exit from the enterocytes. Copyright © 2013. Published by Elsevier Ltd.

Preparation and characterization of nano liposomes of Orthosiphon stamineus ethanolic extract in soybean phospholipids.

PubMed

Aisha, Abdalrahim F A; Majid, Amin Malik Shah Abdul; Ismail, Zhari

2014-03-27

O. stamineus is a medicinal herb with remarkable pharmacological properties. However, poor solubility of the active principles limits its medicinal value. This study sought to prepare nano liposomes of OS ethanolic extract in unpurified soybean phospholipids in order to improve its solubility and permeability. OS liposomes were prepared by the conventional film method, and were characterized for solubility, entrapment efficiency, Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), particle size and zeta potential, release, absorption in everted rat intestinal sacs, and DPPH scavenging effect. OS liposomes showed substantial enhancement of extract's solubility from 956 ± 34 to 3979 ± 139 μg/ml, with entrapment efficiency of 66.2 ± 0.9%. FTIR study indicates interaction between soybean phospholipids and OS extract. TEM and dynamic light scattering showed presence of round anionic nano liposomes with particle size and zeta potential of 152.5 ± 1.1 nm and -49.8 ± 1.0 mV, respectively. A study using the fluorescent probe pyrene showed the critical micellar concentration is 9.2 ± 2.9 μg/ml. Release studies showed 94 ± 0.1% release in non-formulated extract and 62.4 ± 0.1% in OS liposomes. Released extract from OS liposomes showed improvement in DPPH scavenging effect, IC50 = 23.5 ± 1.1 μg/ml compared to 32.4 ± 0.5 μg/ml in non-formulated extract. OS liposomes were stable at pH 5.5 and 7.4, but showed reversible agglomeration at pH 1.6. Absorption in everted rat intestinal sacs showed substantial improvement in permeability of 3'-hydroxy-5, 6, 7, 4″-tetramethoxyflavone, sinensetin, eupatorin, and 3 other unknown compounds. Enhanced solubility, absorption and antioxidant effect may improve the overall pharmacological effects and medicinal value of OS ethanolic extract.

A RADIOAUTOGRAPHIC STUDY OF GLYCERIDE SYNTHESIS IN VIVO DURING INTESTINAL ABSORPTION OF FATS AND LABELED GLUCOSE

PubMed Central

Jersild, Ralph A.

1966-01-01

Radioautography was used to detect the synthesis of labeled glycerides in intestinal absorptive cells following injections of fatty chyme and glucose-6-H3 into ligated segments of upper jejunum of fasting rats. Absorption intervals ranged from 2 to 20 min. Labeling is evident throughout the cells in as short a time as 2 min. Most grains are present over droplets of absorbed fat beginning with those in the endoplasmic reticulum immediately subjacent to the terminal web. With longer absorption periods, frequent grains are present over accumulations of fat droplets in the Golgi cisternae and intercellular spaces. A similar pattern of grains is seen following absorption of either linoleic acid or safflower oil. By comparison, considerably less label is present in the cells when the fat is extracted with alcohol prior to radioautographic procedures, or when labeled glucose alone is absorbed. A significant incorporation of glucose label into newly synthesized glycerides is indicated and confirmed by scintillation counts on saponified lipid extracts. The grain distribution implies an involvement of the extreme apical endoplasmic reticulum in this synthesis. PMID:5971642

Characterization of the oral absorption of several aminopenicillins: determination of intrinsic membrane absorption parameters in the rat intestine in situ

NASA Technical Reports Server (NTRS)

Sinko, P. J.; Amidon, G. L.

1992-01-01

The absorption mechanism of several penicillins was characterized using in situ single-pass intestinal perfusion in the rat. The intrinsic membrane parameters were determined using a modified boundary layer model (fitted value +/- S.E.): Jmax* = 11.78 +/- 1.88 mM, Km = 15.80 +/- 2.92 mM, Pm* = 0, Pc* = 0.75 +/- 0.04 for ampicillin; Jmax* = 0.044 +/- 0.018 mM, Km = 0.058 +/- 0.026 mM, Pm* = 0.558 +/- 0.051, Pc* = 0.757 +/- 0.088 for amoxicillin; and Jmax* = 16.30 +/- 3.40 mM, Km = 14.00 +/- 3.30 mM, Pm* = 0, Pc* = 1.14 +/- 0.05 for cyclacillin. All of the aminopenicillins studied demonstrated saturable absorption kinetics as indicated by their concentration-dependent wall permeabilities. Inhibition studies were performed to confirm the existence of a nonpassive absorption mechanism. The intrinsic wall permeability (Pw*) of 0.01 mM ampicillin was significantly lowered by 1 mM amoxicillin and the Pw* of 0.01 mM amoxicillin was reduced by 2 mM cephradine consistent with competitive inhibition.

Structured triglyceride vehicles for oral delivery of halofantrine: examination of intestinal lymphatic transport and bioavailability in conscious rats.

PubMed

Holm, René; Porter, Christopher J H; Müllertz, Anette; Kristensen, Henning G; Charman, William N

2002-09-01

To compare the influence of triglyceride vehicle intramolecular structure on the intestinal lymphatic transport and systemic absorption of halofantrine in conscious rats. Conscious, lymph cannulated and nonlymph cannulated rats were dosed orally with three structurally different triglycerides; sunflower oil, and two structured triglycerides containing different proportion and position of medium-(M) and long-chain (L) fatty acids on the glycerol backbone. The two structured triglycerides were abbreviated MLM and LML to reflect the structural position on the glycerol. The concentration of halofantrine in blood and lymph samples was analyzed by HPLC. Both the lymphatic transport and the total absorption of halofantrine were enhanced by the use the MLM triglyceride. The estimated total absorption of halofantrine in the lymph cannulated animals was higher than in the nonlymph cannulated animals, and this was most pronounced for the animals dosed with the structured triglycerides. Using MLM as vehicle increases the portal absorption of halofantrine and results in similar lymphatic transport levels when compared to sunflower oil. Total absorption when assessed as absorption in the blood plus lymphatic transport for halofantrine after administration in the MLM triglyceride was higher than after administration in sunflower oil.

Circadian regulation of intestinal lipid absorption by apolipoprotein AIV involves forkhead transcription factors A2 and O1 and microsomal triglyceride transfer protein.

PubMed

Pan, Xiaoyue; Munshi, Mohamed Khalid; Iqbal, Jahangir; Queiroz, Joyce; Sirwi, Alaa Ahmed; Shah, Shrenik; Younus, Abdullah; Hussain, M Mahmood

2013-07-12

We have shown previously that Clock, microsomal triglyceride transfer protein (MTP), and nocturnin are involved in the circadian regulation of intestinal lipid absorption. Here, we clarified the role of apolipoprotein AIV (apoAIV) in the diurnal regulation of plasma lipids and intestinal lipid absorption in mice. Plasma triglyceride in apoAIV(-/-) mice showed diurnal variations similar to apoAIV(+/+) mice; however, the increases in plasma triglyceride at night were significantly lower in these mice. ApoAIV(-/-) mice absorbed fewer lipids at night and showed blunted response to daytime feeding. To explain reasons for these lower responses, we measured MTP expression; intestinal MTP was low at night, and its induction after food entrainment was less in apoAIV(-/-) mice. Conversely, apoAIV overexpression increased MTP mRNA in hepatoma cells, indicating transcriptional regulation. Mechanistic studies revealed that sequences between -204/-775 bp in the MTP promoter respond to apoAIV and that apoAIV enhances expression of FoxA2 and FoxO1 transcription factors and their binding to the identified cis elements in the MTP promoter at night. Knockdown of FoxA2 and FoxO1 abolished apoAIV-mediated MTP induction. Similarly, knockdown of apoAIV in differentiated Caco-2 cells reduced MTP, FoxA2, and FoxO1 mRNA levels, cellular MTP activity, and media apoB. Moreover, FoxA2 and FoxO1 expression showed diurnal variations, and their expression was significantly lower in apoAIV(-/-) mice. These data indicate that apoAIV modulates diurnal changes in lipid absorption by regulating forkhead transcription factors and MTP and that inhibition of apoAIV expression might reduce plasma lipids.

Sweet taste receptors in rat small intestine stimulate glucose absorption through apical GLUT2.

PubMed

Mace, Oliver J; Affleck, Julie; Patel, Nick; Kellett, George L

2007-07-01

Natural sugars and artificial sweeteners are sensed by receptors in taste buds. T2R bitter and T1R sweet taste receptors are coupled through G-proteins, alpha-gustducin and transducin, to activate phospholipase C beta2 and increase intracellular calcium concentration. Intestinal brush cells or solitary chemosensory cells (SCCs) have a structure similar to lingual taste cells and strongly express alpha-gustducin. It has therefore been suggested over the last decade that brush cells may participate in sugar sensing by a mechanism analogous to that in taste buds. We provide here functional evidence for an intestinal sensing system based on lingual taste receptors. Western blotting and immunocytochemistry revealed that all T1R members are expressed in rat jejunum at strategic locations including Paneth cells, SCCs or the apical membrane of enterocytes; T1Rs are colocalized with each other and with alpha-gustducin, transducin or phospholipase C beta2 to different extents. Intestinal glucose absorption consists of two components: one is classical active Na+-glucose cotransport, the other is the diffusive apical GLUT2 pathway. Artificial sweeteners increase glucose absorption in the order acesulfame potassium approximately sucralose > saccharin, in parallel with their ability to increase intracellular calcium concentration. Stimulation occurs within minutes by an increase in apical GLUT2, which correlates with reciprocal regulation of T1R2, T1R3 and alpha-gustducin versus T1R1, transducin and phospholipase C beta2. Our observation that artificial sweeteners are nutritionally active, because they can signal to a functional taste reception system to increase sugar absorption during a meal, has wide implications for nutrient sensing and nutrition in the treatment of obesity and diabetes.

Partially hydrolyzed guar gum increases intestinal absorption of iron in growing rats with iron deficiency anemia.

PubMed

de Cássia Freitas, Karine; Amancio, Olga Maria Silvério; Ferreira Novo, Neil; Fagundes-Neto, Ulysses; de Morais, Mauro Batista

2006-10-01

The objective of this study was to evaluate the effect of partially hydrolyzed guar gum (PHGG) dietary fiber towards intestinal iron absorption, for dietary intake and on the growth of rats with iron deficiency anemia in comparison to those fed on a diet with cellulose and without dietary fiber. Male Wistar rats (n=24) weaned at 21 days were fed with AIN93-G diet without iron for 2 weeks in order to induce iron deficiency anemia. At 36 days old, the anemic rats were divided into three groups: (1) PHGG group-100g of PHGG per kg of diet; (2) Cellulose group-100g of cellulose per kg of diet; (3) Control group-diet without dietary fiber. All the diets had 25mg of elemental iron/kg of diet added to lead to recovery from iron deficiency anemia. The final hemoglobin values in g/dl, for the PHGG group, the cellulose group and the control group were, respectively: 11.3+/-1.2, 8.6+/-0.7 and 8.1+/-0.9 (P<0.001). The levels of hepatic iron, in mug/g of dry tissue, in the same order, were: 322.2+/-66.6, 217.2+/-59.1 and 203.7+/-42.4 (P<0.001). Apparent iron intestinal absorption was, respectively: 67.5+/-8.9%, 35.4+/-15.3% and 31.3+/-24.9% (P<0.001). The three groups consumed similar quantities of diet. The changes in weight and in body length were similar in the three groups studied. PHGG led to greater intestinal absorption of iron, regeneration of hemoglobin and hepatic levels of iron than diet with cellulose and diet control.

Mechanistic Fluid Transport Model to Estimate Gastrointestinal Fluid Volume and Its Dynamic Change Over Time.

PubMed

Yu, Alex; Jackson, Trachette; Tsume, Yasuhiro; Koenigsknecht, Mark; Wysocki, Jeffrey; Marciani, Luca; Amidon, Gordon L; Frances, Ann; Baker, Jason R; Hasler, William; Wen, Bo; Pai, Amit; Sun, Duxin

2017-11-01

Gastrointestinal (GI) fluid volume and its dynamic change are integral to study drug disintegration, dissolution, transit, and absorption. However, key questions regarding the local volume and its absorption, secretion, and transit remain unanswered. The dynamic fluid compartment absorption and transit (DFCAT) model is proposed to estimate in vivo GI volume and GI fluid transport based on magnetic resonance imaging (MRI) quantified fluid volume. The model was validated using GI local concentration of phenol red in human GI tract, which was directly measured by human GI intubation study after oral dosing of non-absorbable phenol red. The measured local GI concentration of phenol red ranged from 0.05 to 168 μg/mL (stomach), to 563 μg/mL (duodenum), to 202 μg/mL (proximal jejunum), and to 478 μg/mL (distal jejunum). The DFCAT model characterized observed MRI fluid volume and its dynamic changes from 275 to 46.5 mL in stomach (from 0 to 30 min) with mucus layer volume of 40 mL. The volumes of the 30 small intestine compartments were characterized by a max of 14.98 mL to a min of 0.26 mL (0-120 min) and a mucus layer volume of 5 mL per compartment. Regional fluid volumes over 0 to 120 min ranged from 5.6 to 20.38 mL in the proximal small intestine, 36.4 to 44.08 mL in distal small intestine, and from 42 to 64.46 mL in total small intestine. The DFCAT model can be applied to predict drug dissolution and absorption in the human GI tract with future improvements.

Ferroportin mediates the intestinal absorption of iron from a nanoparticulate ferritin core mimetic in mice

PubMed Central

Aslam, Mohamad F.; Frazer, David M.; Faria, Nuno; Bruggraber, Sylvaine F. A.; Wilkins, Sarah J.; Mirciov, Cornel; Powell, Jonathan J.; Anderson, Greg J.; Pereira, Dora I. A.

2014-01-01

The ferritin core is composed of fine nanoparticulate Fe3+ oxohydroxide, and we have developed a synthetic mimetic, nanoparticulate Fe3+ polyoxohydroxide (nanoFe3+). The aim of this study was to determine how dietary iron derived in this fashion is absorbed in the duodenum. Following a 4 wk run-in on an Fe-deficient diet, mice with intestinal-specific disruption of the Fpn-1 gene (Fpn-KO), or littermate wild-type (WT) controls, were supplemented with Fe2+ sulfate (FeSO4), nanoFe3+, or no added Fe for a further 4 wk. A control group was Fe sufficient throughout. Direct intestinal absorption of nanoFe3+ was investigated using isolated duodenal loops. Our data show that FeSO4 and nanoFe3+ are equally bioavailable in WT mice, and at wk 8 the mean ± sem hemoglobin increase was 18 ± 7 g/L in the FeSO4 group and 30 ± 5 g/L in the nanoFe3+ group. Oral iron failed to be utilized by Fpn-KO mice and was retained in enterocytes, irrespective of the iron source. In summary, although nanoFe3+ is taken up directly by the duodenum its homeostasis is under the normal regulatory control of dietary iron absorption, namely via ferroportin-dependent efflux from enterocytes, and thus offers potential as a novel oral iron supplement.—Aslam, M. F., Frazer, D. M., Faria, N., Bruggraber, S. F. A., Wilkins, S. J., Mirciov, C., Powell, J. J., Anderson, G. J., Pereira, D. I. A. Ferroportin mediates the intestinal absorption of iron from a nanoparticulate ferritin core mimetic in mice. PMID:24776745

Investigations into the absorption of insulin and insulin derivatives from the small intestine of the anaesthetised rat.

PubMed

McGinn, B J; Morrison, J D

2016-06-28

Experiments have been undertaken to determine the extent to which cholic acid conjugates of insulin were absorbed from the small intestine of anaesthetised rats by means of the bile salt transporters of the ileum. The measure used to assess the absorption of the cholyl-insulins was the amount of hypoglycaemia following infusion into the small intestine. Control experiments involving infusion of natural insulin into the ileum showed either nil absorption or absorption of a small amount of insulin as indicated by transient dip in the blood glucose concentration. However, when insulin was co-infused with the bile salt taurocholate, this was followed by a marked hypoglycaemic response which was specific to the ileum and did not occur on infusion into the jejunum. When the two cholyl conjugates of insulin were tested viz. B(29)-Lys-cholyl-insulin and B(1)-Phe-cholyl-insulin, both were biologically active as indicated by hypoglycaemic responses on systemic injection, though their potency was about 40% of that of natural insulin. While there was no evidence for the absorption of B(29)-Lys-cholyl-insulin when infused into the ileum, B(1)-Phe-cholyl-insulin did cause a long lasting hypoglycaemic response, indicating that absorption had occurred. Since the hypoglycaemic response was blocked on co-infusion with taurocholate and was absent for infusion of the conjugate into the jejunum, these results were taken as evidence that B(1)-Phe-cholyl-insulin had been taken up by the ileal bile salt transporters. This would indicate that B(1)-Phe-cholyl-insulin is worthy of further investigation for use in an oral insulin formulation. Copyright © 2016. Published by Elsevier B.V.

Absorption kinetics of vitamin E nanoemulsion and green tea microstructures by intestinal in situ single perfusion technique in rats.

PubMed

Saratale, Rijuta Ganesh; Lee, Hee-Seok; Koo, Yong Eui; Saratale, Ganesh Dattatraya; Kim, Young Jun; Imm, Jee Young; Park, Yooheon

2018-04-01

The absorption kinetics of food ingredients such as nanoemulsified vitamin E and green tea microstructures were evaluated by the intestinal in situ single perfusion technique. Absorption rate, sub-acute oral toxicity and organ morphology in a rat model were examined. The intestinal in situ single perfusion technique and HPLC analysis were applied to investigate the absorption rate of selected materials by examining time-dependent changes in the serum levels of catechin and dl-α-tocopherol. The acute toxicity test and histopathological evaluation were applied to analyze the safety of microsized green tea and nanosized vitamin E in a rat model. Total serum dl-α-tocopherol levels significantly increased with nanosized vitamin E administration (P<0.05). Rats treated to nanosized vitamin E until 90min after administration showed significantly increased absorption rate of serum dl-α-tocopherol levels at each time point (10min interval) (P<0.001). Rats administered 2000mg/kg of nanosized vitamin E and microsized green tea did not show signs of acute toxicity or death after 14days of observation. In addition, macroscopic analysis showed that there were no changes in representative organ sections of rats following the oral administration of food-related nanoscale materials. We successfully demonstrated that using nanosized vitamin E increased absorption rate to a greater extent than normal food-related material, and these results occurs via safety analyses on food-related nanoscale materials for human consumption. These results could be useful for the design and development of novel nanoemulsified vitamin E and microsized green tea formulations that can overcome the problem of their bioavailability and improve their efficacy while still maintaining their essential therapeutic efficacies. Copyright © 2018 Elsevier Ltd. All rights reserved.

The effect of wheat prebiotics on the gut bacterial population and iron status of iron deficient broiler chickens

USDA-ARS?s Scientific Manuscript database

In recent years, there is a lot of interest in improving the intestinal health, and consequently increasing minerals as iron absorption, by managing the intestinal microbial population. This is traditionally done by the consumption of probiotics, which are live microbial food supplements. However, a...

Tight junction gene expression in gastrointestinal tract of dairy calves with coccidiosis and treated with glucagon-like peptide-2

USDA-ARS?s Scientific Manuscript database

Selective permeability of the intestinal epithelium and efficient nutrient absorption are important functions for proper growth and development of calves. Damage to the intestinal mucosa can give rise to harmful long-term health effects and reduce productivity of the mature animal. Tight junction pr...

Glucose Transport into Everted Sacs of the Small Intestine of Mice

ERIC Educational Resources Information Center

Hamilton, Kirk L.; Butt, A. Grant

2013-01-01

The Na[superscript +]-glucose cotransporter is a key transport protein that is responsible for absorbing Na[superscript +] and glucose from the luminal contents of the small intestine and reabsorption by the proximal straight tubule of the nephron. Robert K. Crane originally described the cellular model of absorption of Na[superscript +] and…

Fostering Inflammatory Bowel Disease: Sphingolipid Strategies to Join Forces

PubMed Central

Abdel Hadi, Loubna; Di Vito, Clara; Riboni, Laura

2016-01-01

Complex sphingolipids are essential structural components of intestinal membranes, providing protection and integrity to the intestinal mucosa and regulating intestinal absorption processes. The role of sphingolipid signaling has been established in numerous cellular events, including intestinal cell survival, growth, differentiation, and apoptosis. A significant body of knowledge demonstrates that intestinal sphingolipids play a crucial role, as such and through their signaling pathways, in immunity and inflammatory disorders. In this review, we report on and discuss the current knowledge on the metabolism, signaling, and functional implications of sphingolipids in inflammatory bowel disease (IBD), focusing on the different aspects of sphingolipid actions on inflammatory responses and on the potential of sphingolipid-targeted molecules as anti-IBD therapeutic agents. PMID:26880864

New medications which decrease levothyroxine absorption.

PubMed

John-Kalarickal, Jennifer; Pearlman, Gwen; Carlson, Harold E

2007-08-01

Medications may sometimes interfere with the intestinal absorption of levothyroxine, primarily by forming an insoluble complex with the thyroid hormone in the intestinal lumen. The goal of this study was to examine the acute effects of three previously unstudied medications on levothyroxine absorption. We studied the effects of three medications on thyroxine absorption in seven normal volunteers. On each study day, the subjects ingested 1 mg levothyroxine sodium, either taken separately or co-administered with sevelamer hydrochloride (Renagel, a phosphate-binding medication used in the treatment of hyperphosphatemia), chromium picolinate (an over-the-counter nutritional supplement), or ezetimibe (Zetia, a drug used in the treatment of hypercholesterolemia). Serum thyroxine was measured at intervals over a 6-hour period following drug ingestion. Sevelamer hydrochloride and chromium picolinate each significantly (p < 0.05) decreased the area under the serum thyroxine concentration curve, while ezetimibe had no effect. Hypothyroid patients taking sevelamer hydrochloride or chromium picolinate should be advised to separate the time of ingestion of these drugs from their thyroid hormone preparation by several hours.

Changes of lipid and fatty acid absorption induced by high dose of citric acid ester and lecithin emulsifiers.

PubMed

Sadouki, Mohamed; Bouchoucha, Michel

2014-09-01

To describe the effect of two food emulsifiers, lecithin (E322) and citric acid esters of mono-and diglycerides of fatty acids (E472c), on the intestinal absorption of lipids. The experiment was conducted on 24 male Wistar rats randomly assigned in three groups. For two groups of six rats, 30% of the lipid intake was replaced with lecithin (L) or citric acid ester of mono and diglycerides, (E); the remaining 12 rats were the control group (C). Diet and fecal fat analysis was used to determine the apparent lipid absorption (ALA) and fatty acids. ALA was significantly lower in the group E than in the groups C and L (p < 0.001). ALA of long saturated chain fatty acids decreased while the length of the carbon chains increased, and this decrease was higher in the group E. E472c emulsifier decreased the intestinal absorption of lipids.

Topical methotrexate alters solute and water transport in the rat jejunum in vivo and rabbit ileum in vitro.

PubMed Central

Pinkerton, C R; Booth, I W; Milla, P J

1985-01-01

The topical effect of methotrexate (MTX) on small intestinal hexose and ion transport has been studied using an in vivo steady state jejunal perfusion technique in the rat, and short circuited rabbit terminal ileum in Ussing chambers in vitro. In rat jejunum, perfusion with MTX (1 mumol/l) caused significant reductions in water, sodium, and glucose absorption within 110 minutes of exposure. Fructose absorption was, however, unimpaired. The same concentration of MTX, when added to the mucosal side of distal rabbit ileum caused significant increases in transmucosal potential difference, short circuit current and the unidirectional flux of chloride from serosa to mucosa. In the presence of a subphysiological magnesium concentration (0.3 mmol/l), MTX resulted in the abolition of net sodium absorption and the conversion of net chloride absorption to secretion. We conclude that MTX has a topical effect on small intestinal transport which is independent of its effect on crypt cell kinetics. PMID:4018634

Altered small intestinal absorptive enzyme activities in leptin-deficient obese mice: influence of bowel resection.

PubMed

Kiely, James M; Noh, Jae H; Svatek, Carol L; Pitt, Henry A; Swartz-Basile, Deborah A

2006-07-01

Residual bowel increases absorption after massive small bowel resection. Leptin affects intestinal adaptation, carbohydrate, peptide, and lipid handling. Sucrase, peptidase, and acyl coenzyme A:monoacylglycerol acyltransferase (MGAT) are involved in carbohydrate, protein, and lipid absorption. We hypothesized that leptin-deficient obese mice would have altered absorptive enzymes compared with controls before and after small bowel resection. Sucrase, peptidase (aminopeptidase N [ApN], dipeptidyl peptidase IV [DPPIV]), and MGAT activities were determined from lean control (C57BL/6J, n = 16) and leptin-deficient (Lep(ob), n = 16) mice small bowel before and after 50% resection. Ileal sucrase activity was greater in obese mice before and after resection. Jejunal ApN and DPPIV activities were lower for obese mice before resection; ileal ApN activity was unaltered after resection for both strains. Resection increased DPPIV activity in both strains. Jejunal MGAT in obese mice decreased postresection. In both strains, ileal MGAT activity decreased after resection, and obese mice had greater activity in remnant ileum. After small bowel resection, leptin-deficient mice have increased sucrase activity and diminished ileal ApN, DPPIV, and MGAT activity compared with controls. Therefore, we conclude that leptin deficiency alters intestinal enzyme activity in unresected animals and after small bowel resection. Altered handling of carbohydrate, protein, and lipid may contribute to obesity and diabetes in leptin-deficient mice.

Lactobacillus acidophilus ATCC 4356 Prevents Atherosclerosis via Inhibition of Intestinal Cholesterol Absorption in Apolipoprotein E-Knockout Mice

PubMed Central

Wang, Jinfeng; Quan, Guihua; Wang, Xiaojun; Yang, Longfei; Zhong, Lili

2014-01-01

The objective of this study was to investigate the effect of Lactobacillus acidophilus ATCC 4356 on the development of atherosclerosis in apolipoprotein E-knockout (ApoE−/−) mice. Eight-week-old ApoE−/− mice were fed a Western diet with or without L. acidophilus ATCC 4356 daily for 16 weeks. L. acidophilus ATCC 4356 protected ApoE−/− mice from atherosclerosis by reducing their plasma cholesterol levels from 923 ± 44 to 581 ± 18 mg/dl, likely via a marked decrease in cholesterol absorption caused by modulation of Niemann-Pick C1-like 1 (NPC1L1). In addition, suppression of cholesterol absorption induced reverse cholesterol transport (RCT) in macrophages through the peroxisome proliferator-activated receptor/liver X receptor (PPAR/LXR) pathway. Fecal lactobacillus and bifidobacterium counts were significantly (P < 0.05) higher in the L. acidophilus ATCC 4356 treatment groups than in the control groups. Furthermore, L. acidophilus ATCC 4356 was detected in the rat small intestine, colon, and feces during the feeding trial. The bacterial levels remained high even after the administration of lactic acid bacteria had been stopped for 2 weeks. These results suggest that administration of L. acidophilus ATCC 4356 can protect against atherosclerosis through the inhibition of intestinal cholesterol absorption. Therefore, L. acidophilus ATCC 4356 may be a potential therapeutic material for preventing the progression of atherosclerosis. PMID:25261526

Loss of the anion exchanger DRA (Slc26a3), or PAT1 (Slc26a6), alters sulfate transport by the distal ileum and overall sulfate homeostasis.

PubMed

Whittamore, Jonathan M; Hatch, Marguerite

2017-09-01

The ileum is considered the primary site of inorganic sulfate ([Formula: see text]) absorption. In the present study, we explored the contributions of the apical chloride/bicarbonate (Cl - /[Formula: see text]) exchangers downregulated in adenoma (DRA; Slc26a3), and putative anion transporter 1 (PAT1; Slc26a6), to the underlying transport mechanism. Transepithelial 35 [Formula: see text] and 36 Cl - fluxes were determined across isolated, short-circuited segments of the distal ileum from wild-type (WT), DRA-knockout (KO), and PAT1-KO mice, together with measurements of urine and plasma sulfate. The WT distal ileum supported net sulfate absorption [197.37 ± 13.61 (SE) nmol·cm -2 ·h -1 ], but neither DRA nor PAT1 directly contributed to the unidirectional mucosal-to-serosal flux ([Formula: see text]), which was sensitive to serosal (but not mucosal) DIDS, dependent on Cl - , and regulated by cAMP. However, the absence of DRA significantly enhanced net sulfate absorption by one-third via a simultaneous rise in [Formula: see text] and a 30% reduction to the secretory serosal-to-mucosal flux ([Formula: see text]). We propose that DRA, together with PAT1, contributes to [Formula: see text] by mediating sulfate efflux across the apical membrane. Associated with increased ileal sulfate absorption in vitro, plasma sulfate was 61% greater, and urinary sulfate excretion ( U SO4 ) 2.2-fold higher, in DRA-KO mice compared with WT controls, whereas U SO4 was increased 1.8-fold in PAT1-KO mice. These alterations to sulfate homeostasis could not be accounted for by any changes to renal sulfate handling suggesting that the source of this additional sulfate was intestinal. In summary, we characterized transepithelial sulfate fluxes across the mouse distal ileum demonstrating that DRA (and to a lesser extent, PAT1) secretes sulfate with significant implications for intestinal sulfate absorption and overall homeostasis. NEW & NOTEWORTHY Sulfate is an essential anion that is actively absorbed from the small intestine involving members of the Slc26 gene family. Here, we show that the main intestinal chloride transporter Slc26a3, known as downregulated in adenoma (DRA), also handles sulfate and contributes to its secretion into the lumen. In the absence of functional DRA (as in the disease congenital chloride diarrhea), net intestinal sulfate absorption was significantly enhanced resulting in substantial alterations to overall sulfate homeostasis. Copyright © 2017 the American Physiological Society.

NPC1L1 and Cholesterol Transport

PubMed Central

Betters, Jenna L.; Yu, Liqing

2010-01-01

The polytopic transmembrane protein, Niemann-Pick C1-Like 1 (NPC1L1), is enriched in the apical membrane of small intestine absorptive enterocytes where it mediates extracellular sterol transport across the brush border membrane. It is essential for intestinal sterol absorption and is the molecular target of ezetimibe, a potent cholesterol absorption inhibitor that lowers blood cholesterol in humans. NPC1L1 is also highly expressed in human liver. The hepatic function of NPC1L1 may be to limit excessive biliary cholesterol loss. NPC1L1-dependent sterol uptake seems to be a clathrin-mediated endocytic process and is regulated by cellular cholesterol content. Recently, NPC1L1 inhibition has been shown to have beneficial effects on components of the metabolic syndrome, such as obesity, insulin resistance, fatty liver, in addition to atherosclerosis. PMID:20307540

Increased intestinal absorption in the rat caused by sodium lauryl sulphate, and its possible relation to the cAMP system.

PubMed

Briseid, G; Briseid, K; Kirkevold, K

1976-01-01

The increases in the absorption of ouabain, phenolsulphonphthalein and pralidoxime caused by 17 mM sodium lauryl sulphate (SLS) from jejunal loops of anaesthetized rats were significantly reduced if sodium and chloride (Briseid et al., 1974) or chloride and bicarbonate were replaced by other ions in the loop fluid. Separate substitutions of sodium, chloride of bicarbonate did not significantly alter the SLS-caused absorption, except that the substitution of choline for sodium reduced the absorption of pralidoxime, both in the presence and in the absence of SLS. The increases in the absorption of phenolsulphonphthalein and pralidoxime caused by SLS were potentiated by theophylline (25 mM) and reduced by imidazole (25 mM). The addition of dibutyryl cyclic AMP (2.5 mM) to the loop fluid increased this absorption of the test substances. This effect was reduced by imidazole, but under the experimental conditions it was not potentiated by theophylline. Determinations of cyclic AMP in the rat intestinal mucosa showed that the level of this substance was significantly higher in the presence than in the absence of SLS. The experimental conditions were as described for the absorption experiments. It is concluded that the data obtained support the idea of an increased level of cyclic AMP as the main basis for the effect of SLS on the absorption.

Dgat1 and Dgat2 regulate enterocyte triacylglycerol distribution and alter proteins associated with cytoplasmic lipid droplets in response to dietary fat

PubMed Central

Hung, Yu-Han; Carreiro, Alicia L.; Buhman, Kimberly K.

2017-01-01

Enterocytes, the absorptive cells of the small intestine, mediate efficient absorption of dietary fat (triacylglycerol, TAG). The digestive products of dietary fat are taken up by enterocytes, re-esterified into TAG, and packaged on chylomicrons (CMs) for secretion into blood or temporarily stored within cytoplasmic lipid droplets (CLDs). Altered enterocyte TAG distribution impacts susceptibility to high fat diet associated diseases, but molecular mechanisms directing TAG toward these fates are unclear. Two enzymes, acyl CoA: diacylglycerol acyltransferase 1 (Dgat1) and Dgat2, catalyze the final, committed step of TAG synthesis within enterocytes. Mice with intestine-specific overexpression of Dgat1 (Dgat1Int) or Dgat2 (Dgat2Int), or lack of Dgat1 (Dgat1−/−), were previously found to have altered intestinal TAG secretion and storage. We hypothesized that varying intestinal Dgat1 and Dgat2 levels alters TAG distribution in subcellular pools for CM synthesis as well as the morphology and proteome of CLDs. To test this we used ultrastructural and proteomic methods to investigate intracellular TAG distribution and CLD-associated proteins in enterocytes from Dgat1Int, Dgat2Int, and Dgat1−/− mice 2 hours after a 200 μl oral olive oil gavage. We found that varying levels of intestinal Dgat1 and Dgat2 altered TAG pools involved in CM assembly and secretion, the number or size of CLDs present in enterocytes, and the enterocyte CLD proteome. Overall, these results support a model where Dgat1 and Dgat2 function coordinately to regulate the process of dietary fat absorption by preferentially synthesizing TAG for incorporation into distinct subcellular TAG pools in enterocytes. PMID:28249764

Increasing the throughput and productivity of Caco-2 cell permeability assays using liquid chromatography-mass spectrometry: application to resveratrol absorption and metabolism.

PubMed

Li, Yongmei; Shin, Young Geun; Yu, Chongwoo; Kosmeder, Jerome W; Hirschelman, Wendy H; Pezzuto, John M; van Breemen, Richard B

2003-12-01

The Caco-2 cell monolayer permeability assay has become a standard model of human intestinal absorption and transport. This paper reviews recent progress in increasing the throughput of Caco-2 cell monolayer assays and in expanding the scope of this assay to include modeling intestinal drug metabolism. The state-of-the-art in Caco-2 cell monolayer permeability assays combines multi-well plates fitted with semi-permeable inserts on which Caco-2 cells have been cultured with liquid chromatography-mass spectrometry (LC-MS) or LC-tandem mass spectrometry (LC-MS-MS) for the quantitative analysis of test compounds and the identification of their intestinal metabolites. After reviewing the progress in increasing the throughput of Caco-2 cell monolayer assays for both modeling human intestinal permeability or transport and the metabolism of xenobiotic compounds, we demonstrate the application of LC-MS and LC-MS-MS to the measurement of resveratrol permeability and metabolism in the Caco-2 model. trans-Resveratrol (trans-3,5,4'-trihydroxystilbene) is a polyphenolic compound occurring in grapes, peanuts and other food sources, that is under investigation as a cancer chemoprevention agent. The apparent permeability coefficient for apical (AP) to basolateral (BL) movement of resveratrol was 2.0 x 10(-5)cm/sec. Resveratrol was not a substrate for P-glycoprotein or the multi-drug resistance associated proteins (MRP). No phase I metabolites were observed, but the phase II conjugates resveratrol-3-glucuronide and resveratrol-3-sulfate was identified based on LC-MS and LC-MS-MS analysis and comparison with synthetic standards. Although these data indicate that resveratrol diffuses rapidly across the intestinal epithelium, extensive phase II metabolism during absorption might reduce resveratrol bioavailability.

Intestinal transport: studies with isolated epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kimmich, G.A.

1979-12-01

Isolated intestinal epithelial cells have been extremely useful for characterizing the nature of intestinal absorption processes and for providing insight into the energetics of Na/sup +/-dependent transport systems. This report describes a number of experimental approaches which have been used for investigating the specific epithelial transport systems involved in sugar absorption, but provides information which ultimately should prove useful for characterizing a number of different intestinal transport events. Similar experiments should also prove useful for exploring the effect of environmental agents on the function of intestinal tissue. In the case of sugars, net absorption is accomplished via a mucosal, Na/supmore » +/-dependent concentrative transport system acting in sequence with a passive serosal system which does not require Na/sup +/. The serosal system limits the full gradient-forming capability of the muscosal system. Agents such as phloretin or cytochalasin B which inhibit serosal transport allow the cells to establish sugar gradients as high as 70 fold in contrast to 10 to 15 fold gradients observed for control cells. Sevety-fold sugar gradients cannot be explained in terms of the energy available in the electrochemical potential for Na/sup +/ if the Na/sub 2/: sugar coupling stoichiometry is 1:1 as commonly assumed. New information indicates that the true Na/sup +/:sugar stoichiometry is in fact 2:1. Flow of two Na/sup +/ ions per sugar molecule down the transmembrane electrochemical potential for Na/sup +/ provides more than sufficient energy to account for observed 70 fold sugar gradients. If flow of sugar by other routes could be completely inhibited, theoretical sugar gradients as high as 400 could be achieved assuming that the cells maintain a membrane potential of -36 mV as measured for intact tissue.« less

Amino acid derivatives of 5-ASA as novel prodrugs for intestinal drug delivery.

PubMed

Clerici, C; Gentili, G; Boschetti, E; Santucci, C; Aburbeh, A G; Natalini, B; Pellicciari, R; Morelli, A

1994-12-01

In an attempt to obtain site-specific delivery of 5-ASA in the intestinal tract, we have determined the extent of absorption and metabolism of a number of novel 5-ASA derivatives, namely, (N-L-glutamyl)-amino-2-salicylic acid (1), (N-L-aspartyl)-amino-2-salicylic-acid (2), 5-aminosalicyl-L-proline-L-leucine (3), and 5-(N-L-glutamyl)-aminosalicyl-L-proline-L-leucine (4), which are selectively cleaved by intestinal brush border aminopeptidase A and carboxypeptidases. These novel prodrugs, 5-ASA, and sulfasalazine were administered to adult Fisher rats (N = 30) and to animals that had undergone prior colostomy (N = 30). Urine and feces were collected at timed intervals for 48 hr and the metabolites, 5-ASA, and N-acetyl-5-ASA were measured by high-performance liquid chromatography. The absorption and metabolism of all compounds were essentially identical in colostomized and normal animals. 5-ASA exhibited a rapid proximal intestinal absorption as evidenced by the high cumulative urinary excretion (> 65%) and low fecal excretion. Sulfasalazine, as expected, exhibited a lower urinary recovery (< 35%) and higher fecal excretion of 5-ASA and its metabolite. The novel glutamate and aspartate derivatives (1 and 2) behaved similarly to sulfasalazine, while administration of the proline-leucine derivative (3) resulted in urinary and fecal recovery values intermediate with respect to those observed with 5-ASA and sulfasalazine. 5-(N-L-Glutamyl)-aminosalicyl-L-proline-L-leucine yielded the highest fecal recovery of 5-ASA and its N-acetyl derivative, indicating a more efficient delivery to the distal bowel. Amino acid derivatives of 5-ASA appear to be potentially useful prodrugs for the site-specific delivery of 5-ASA to different regions of the intestinal tract.

Dgat1 and Dgat2 regulate enterocyte triacylglycerol distribution and alter proteins associated with cytoplasmic lipid droplets in response to dietary fat.

PubMed

Hung, Yu-Han; Carreiro, Alicia L; Buhman, Kimberly K

2017-06-01

Enterocytes, the absorptive cells of the small intestine, mediate efficient absorption of dietary fat (triacylglycerol, TAG). The digestive products of dietary fat are taken up by enterocytes, re-esterified into TAG, and packaged on chylomicrons (CMs) for secretion into blood or temporarily stored within cytoplasmic lipid droplets (CLDs). Altered enterocyte TAG distribution impacts susceptibility to high fat diet associated diseases, but molecular mechanisms directing TAG toward these fates are unclear. Two enzymes, acyl CoA: diacylglycerol acyltransferase 1 (Dgat1) and Dgat2, catalyze the final, committed step of TAG synthesis within enterocytes. Mice with intestine-specific overexpression of Dgat1 (Dgat1 Int ) or Dgat2 (Dgat2 Int ), or lack of Dgat1 (Dgat1 -/- ), were previously found to have altered intestinal TAG secretion and storage. We hypothesized that varying intestinal Dgat1 and Dgat2 levels alters TAG distribution in subcellular pools for CM synthesis as well as the morphology and proteome of CLDs. To test this we used ultrastructural and proteomic methods to investigate intracellular TAG distribution and CLD-associated proteins in enterocytes from Dgat1 Int , Dgat2 Int , and Dgat1 -/- mice 2h after a 200μl oral olive oil gavage. We found that varying levels of intestinal Dgat1 and Dgat2 altered TAG pools involved in CM assembly and secretion, the number or size of CLDs present in enterocytes, and the enterocyte CLD proteome. Overall, these results support a model where Dgat1 and Dgat2 function coordinately to regulate the process of dietary fat absorption by preferentially synthesizing TAG for incorporation into distinct subcellular TAG pools in enterocytes. Copyright © 2017 Elsevier B.V. All rights reserved.

Extensive intestinal first-pass metabolism of arctigenin: evidenced by simultaneous monitoring of both parent drug and its major metabolites.

PubMed

Gao, Qiong; Zhang, Yufeng; Wo, Siukwan; Zuo, Zhong

2014-03-01

The current study aims to investigate intestinal absorption and metabolism of arctigenin (AR) through simultaneous monitoring of AR and its major metabolites in rat plasma. An UPLC/MS/MS assay was developed with chromatographic separation of all analytes achieved by a C18 Column (3.9mm×150mm, 3.5μm) and a gradient elution with acetonitrile and 0.1% formic acid within 9min. Sample extraction with acetonitrile was optimized to achieve satisfactory recovery for both AR and its major metabolites. The lower limit of quantification (LLOQ) for all analytes was 25ng/ml. The intra-day and inter-day precision and accuracy of each analyte at LLOQ and three quality control (QC) concentrations (low, middle and high) in rat plasma was within 15.0% RSD and 15.0% bias. The extraction recoveries were within the range of 83.8-94.0% for all analytes. The developed and validated assay was then applied to the absorption study of AR in both Caco-2 cell monolayer model and in situ single-pass rat intestinal perfusion model. High absorption permeability of AR was demonstrated in both models with Papp of (1.76±0.48)×10(-5) (A→B) (Caco-2) and Pblood of (8.6±3.0)×10(-6)cm/s (intestinal perfusion). Extensive first-pass metabolism of AR to arctigenic acid (AA) and arctigenin-4'-O-glucuronide (AG) was identified in rat intestinal perfusion study with Cummins's extraction ratios of 0.458±0.012 and 0.085±0.013, respectively. The current assay method demonstrated to be a practical tool for pharmacokinetics investigation of AR with complicated metabolism pathways and multiple metabolites. Copyright © 2013 Elsevier B.V. All rights reserved.

Development and Validation of an in vitro Experimental GastroIntestinal Dialysis Model with Colon Phase to Study the Availability and Colonic Metabolisation of Polyphenolic Compounds.

PubMed

Breynaert, Annelies; Bosscher, Douwina; Kahnt, Ariane; Claeys, Magda; Cos, Paul; Pieters, Luc; Hermans, Nina

2015-08-01

The biological effects of polyphenols depend on their mechanism of action in the body. This is affected by bioconversion by colon microbiota and absorption of colonic metabolites. We developed and validated an in vitro continuous flow dialysis model with colon phase (GastroIntestinal dialysis model with colon phase) to study the gastrointestinal metabolism and absorption of phenolic food constituents. Chlorogenic acid was used as model compound. The physiological conditions during gastrointestinal digestion were mimicked. A continuous flow dialysis system simulated the one-way absorption by passive diffusion from lumen to mucosa. The colon phase was developed using pooled faecal suspensions. Several methodological aspects including implementation of an anaerobic environment, adapted Wilkins Chalgren broth medium, 1.10(8) CFU/mL bacteria suspension as inoculum, pH adaptation to 5.8 and implementation of the dialysis system were conducted. Validation of the GastroIntestinal dialysis model with colon phase system showed a good recovery and precision (CV < 16 %). Availability of chlorogenic acid in the small intestinal phase (37 ± 3 %) of the GastroIntestinal dialysis model with colon phase is comparable with in vivo studies on ileostomy patients. In the colon phase, the human faecal microbiota deconjugated chlorogenic acid to caffeic acid, 3,4-dihydroxyphenyl propionic acid, 4-hydroxybenzoic acid, 3- or 4-hydroxyphenyl acetic acid, 2-methoxy-4-methylphenol and 3-phenylpropionic acid. The GastroIntestinal dialysis model with colon phase is a new, reliable gastrointestinal simulation system. It permits a fast and easy way to predict the availability of complex secondary metabolites, and to detect metabolites in an early stage after digestion. Isolation and identification of these metabolites may be used as references for in vivo bioavailability experiments and for investigating their bioactivity in in vitro experiments. Georg Thieme Verlag KG Stuttgart · New York.

Role of interleukin 10 in norfloxacin prevention of luminal free endotoxin translocation in mice with cirrhosis.

PubMed

Gómez-Hurtado, Isabel; Moratalla, Alba; Moya-Pérez, Ángela; Peiró, Gloria; Zapater, Pedro; González-Navajas, José M; Giménez, Paula; Such, José; Sanz, Yolanda; Francés, Rubén

2014-10-01

Bacterial endotoxin is present in patients with advanced cirrhosis and can induce an immunogenic response without an overt infection. Norfloxacin is a gram-negative bactericidal drug able to maintain low endotoxin levels and stimulate IL-10 production. We aimed at investigating the role of IL-10 in decreasing endotoxin absorption in cirrhotic mice treated with norfloxacin. Cirrhosis was induced by carbon tetrachloride or bile duct ligation in wild type and IL10-deficient mice with or without norfloxacin prior to an intragastrical administration of E. coli, K. pneumonia or E. faecalis. Spontaneous and induced bacterial translocation, free endotoxin and cytokine levels were evaluated in mesenteric lymph nodes. Intestinal permeability was followed by fluorimetry and barrier integrity markers were measured in disrupted intestinal samples. The inflammatory-modulating mechanism was characterized in purified intestinal mononuclear cells. Norfloxacin reduced spontaneous and induced MLN positive-cultures in wild type and IL-10-deficient animals. However, reduction of free endotoxin levels was associated with norfloxacin in wild type but not in IL-10-deficient mice. Wild type but not IL-10-deficient mice treated with norfloxacin significantly normalized intestinal permeability and improved gut barrier integrity markers. The toll-like receptor 4-mediated pro-inflammatory milieu was modulated by norfloxacin in a concentration-dependent manner in cultured intestinal mononuclear cells of wild type mice but not of IL-10-deficient mice. The restoration of IL-10 levels in IL-10-deficient animals reactivated the norfloxacin effect on inflammatory-modulation, gut barrier permeability, and luminal endotoxin absorption. Norfloxacin not only reduces gram-negative intestinal flora but also participates in an IL-10-driven modulation of gut barrier permeability, thus reducing luminal free endotoxin absorption in experimental cirrhosis. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Fluid mechanics of eating, swallowing and digestion - overview and perspectives.

PubMed

Engmann, Jan; Burbidge, Adam S

2013-02-26

From a very simplistic viewpoint, the human digestive system can be regarded as a long tube (with dramatic variations in diameter, cross-section, wall properties, pumping mechanisms, regulating valves and in-line sensors). We single out a few fluid mechanical phenomena along the trajectory of a food bolus from the mouth to the small intestine and discuss how they influence sensorial perception, safe transport, and nutrient absorption from a bolus. The focus is on lubrication flows between the tongue and palate, the oropharyngeal stage of swallowing and effects of flow on absorption in the small intestine. Specific challenges and opportunities in this research area are highlighted.

Changes in plasma glucose in Otsuka Long-Evans Tokushima Fatty rats after oral administration of maple syrup.

PubMed

Nagai, Noriaki; Yamamoto, Tetsushi; Tanabe, Wataru; Ito, Yoshimasa; Kurabuchi, Satoshi; Mitamura, Kuniko; Taga, Atsushi

2015-01-01

We investigate whether maple syrup is a suitable sweetener in the management of type 2 diabetes using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. The enhancement in plasma glucose (PG) and glucose absorption in the small intestine were lower after the oral administration of maple syrup than after sucrose administration in OLETF rats, and no significant differences were observed in insulin levels. These data suggested that maple syrup might inhibit the absorption of glucose from the small intestine and preventing the enhancement of PG in OLETF rats. Therefore, maple syrup might help in the prevention of type 2 diabetes.

Prediction of intestinal absorption and blood-brain barrier penetration by computational methods.

PubMed

Clark, D E

2001-09-01

This review surveys the computational methods that have been developed with the aim of identifying drug candidates likely to fail later on the road to market. The specifications for such computational methods are outlined, including factors such as speed, interpretability, robustness and accuracy. Then, computational filters aimed at predicting "drug-likeness" in a general sense are discussed before methods for the prediction of more specific properties--intestinal absorption and blood-brain barrier penetration--are reviewed. Directions for future research are discussed and, in concluding, the impact of these methods on the drug discovery process, both now and in the future, is briefly considered.

Transport, metabolism, and endosomal trafficking-dependent regulation of intestinal fructose absorption

PubMed Central

Patel, Chirag; Douard, Veronique; Yu, Shiyan; Gao, Nan; Ferraris, Ronaldo P.

2015-01-01

Dietary fructose that is linked to metabolic abnormalities can up-regulate its own absorption, but the underlying regulatory mechanisms are not known. We hypothesized that glucose transporter (GLUT) protein, member 5 (GLUT5) is the primary fructose transporter and that fructose absorption via GLUT5, metabolism via ketohexokinase (KHK), as well as GLUT5 trafficking to the apical membrane via the Ras-related protein-in-brain 11 (Rab11)a-dependent endosomes are each required for regulation. Introducing fructose but not lysine and glucose solutions into the lumen increased by 2- to 10-fold the heterogeneous nuclear RNA, mRNA, protein, and activity levels of GLUT5 in adult wild-type mice consuming chow. Levels of GLUT5 were >100-fold that of candidate apical fructose transporters GLUTs 7, 8, and 12 whose expression, and that of GLUT 2 and the sodium-dependent glucose transporter protein 1 (SGLT1), was not regulated by luminal fructose. GLUT5-knockout (KO) mice exhibited no facilitative fructose transport and no compensatory increases in activity and expression of SGLT1 and other GLUTs. Fructose could not up-regulate GLUT5 in GLUT5-KO, KHK-KO, and intestinal epithelial cell-specific Rab11a-KO mice. The fructose-specific metabolite glyceraldehyde did not increase GLUT5 expression. GLUT5 is the primary transporter responsible for facilitative absorption of fructose, and its regulation specifically requires fructose uptake and metabolism and normal GLUT5 trafficking to the apical membrane.—Patel, C., Douard, V., Yu, S., Gao, N., Ferraris, R. P. Transport, metabolism, and endosomal trafficking-dependent regulation of intestinal fructose absorption. PMID:26071406

Soybean extracts increase cell surface ZIP4 abundance and cellular zinc levels: a potential novel strategy to enhance zinc absorption by ZIP4 targeting.

PubMed

Hashimoto, Ayako; Ohkura, Katsuma; Takahashi, Masakazu; Kizu, Kumiko; Narita, Hiroshi; Enomoto, Shuichi; Miyamae, Yusaku; Masuda, Seiji; Nagao, Masaya; Irie, Kazuhiro; Ohigashi, Hajime; Andrews, Glen K; Kambe, Taiho

2015-12-01

Dietary zinc deficiency puts human health at risk, so we explored strategies for enhancing zinc absorption. In the small intestine, the zinc transporter ZIP4 functions as an essential component of zinc absorption. Overexpression of ZIP4 protein increases zinc uptake and thereby cellular zinc levels, suggesting that food components with the ability to increase ZIP4 could potentially enhance zinc absorption via the intestine. In the present study, we used mouse Hepa cells, which regulate mouse Zip4 (mZip4) in a manner indistinguishable from that in intestinal enterocytes, to screen for suitable food components that can increase the abundance of ZIP4. Using this ZIP4-targeting strategy, two such soybean extracts were identified that were specifically able to decrease mZip4 endocytosis in response to zinc. These soybean extracts also effectively increased the abundance of apically localized mZip4 in transfected polarized Caco2 and Madin-Darby canine kidney cells and, moreover, two apically localized mZip4 acrodermatitis enteropathica mutants. Soybean components were purified from one extract and soyasaponin Bb was identified as an active component that increased both mZip4 protein abundance and zinc levels in Hepa cells. Finally, we confirmed that soyasaponin Bb is capable of enhancing cell surface endogenous human ZIP4 in human cells. Our results suggest that ZIP4 targeting may represent a new strategy to improve zinc absorption in humans. © 2015 Authors; published by Portland Press Limited.

Enhancement of intestinal water absorption and sodium transport by glycerol in rats.

PubMed

Wapnir, R A; Sia, M C; Fisher, S E

1996-12-01

Glycerol (Gly) is a hydrophilic, absorbable, and energy-rich solute that could make water absorption more efficient. We investigated the use of Gly in a high-energy beverage containing corn syrup (CS) by using a small intestine perfusion procedure in the rat, an approach shown earlier to provide good preclinical information. The effectiveness of several formulations with Gly and CS was compared with commercial products and to experimental formulas where Gly substituted for glucose (Glc). The CS-Gly combination was more effective than preparations on the market containing sucrose and Glc-fructose syrups (G-P and G-L, respectively) in maintaining a net water absorption balance in the test jejunal segment [CS-Gly = 0.21 +/- 0.226, G-L = -1.516 +/- 0.467, and G-P = -0.299 +/- 0.106 (SE) microliter.min-1.cm-1 (P = 0.0113)] and in reducing sodium release into the lumen [CS-Gly = -133.2 +/- 16.2, G-L = -226.7 +/- 25.2, and G-P = -245.6 +/- 23.4 nmol.min-1.cm-1 (P = 0.0022)]. In other preparations, at equal CS concentrations (60 and 80 g/l, respectively), Gly clearly improved net water absorption over a comparable Glc-containing product [CS60-Gly = 0.422 +/- 0.136 and CS80-Gly = 0.666 +/- 0.378 vs. CS60-Glc = -0.282 +/- 0.200 and CS80-Glc = -1.046 +/- 0.480 microliters.min-1.cm-1 (P = 0.0019)]. On the basis of the data of this rat intestine perfusion model, Gly could be a useful ingredient in energy-rich beverages and might enhance fluid absorption in humans.

Mechanistic and regulatory aspects of intestinal iron absorption

PubMed Central

Gulec, Sukru; Anderson, Gregory J.

2014-01-01

Iron is an essential trace mineral that plays a number of important physiological roles in humans, including oxygen transport, energy metabolism, and neurotransmitter synthesis. Iron absorption by the proximal small bowel is a critical checkpoint in the maintenance of whole-body iron levels since, unlike most other essential nutrients, no regulated excretory systems exist for iron in humans. Maintaining proper iron levels is critical to avoid the adverse physiological consequences of either low or high tissue iron concentrations, as commonly occurs in iron-deficiency anemia and hereditary hemochromatosis, respectively. Exquisite regulatory mechanisms have thus evolved to modulate how much iron is acquired from the diet. Systemic sensing of iron levels is accomplished by a network of molecules that regulate transcription of the HAMP gene in hepatocytes, thus modulating levels of the serum-borne, iron-regulatory hormone hepcidin. Hepcidin decreases intestinal iron absorption by binding to the iron exporter ferroportin 1 on the basolateral surface of duodenal enterocytes, causing its internalization and degradation. Mucosal regulation of iron transport also occurs during low-iron states, via transcriptional (by hypoxia-inducible factor 2α) and posttranscriptional (by the iron-sensing iron-regulatory protein/iron-responsive element system) mechanisms. Recent studies demonstrated that these regulatory loops function in tandem to control expression or activity of key modulators of iron homeostasis. In health, body iron levels are maintained at appropriate levels; however, in several inherited disorders and in other pathophysiological states, iron sensing is perturbed and intestinal iron absorption is dysregulated. The iron-related phenotypes of these diseases exemplify the necessity of precisely regulating iron absorption to meet body demands. PMID:24994858

Comparison across Three Hybrid Lipid-Based Drug Delivery Systems for Improving the Oral Absorption of the Poorly Water-Soluble Weak Base Cinnarizine.

PubMed

Joyce, Paul; Yasmin, Rokhsana; Bhatt, Achal; Boyd, Ben J; Pham, Anna; Prestidge, Clive A

2017-11-06

Three state-of-the-art drug delivery vehicles engineered by nanostructuring lipid colloids within solid particle matrices were fabricated for the oral delivery of the poorly water-soluble, weak base, cinnarizine (CIN). The lipid and solid phase of each formulation was varied to systematically analyze the impact of key material characteristics, such as nanostructure and surface chemistry, on the in vitro and in vivo fate of CIN. The three systems formulated were: silica-stabilized lipid cubosomes (SSLC), silica-solid lipid hybrid (SSLH), and polymer-lipid hybrid (PLH) particles. Significant biopharmaceutical advantages were presented for CIN when solubilized in the polymer (poly(lactic-co-glycolic) acid; PLGA) and lipid phase of PLH particles compared to the lipid phases of SSLC and SSLH particles. In vitro dissolution in simulated intestinal conditions highlighted reduced precipitation of CIN when administered within PLH particles, given by a 4-5-fold improvement in the extent of CIN dissolution compared to the other delivery vehicles. Furthermore, CIN solubilization was enhanced 1.5-fold and 6-fold under simulated fasted state lipid digestion conditions when formulated with PLH particles compared to SSLH and SSLC particles, respectively. In vivo pharmacokinetics correlated well with in vitro solubilization data, whereby oral CIN bioavailability in rats, when encapsulated in the corresponding formulations, increased from SSLC < SSLH < PLH. The pharmacokinetic data obtained throughout this study indicated a synergistic effect between PLGA nanoparticles and lipid droplets in preventing CIN precipitation and thus, enhancing oral absorption. This synergy can be harnessed to efficiently deliver challenging poorly water-soluble, weak bases through oral administration.

Vitamin D endocrine system after short-term space flight

NASA Technical Reports Server (NTRS)

Rhoten, William B. (Principal Investigator); Sergeev, Igor N. (Principal Investigator)

1996-01-01

The exposure of the body to microgravity during space flight causes a series of well-documented changes in Ca(2+) metabolism, yet the cellular/molecular mechanisms leading to these changes are poorly understood. There is some evidence for microgravity-induced alterations in the vitamin D endocrine system, which is known to be primarily involved in the regulation of Ca(2+) metabolism. Vitamin D-dependent Ca(2+) binding proteins, or calbindins, are believed to have a significant role in maintaining cellular Ca(2+) homeostasis. We used immunocytochemical, biochemical and molecular approaches to analyze the expression of calbindin-D(sub 28k) and calbindin-D(sub 9k) in kidneys and intestines of rats flown for 9 days aboard the Spacelab 3 mission. The effects of microgravity on calbindins in rats in space vs. 'grounded' animals (synchronous Animal Enclosure Module controls and tail suspension controls) were compared. Exposure to microgravity resulted in a significant decrease in calbindin-D(sub 28k) content in kidneys and calbindin-D(sub 9k) in the intestine of flight and suspended animals, as measured by enzyme-linked immunosorbent assay (ELISA). Immunocytochemistry (ICC) in combination with quantitative computer image analysis was used to measure in situ the expression of calbindins in kidneys and intestine, and insulin in pancreas. There was a large decrease in the distal tubular cell-associated calbindin-D(sub 28k) and absorptive cell-associated calbindin-D(sub 9k) immunoreactivity in the space and suspension kidneys and intestine, as compared with matched ground controls. No consistent differences in pancreatic insulin immunoreactivity between space, suspension and ground controls was observed. There were significant correlations between results by quantitative ICC and ELISA. Western blot analysis showed no consistent changes in the low levels of intestinal and renal vitamin D receptors. These findings suggest that a decreased expression of calbindins after a short-term exposure to microgravity and modelled weightlessness, may affect cellular Ca(2+) homeostasis and contribute to Ca(2+) and bone metabolism disorders induced by space flight.

Expression of a novel isoform of Na+/H+ exchanger 3 in the kidney and intestine of banded houndshark, Triakis scyllium

PubMed Central

Li, Shanshan; Takabe, Souichirou; Chen, An-Ping; Romero, Michael F.; Umezawa, Takahiro; Nakada, Tsutomu; Hyodo, Susumu; Hirose, Shigehisa

2013-01-01

Na+/H+ exchanger 3 (NHE3) provides one of the major Na+ absorptive pathways of the intestine and kidney in mammals, and recent studies of aquatic vertebrates (teleosts and elasmobranchs) have demonstrated that NHE3 is expressed in the gill and plays important roles in ion and acid-base regulation. To understand the role of NHE3 in elasmobranch osmoregulatory organs, we analyzed renal and intestinal expressions and localizations of NHE3 in a marine elasmobranch, Japanese banded houndshark (Triakis scyllium). mRNA for Triakis NHE3 was most highly expressed in the gill, kidney, spiral intestine, and rectum. The kidney and intestine expressed a transcriptional isoform of NHE3 (NHE3k/i), which has a different amino terminus compared with that of NHE3 isolated from the gill (NHE3g), suggesting that NHE3k/i and NHE3g arise from a single gene by alternative promoter usage. Immunohistochemical analyses of the Triakis kidney demonstrated that NHE3k/i is expressed in the apical membrane of a part of the proximal and late distal tubules in the sinus zone. In the bundle zone of the kidney, NHE3k/i was expressed in the apical membrane of the early distal tubules known as the diluting segment. In the spiral intestine and rectum, NHE3k/i was localized toward the apical membrane of the epithelial cells. The transcriptional levels of NHE3k/i were increased in the kidney when Triakis was acclimated in 130% seawater, whereas those in the spiral intestine were increased in fish acclimated in diluted seawater. These results suggest that NHE3 is involved in renal Na+ reabsorption, urine acidification, and intestinal Na+ absorption in elasmobranchs. PMID:23485868

Deletion of the Intestinal Plasma Membrane Calcium Pump, Isoform 1, Atp2b1, in Mice is Associated with Decreased Bone Mineral Density and Impaired Responsiveness to 1, 25-Dihydroxyvitamin D3

PubMed Central

Ryan, Zachary C.; Craig, Theodore A.; Filoteo, Adelaida G.; Westendorf, Jennifer J.; Cartwright, Elizabeth J.; Neyses, Ludwig; Strehler, Emanuel E.; Kumar, Rajiv

2016-01-01

The physiological importance of the intestinal plasma membrane calcium pump, isoform 1, (Pmca1, Atp2b1), in calcium absorption and homeostasis has not been previously demonstrated in vivo. Since global germ-line deletion of the Pmca1 in mice is associated with embryonic lethality, we selectively deleted the Pmca1 in intestinal absorptive cells. Mice with loxP sites flanking exon 2 of the Pmca1 gene (Pmca1fl/fl) were crossed with mice expressing Cre recombinase in the intestine under control of the villin promoter to give mice in which the Pmca1 had been deleted in the intestine (Pmca1EKO mice). Pmca1EKO mice were born at a reduced frequency and were small at the time of birth when compared to wild-type (Wt) litter mates. At two months of age, Pmca1EKO mice fed a 0.81% calcium, 0.34% phosphorus, normal vitamin D diet had reduced whole body bone mineral density (P <0.037), and reduced femoral bone mineral density (P <0.015). There was a trend towards lower serum calcium and higher serum parathyroid hormone (PTH) and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) concentrations in Pmca1EKO mice compared to Wt mice but the changes were not statistically significant. The urinary phosphorus/creatinine ratio was increased in Pmca1EKO mice (P <0.004). Following the administration of 200 ng of 1α,25(OH)2D3 intraperitoneally to Wt mice, active intestinal calcium transport increased ∼2-fold, whereas Pmca1EKO mice administered an equal amount of 1α,25(OH)2D3 failed to show an increase in active calcium transport. Deletion of the Pmca1 in the intestine is associated with reduced growth and bone mineralization, and a failure to up-regulate calcium absorption in response to 1α,25(OH)2D3. PMID:26392310

The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes.

PubMed

Rubino, Francesco; Forgione, Antonello; Cummings, David E; Vix, Michel; Gnuli, Donatella; Mingrone, Geltrude; Castagneto, Marco; Marescaux, Jacques

2006-11-01

Most patients who undergo Roux-en-Y gastric bypass (RYGB) experience rapid resolution of type 2 diabetes. Prior studies indicate that this results from more than gastric restriction and weight loss, implicating the rearranged intestine as a primary mediator. It is unclear, however, if diabetes improves because of enhanced delivery of nutrients to the distal intestine and increased secretion of hindgut signals that improve glucose homeostasis, or because of altered signals from the excluded segment of proximal intestine. We sought to distinguish between these two mechanisms. Goto-Kakizaki (GK) type 2 diabetic rats underwent duodenal-jejunal bypass (DJB), a stomach-preserving RYGB that excludes the proximal intestine, or a gastrojejunostomy (GJ), which creates a shortcut for ingested nutrients without bypassing any intestine. Controls were pair-fed (PF) sham-operated and untreated GK rats. Rats that had undergone GJ were then reoperated to exclude the proximal intestine; and conversely, duodenal passage was restored in rats that had undergone DJB. Oral glucose tolerance (OGTT), food intake, body weight, and intestinal nutrient absorption were measured. There were no differences in food intake, body weight, or nutrient absorption among surgical groups. DJB-treated rats had markedly better oral glucose tolerance compared with all control groups as shown by lower peak and area-under-the-curve glucose values (P < 0.001 for both). GJ did not affect glucose homeostasis, but exclusion of duodenal nutrient passage in reoperated GJ rats significantly improved glucose tolerance. Conversely, restoration of duodenal passage in DJB rats reestablished impaired glucose tolerance. This study shows that bypassing a short segment of proximal intestine directly ameliorates type 2 diabetes, independently of effects on food intake, body weight, malabsorption, or nutrient delivery to the hindgut. These findings suggest that a proximal intestinal bypass could be considered for diabetes treatment and that potentially undiscovered factors from the proximal bowel might contribute to the pathophysiology of type 2 diabetes.

The contribution of malabsorption to the reduction in net energy absorption after long-limb Roux-en-Y gastric bypass.

PubMed

Odstrcil, Elizabeth A; Martinez, Juan G; Santa Ana, Carol A; Xue, Beiqi; Schneider, Reva E; Steffer, Karen J; Porter, Jack L; Asplin, John; Kuhn, Joseph A; Fordtran, John S

2010-10-01

Roux-en-Y gastric bypass (RYGB) restricts food intake, and when the Roux limb is elongated to 150 cm, the procedure is believed to induce malabsorption. Our objective was to measure total reduction in intestinal absorption of combustible energy after RYGB and the extent to which this was due to restriction of food intake or malabsorption of ingested macronutrients. Long-limb RYGB was performed in 9 severely obese patients. Dietary intake and intestinal absorption of fat, protein, carbohydrate, and combustible energy were measured before and at 2 intervals after bypass. By using coefficients of absorption to measure absorptive function, equations were developed to calculate the daily gram and kilocalorie quantities of ingested macronutrients that were not absorbed because of malabsorption or restricted food intake. Coefficients of fat absorption were 92 ± 1.3% before bypass, 72 ± 5.5% 5 mo after bypass, and 68 ± 8.7% 14 mo after bypass. There were no statistically significant effects of RYGB on protein or carbohydrate absorption coefficients, although protein coefficients decreased substantially in some patients. Five months after bypass, malabsorption reduced absorption of combustible energy by 124 ± 57 kcal/d, whereas restriction of food intake reduced energy absorption by 2062 ± 271 kcal/d. Fourteen months after bypass, malabsorption reduced energy absorption by 172 ± 60 kcal/d compared with 1418 ± 171 kcal/d caused by restricted food intake. On average, malabsorption accounted for ≈6% and 11% of the total reduction in combustible energy absorption at 5 and 14 mo, respectively, after this gastric bypass procedure.

Prevalence and Predictors of Intestinal Parasites among Food Handlers in Yebu Town, Southwest Ethiopia

PubMed Central

Tefera, Tamirat; Mebrie, Getye

2014-01-01

Background As a result of urbanization, eating and drinking from food service establishments is becoming a common practice in developing countries like Ethiopia, which increases the chances of food borne diseases. The health status and hygiene practices of food handlers are the major determinants of food contamination. In developing countries where there are poor regulatory systems for food hygiene, food handlers are often appointed without screening for possible infections associated with poor hygiene like intestinal parasites. Objective This study aimed at determining the prevalence and predictors of intestinal parasites and assessing the hygiene practices among food handlers in Yebu Town, southwest Ethiopia. Methods A cross-sectional study was conducted among a total of 118 food handlers in Yebu Town in January 2011. Fresh stool specimens were collected and processed using both direct wet mount and Formol ether concentration techniques. Results The overall prevalence of intestinal parasites among the study subjects was 44.1% (52/118). Ascaris lumbricoides and hookworm spp were the predominant parasites identified from the stool of study participants. Age above 35 years (AOR: 4.8, 95% CI: 1.1, 21.8), no regular practice of washing hands before a meal (AOR: 7.8, 95% CI: 2.8, 24.8), and untrimmed finger nail (AOR: 14.7, 95% CI: 2.8, 75.4) were independent predictors of intestinal parasitic infection among the food handlers. Conclusion The present study showed high prevalence of intestinal parasites among the study subjects. The study also revealed poor personal hygiene like poor practice of hand washing and poor finger nail hygiene. Therefore, much has to be done to improve the personal hygiene of the food handlers. Pre-placement and periodic screening of food handlers for parasites and prompt treatment, and health education on regular trimming or cleaning of fingernails would be the way forward for prevention of food borne diseases. PMID:25329050

Prevalence and predictors of intestinal parasites among food handlers in Yebu Town, southwest Ethiopia.

PubMed

Tefera, Tamirat; Mebrie, Getye

2014-01-01

As a result of urbanization, eating and drinking from food service establishments is becoming a common practice in developing countries like Ethiopia, which increases the chances of food borne diseases. The health status and hygiene practices of food handlers are the major determinants of food contamination. In developing countries where there are poor regulatory systems for food hygiene, food handlers are often appointed without screening for possible infections associated with poor hygiene like intestinal parasites. This study aimed at determining the prevalence and predictors of intestinal parasites and assessing the hygiene practices among food handlers in Yebu Town, southwest Ethiopia. A cross-sectional study was conducted among a total of 118 food handlers in Yebu Town in January 2011. Fresh stool specimens were collected and processed using both direct wet mount and Formol ether concentration techniques. The overall prevalence of intestinal parasites among the study subjects was 44.1% (52/118). Ascaris lumbricoides and hookworm spp were the predominant parasites identified from the stool of study participants. Age above 35 years (AOR: 4.8, 95% CI: 1.1, 21.8), no regular practice of washing hands before a meal (AOR: 7.8, 95% CI: 2.8, 24.8), and untrimmed finger nail (AOR: 14.7, 95% CI: 2.8, 75.4) were independent predictors of intestinal parasitic infection among the food handlers. The present study showed high prevalence of intestinal parasites among the study subjects. The study also revealed poor personal hygiene like poor practice of hand washing and poor finger nail hygiene. Therefore, much has to be done to improve the personal hygiene of the food handlers. Pre-placement and periodic screening of food handlers for parasites and prompt treatment, and health education on regular trimming or cleaning of fingernails would be the way forward for prevention of food borne diseases.

High rates of intestinal bicarbonate secretion in seawater tilapia (Oreochromis mossambicus).

PubMed

Ruiz-Jarabo, I; Gregório, S F; Gaetano, P; Trischitta, F; Fuentes, J

2017-05-01

Osmoregulation in fish is a complex process that requires the orchestrated cooperation of many tissues. In fish facing hyperosmotic environments, the intestinal absorption of some monovalent ions and the secretion of bicarbonate are key processes to favor water absorption. In the present study, we showed that bicarbonate levels in the intestinal fluid are several fold higher in seawater than in freshwater acclimated tilapia (Oreochromis mossambicus). In addition, we analyzed gene expression of the main molecular mechanisms involved in HCO 3 - movements i.e. slc26a6, slc26a3, slc4a4 and v-type H-ATPase sub C in the intestine of tilapia acclimated to both seawater and freshwater. Our results show an anterior/posterior functional regionalization of the intestine in tilapia in terms of expression patterns, which is affected by environmental salinity mostly in the anterior and mid intestine. Analysis of bicarbonate secretion using pH-Stat in tissues mounted in Ussing chambers reveals high rates of bicarbonate secretion in tilapia acclimated to seawater from anterior intestine to rectum ranging between ~900 and ~1700nmolHCO 3 - cm -2 h -1 . However, a relationship between the expression of slc26a6, slc26a3, slc4a4 and the rate of bicarbonate secretion seems to be compromised in the rectum. In this region, the low expression of the bicarbonate transporters could not explain the high bicarbonate secretion rates here described. However, we postulate that the elevated v-type H-ATPase mRNA expression in the rectum could be involved in this process. Copyright © 2017 Elsevier Inc. All rights reserved.

Expression profiling of the solute carrier gene family in chicken intestine from the late embryonic to early post-hatch stages.

PubMed

Li, H; Gilbert, E R; Zhang, Y; Crasta, O; Emmerson, D; Webb, K E; Wong, E A

2008-08-01

Intestinal development during late embryogenesis and early post-hatch has a long-term influence on digestive and absorptive capacity in chickens. The objective of this research was to obtain a global view of intestinal solute carrier (SLC) gene family member expression from late embryogenesis until 2 weeks post-hatch with a focus on SLC genes involved in uptake of sugars and amino acids. Small intestine samples from male chicks were collected on embryonic days 18 (E18) and 20 (E20), day of hatch and days 1, 3, 7 and 14 post-hatch. The expression profiles of 162 SLC genes belonging to 41 SLC families were determined using Affymetrix chicken genome microarrays. The majority of SLC genes showed little or no difference in level of expression during E18-D14. A number of well-known intestinal transporters were upregulated between E18 and D14 including the amino acid transporters rBAT, y(+)LAT-2 and EAAT3, the peptide transporter PepT1 and the sugar transporters SGLT1, GLUT2 and GLUT5. The amino acid transporters CAT-1 and CAT-2 were downregulated. In addition, several glucose and amino acid transporters that are novel to our understanding of nutrient absorption in the chicken intestine were discovered through the arrays (SGLT6, SNAT1, SNAT2 and AST). These results represent a comprehensive characterization of the expression profiles of the SLC family of genes at different stages of development in the chicken intestine and lay the ground work for future nutritional studies.

Regional-dependent intestinal permeability and BCS classification: elucidation of pH-related complexity in rats using pseudoephedrine.

PubMed

Fairstein, Moran; Swissa, Rotem; Dahan, Arik

2013-04-01

Based on its lower Log P value relative to metoprolol, a marker for the low/high-permeability (P(eff)) class boundary, pseudoephedrine was provisionally classified as BCS low-permeability compound. On the other hand, following oral administration, pseudoephedrine fraction dose absorbed (F(abs)) and systemic bioavailability approaches 100%. This represents a challenge to the generally recognized P(eff)-F(abs) correlation. The purpose of this study was to elucidate the underlying mechanisms behind the confusion in pseudoephedrine's BCS classification. Pseudoephedrine's BCS solubility class was determined, and its physicochemical properties and intestinal permeability were thoroughly investigated, both in vitro and in vivo in rats, considering the complexity of the whole of the small intestine. Pseudoephedrine was found to be unequivocally a high-solubility compound. All of the permeability studies revealed similar phenomenon; at any given intestinal segment/pH, the permeability of metoprolol was higher than that of pseudoephedrine, however, as the intestinal region becomes progressively distal, and the pH gradually increases, pseudoephedrine's permeability rises above that of metoprolol in the former segment. This unique permeability pattern likely explains pseudoephedrine's complete absorption. In conclusion, pseudoephedrine is a BCS Class I compound; no discrepancy between P(eff) and F(abs) is involved in its absorption. Rather, it reflects the complexity behind P(eff) when considering the whole of the intestine. We propose to allow high-permeability classification to drugs with P(eff) that matches/exceeds the low/high class benchmark anywhere throughout the intestinal tract and not restricted necessarily to the jejunum.

Intestinal and Blood-Brain Barrier Permeability of Ginkgolides and Bilobalide: In Vitro and In Vivo Approaches

USDA-ARS?s Scientific Manuscript database

In this study intestinal and blood brain barrier (BBB) transport of ginkgolides A, B, C, J and bilobalide, isolated from Ginkgo biloba (Family-Ginkgoaceae), was evaluated in Caco-2 and MDR1-MDCK cell monolayer models. Transepithelial transport was examined for 2 hours in both absorptive and secretor...

Cefuroxime axetil solid dispersion with polyglycolized glycerides for improved stability and bioavailability.

PubMed

Dhumal, Ravindra S; Biradar, Shailesh V; Aher, Suyog; Paradkar, Anant R

2009-06-01

Cefuroxime axetil (CA), a poorly soluble, broad spectrum cephalosporin ester prodrug, is hydrolysed by intestinal esterase prior to absorption, leading to poor and variable bioavailability. The objective was therefore to formulate a stable amorphous solid dispersion of the drug with enhanced solubility and stability against enzymatic degradation. Spray drying was used to obtain a solid dispersion of CA with Gelucire 50/13 and Aerosil 200 (SDCAGA), and a solid dispersion of CA with polyvinyl pyrrolidone (SDCAP); amorphous CA (ACA) was obtained by spray drying CA alone. The formulations were characterized by differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy and Fourier transform infrared spectroscopy studies, and compared for solubility, dissolution and bioavailability in rats. SDCAP and SDCAGA showed improved solubility and dissolution profiles owing to amorphization and formation of solid dispersions with hydrophilic carriers. The improved stability of amorphous CA in solid dispersions compared to ACA alone was attributed to hydrogen bonding interactions involving the amide of CA with the carbonyl of polyvinyl pyrrolidone in SDCAP, whereas in SDCAGA the interactions were at multiple sites involving the amide and carbonyl of CA with the carbonyl and hydroxyl of Gelucire 50/13. However, SDCAGA showed superior bioavailability compared to SDCAP, ACA and CA. Improvement in physical stability of solid dispersions was attributed to hydrogen bonding, while improvement in bioavailability of SDCAGA compared to SDCAP, in spite of comparable solubility and dissolution profile, may be attributed to Gelucire, which utilizes intestinal esterase for lipolysis, protecting the prodrug from enzymatic degradation to its non-absorbable base form.

Mechanisms of calcium transport in small intestine. Overall review of the contract, September 1, 1972--March 1, 1976

DOE Office of Scientific and Technical Information (OSTI.GOV)

DeLuca, H.F.

1976-01-01

Progress is reported in the following areas of research: role of high molecular weight protein in calcium transport in vitamin D deficient chicks; subcellular localization of 1,25-(OH)/sub 2/D/sub 3/; receptor proteins for 1,25-(OH)/sub 2/D/sub 3/; effects of high calcium diet, strontium diet, EHDP, and parathyroidectomy on intestinal calcium transport in chicks; effects of analogs of 1,25-(OH)/sub 2/D/sub 3/ on intestinal calcium transport; discrimination by chicks against vitamin D/sub 2/ compounds by metabolism; effects of extract of Solanum malacoxylan on intestinal calcium absorption in nephrectomized rats; and role of vitamin D in phosphate transport reactions in the intestine. (HLW)

A Novel Local Recycling Mechanism That Enhances Enteric Bioavailability of Flavonoids and Prolongs Their Residence Time in the Gut

PubMed Central

Xia, Bijun; Zhou, Qiong; Zheng, Zhijie; Ye, Ling; Hu, Ming; Liu, Zhongqiu

2013-01-01

Recycling in the gastrointestinal tract is important for endogenous substances such as bile acids and for xenobiotics such as flavonoids. Although both enterohepatic and enteric recycling mechanisms are well recognized, no one has discussed the third recycling mechanism for glucuronides: local recycling. The intestinal absorption and metabolism of wogonin and wogonoside (wogonin-7-glucuronide) was characterized by using a four-site perfused rat intestinal model, and hydrolysis of wogonoside was measured in various enzyme preparations. In the perfusion model, the wogonoside and wogonin were inter-converted in all four perfused segments. Absorption of wogonoside and conversion to its aglycone at upper small intestine was inhibited in the presence of a glucuronidase inhibitor (saccharolactone) but was not inhibited by a LPH inhibitor gluconolactone or antibiotics. Further investigation indicated that hydrolysis of wogonoside in the blank intestinal perfusate was not correlated with bacteria counts. Kinetic studies indicated that Km values from blank duodenal and jejunal perfusate were essentially identical to the Km values from intestinal S9 fraction but were much higher (>2-fold) than those from the microbial enzyme extract. Lastly, jejunal perfusate and S9 fraction share the same optimal pH, which was different from those of fecal extract. In conclusion, local recycling of wogonin and wogonoside is the first demonstrated example that this novel mechanism is functional in the upper small intestine without significant contribution from bacteria β-glucuronidase. PMID:23033922

A novel local recycling mechanism that enhances enteric bioavailability of flavonoids and prolongs their residence time in the gut.

PubMed

Xia, Bijun; Zhou, Qiong; Zheng, Zhijie; Ye, Ling; Hu, Ming; Liu, Zhongqiu

2012-11-05

Recycling in the gastrointestinal tract is important for endogenous substances such as bile acids and for xenobiotics such as flavonoids. Although both enterohepatic and enteric recycling mechanisms are well recognized, no one has discussed the third recycling mechanism for glucuronides: local recycling. The intestinal absorption and metabolism of wogonin and wogonoside (wogonin-7-glucuronide) was characterized by using a four-site perfused rat intestinal model, and hydrolysis of wogonoside was measured in various enzyme preparations. In the perfusion model, the wogonoside and wogonin were interconverted in all four perfused segments. Absorption of wogonoside and conversion to its aglycon at the upper small intestine was inhibited in the presence of a glucuronidase inhibitor (saccharolactone) but was not inhibited by lactase phlorizin hydrolase (LPH) inhibitor gluconolactone or antibiotics. Further investigation indicated that hydrolysis of wogonoside in the blank intestinal perfusate was not correlated with bacterial counts. Kinetic studies indicated that K(m) values from blank duodenal and jejunal perfusate were essentially identical to the K(m) values from intestinal S9 fraction but were much higher (>2-fold) than those from the microbial enzyme extract. Lastly, jejunal perfusate and S9 fraction share the same optimal pH, which was different from those of fecal extract. In conclusion, local recycling of wogonin and wogonoside is the first demonstrated example that this novel mechanism is functional in the upper small intestine without significant contribution from bacteria β-glucuronidase.

A vegetable oil feeding history affects digestibility and intestinal fatty acid uptake in juvenile rainbow trout Oncorhynchus mykiss.

PubMed

Geurden, Inge; Jutfelt, Fredrik; Olsen, Rolf-Erik; Sundell, Kristina S

2009-04-01

Future expansion of aquaculture relies on the use of alternatives to fish oil in fish feed. This study examined to what extent the nature of the feed oil affects intestinal lipid uptake properties in rainbow trout. The fish were fed a diet containing fish (FO), rapeseed (RO) or linseed (LO) oil for 8 weeks after which absorptive properties were assessed. Differences in digestibility due to feed oil history were measured using diet FO with an indigestible marker. Intestinal integrity, paracellular permeability, in vitro transepithelial fatty acid transport (3H-18:3n-3 and 14C-16:0) and their incorporation into intestinal epithelia were compared using Ussing chambers. Feed oil history did not affect the triacylglycerol/phosphatidylcholine ratio (TAG/PC) of the newly synthesized lipids in the segments. The lower TAG/PC ratio with 16:0 (2:1) than with 18:3 (10:1) showed the preferential incorporation of 16:0 into polar lipids. The FO-feeding history decreased permeability and increased transepithelial resistance of the intestinal segments. Transepithelial passage rates of 18:3n-3 were higher when pre-fed LO compared to RO or FO. Similarly, pre-feeding LO increased apparent lipid and fatty acid digestibilities compared to RO or FO. These results demonstrate that the absorptive intestinal functions in fish can be altered by the feed oil history and that the effect remains after a return to a standard fish oil diet.

Oxalate and Sucralose Absorption in Idiopathic Calcium Oxalate Stone Formers

PubMed Central

Knight, John; Jiang, Juquan; Wood, Kyle D.; Holmes, Ross P.; Assimos, Dean G.

2011-01-01

Objectives Oxalate has been hypothesized to undergo absorption in the large and small intestine by both paracellular and transepithelial transport. Sucralose is a chlorinated sugar that is absorbed by paracellular mechanisms. This study's objective was to better understand intestinal oxalate transport by correlating oxalate and sucralose absorption in idiopathic calcium oxalate stone formers. Methods Idiopathic calcium oxalate stone formers were recruited to provide urine specimens on both a self-selected diet and following a meal containing 90 mg of 13C2-oxalate and 5 grams of sucralose, and a stool sample for determination of Oxalobacter formigenes colonization. The 24 hour urine collections were fractionated into the first 6 hours and the subsequent 18 hours. Sucralose and oxalate excretion were measured during these periods and used to estimate absorption. Results A total of 38 subjects were evaluated. The majority of both the 13C2-oxalate and sucralose absorption occurred within the 0-6 hour collection. The 13C2-oxalate and sucralose absorptions were significantly correlated at the 0-6 hour, the 6-24 hour, and the total 24 hour time periods (p<0.04). All five oxalate hyperabsorbers(> 15% absorption) also absorbed significantly more sucralose during the 0-6 hour and whole 24 hour time points (p<0.04). Oxalobacter formigenes colonization did not significantly alter oxalate absorption. Conclusion The results suggest that the majority of oxalate is absorbed in the proximal portion of the gastrointestinal tract and that paracelluar transport is involved. Augmented paracellular transport, as evidenced by increased sucralose absorption, may also influence oxalate absorption. PMID:21676449

Characterizing intestinal strictures with acoustic resolution photoacoustic microscopy

NASA Astrophysics Data System (ADS)

Lei, Hao; Xu, Guan; Liu, Shengchun; Johnson, Laura A.; Moons, David S.; Higgins, Peter D. R.; Rice, Michael D.; Ni, Jun; Wang, Xueding

2016-03-01

Crohn's disease (CD) is an autoimmune disease, which may cause obstructing intestinal strictures due to inflammation, fibrosis (deposition of collagen), or a combination of both. Identifying the different stages of the disease progression is still challenging. In this work, we indicated the feasibility of non-invasively characterizing intestinal strictures using photoacoustic imaging (PAI), utilizing the uniquely optical absorption of hemoglobin and collagen. Surgically removed human intestinal stricture specimens were investigated with a prototype PAI system. 2D PA images with acoustic resolution at wavelength 532, 1210 and 1310 nm were formulated, and furthermore, the PA histochemical components images which show the microscopic distributions of histochemical components were solved. Imaging experiments on surgically removed human intestinal specimens has demonstrated the solved PA images were significantly different associated with the presence of fibrosis, which could be applied to characterize the intestinal strictures for given specimens.

Simple test of intestinal calcium absorption measured by stable strontium.

PubMed Central

Milsom, S; Ibbertson, K; Hannan, S; Shaw, D; Pybus, J

1987-01-01

A clinical test of intestinal calcium absorption has been developed using non-radioactive stable strontium as a calcium tracer. In nine elderly subjects there was a close correlation between the fractional absorption of strontium and radioactive calcium (45Ca) during a five hour period after the simultaneous oral administration of the two tracers. Comparable precision was achieved with each tracer in six subjects in whom the test was repeated after two weeks. The effect of food on strontium absorption was examined in a further 33 normal subjects (age 21-60 years), and the administration of the strontium with a standard breakfast was shown to reduce the variance at individual time points. A simplified test in which serum strontium concentration was measured four hours after the oral dose given with a standard breakfast was adopted as the routine procedure. The normal range (mean (2 SD], established over 97 tests in 53 patients, was 7.0-18.0% of the dose in the extracellular fluid. A further 30 patients with possible disorders of calcium absorption (10 with primary hyperparathyroidism and 20 with coeliac disease) were studied by this standard test. In both groups of patients the mean four hour strontium values were significantly different from normal. This standard strontium absorption test allows assessment of calcium absorption with sufficient sensitivity and precision to have a wide application in clinical practice. PMID:3115389

Drug-nutrient interactions: inhibition of amino acid intestinal absorption by fluoxetine.

PubMed

Urdaneta, E; Idoate, I; Larralde, J

1998-05-01

Fluoxetine is one of the most widely used antidepressants and nowadays it is also being used to manage obesity problems. In our laboratory we demonstrated that the drug inhibited sugar absorption (Monteiro et al. 1993). The aim of the present work was to determine the effect of fluoxetine on intestinal leucine absorption. Using a procedure of successive absorptions in vivo the drug diminished amino acid absorption by 30% (P < 0.001). Experiments in vitro in isolated jejunum also revealed a reduction in leucine uptake of 37% (P < 0.001). In both cases fluoxetine only affected mediated transport without altering diffusion. In a preparation enriched in basolateral membrane, fluoxetine inhibited the Na+,K(+)-ATPase (EC 3.6.1.37) activity (55%; P < 0.001) in a non-competitive manner with an inhibition constant (Ki) value of 0.92 mM. Leucine uptake by brush-border membrane vesicles was diminished by the drug (a reduction of 48% was observed at 30s, P < 0.001); only the apical Na(+)-dependent transport system of the amino acid was modified and the inhibition was non-competitive. Leucine uptake in the presence of lysine indicated that transporter B was involved. These results suggest that fluoxetine reduces leucine absorption by its action on the basolateral and apical membrane of the enterocyte; the nutritional status of the patients under drug treatment may be affected as neutral amino acid absorption is decreased.

Lycopene reduces cholesterol absorption through the downregulation of Niemann-Pick C1-like 1 in Caco-2 cells.

PubMed

Zou, Jun; Feng, Dan

2015-11-01

Elevated blood cholesterol is an important risk factor associated with atherosclerosis and coronary heart disease. Tomato lycopene has been found to have a hypocholesterolemic effect, and the effect was considered to be related to inhibition of cholesterol synthesis. However, since plasma cholesterol levels are also influenced by the absorption of cholesterol in the gut, the present study is to investigate whether lycopene affects cholesterol absorption in the intestinal Caco-2 cells. The Caco-2 cells were pretreated with lycopene at different concentrations for 24 h and then incubated with radioactive micellar cholesterol for 2 h. The absorption of radioactive cholesterol was quantified by liquid scintillation. The expression of Niemann-Pick C1-like 1 (NPC1L1) and liver X receptor α (LXRα) was analyzed by Western blot and qPCR. We found that lycopene dose dependently inhibited cholesterol absorption and the expression of NPC1L1 protein and NPC1L1 mRNA. The inhibitory effects of lycopene on cholesterol absorption and NPC1L1 expression could be prevented by blockade of the LXRα pathway. This study provides the first evidence that lycopene inhibits cholesterol absorption in the intestinal cells and this inhibitory effect of lycopene is mediated, at least in part, by LXRα-NPC1L1 signaling pathway. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Anatomical and histological characteristics of the intestine of the topmouth culter (Culter alburnus).

PubMed

Cao, X J; Wang, W M; Song, F

2011-08-01

With 3 figures and 1 table Topmouth culter (Culter alburnus), a freshwater carnivorous fish of the Cyprinidae, is one of the most popular fish species in aquatic market in China. The anatomy and histology features of fish intestine are very useful for understanding digestive physiology, diagnosing some intestinal diseases and formulating suitable feeds. Thus, here we first characterize topmouth culter intestine via light microscope, transmission electron microscope and scan electron microscope. The 'Z' shaped intestine can be divided into three parts (e.g. the anterior intestine, middle intestine and posterior intestine), with an intestinal coefficient of 0.68. The anterior intestine possessed the longest mucosa folds and thickest muscularis among the three intestinal parts, and microvilli were very well-developed whilst many mitochondria, endoplasmic reticulums and lysosomes were found in which. This indicated the anterior intestine was a main region for digestion and absorption of food in the topmouth culter. While the vacuoles observed in the posterior intestine may be closely related to the intracellular digestion. Neutral and acid mucus were strongly present throughout the intestine. This detailed descriptive paper will be very helpful for studies of topmouth culter related to its digestive physiology, intestinal disease control and feed nutrient. © 2011 Blackwell Verlag GmbH.

Regional expression and dietary regulation of rat small intestinal peptide and amino acid transporter mRNAs.

PubMed

Erickson, R H; Gum, J R; Lindstrom, M M; McKean, D; Kim, Y S

1995-11-02

RT-PCR was used to obtain rat small intestinal cDNAs for two peptide transporters, showing conclusively for the first time that both are present in normal intestinal mucosa. Sequencing of these cDNAs showed them to be highly homologous and similar to two different types of peptide transport proteins from either colorectal carcinoma cells (Caco-2) or human and rabbit intestine. An even distribution profile of steady state levels of mRNA for both peptide transporters was observed along the longitudinal axis of small intestine. Both were upregulated in the distal regions of intestine by a high protein diet. Also, high levels of the rat high affinity glutamate transporter EAAC1 were observed in the distal intestine. These results suggest that the distal regions of small intestine play an important role in the absorption of some amino acids and peptides. Furthermore this area appears to be a primary site where dietary-induced changes in peptide and amino acid transport occurs.

In Vivo Absorption and Disposition of Cefadroxil after Escalating Oral Doses in Wild-Type and PepT1 Knockout Mice

PubMed Central

Posada, Maria M.; Smith, David E.

2013-01-01

Purpose To determine the effect of PepT1 on the absorption and disposition of cefadroxil, including the potential for saturable intestinal uptake, after escalating oral doses of drug. Methods The absorption and disposition kinetics of [3H]cefadroxil was determined in wild-type and PepT1 knockout mice after 44.5, 89.1, 178, and 356 nmol/g oral doses of drug. The pharmacokinetics of [3H]cefadroxil was also determined in both genotypes after 44.5 nmol/g intravenous bolus doses. Results PepT1 deletion reduced the area under the plasma concentration-time profile (AUC0-120) of cefadroxil by 10-fold, the maximum plasma concentration (Cmax) by 17.5-fold, and increased the time to reach a maximum plasma concentration (Tmax) by 3-fold. There was no evidence of nonlinear intestinal absorption since AUC0-120 and Cmax values changed in a dose-proportional manner. Moreover, the pharmacokinetics of cefadroxil was not different between genotypes after intravenous bolus doses, indicating that PepT1 did not affect drug disposition. Finally, no differences were observed in the peripheral tissue distribution of cefadroxil (i.e., outside gastrointestinal tract) once these tissues were corrected for differences in perfusing blood concentrations. Conclusions The findings demonstrate convincingly the critical role of intestinal PepT1 in both the rate and extent of oral administration for cefadroxil and potentially other aminocephalosporin drugs. PMID:23959853

Lactobacillus acidophilus ATCC 4356 prevents atherosclerosis via inhibition of intestinal cholesterol absorption in apolipoprotein E-knockout mice.

PubMed

Huang, Ying; Wang, Jinfeng; Quan, Guihua; Wang, Xiaojun; Yang, Longfei; Zhong, Lili

2014-12-01

The objective of this study was to investigate the effect of Lactobacillus acidophilus ATCC 4356 on the development of atherosclerosis in apolipoprotein E-knockout (ApoE(-/-)) mice. Eight-week-old ApoE(-/-) mice were fed a Western diet with or without L. acidophilus ATCC 4356 daily for 16 weeks. L. acidophilus ATCC 4356 protected ApoE(-/-) mice from atherosclerosis by reducing their plasma cholesterol levels from 923 ± 44 to 581 ± 18 mg/dl, likely via a marked decrease in cholesterol absorption caused by modulation of Niemann-Pick C1-like 1 (NPC1L1). In addition, suppression of cholesterol absorption induced reverse cholesterol transport (RCT) in macrophages through the peroxisome proliferator-activated receptor/liver X receptor (PPAR/LXR) pathway. Fecal lactobacillus and bifidobacterium counts were significantly (P < 0.05) higher in the L. acidophilus ATCC 4356 treatment groups than in the control groups. Furthermore, L. acidophilus ATCC 4356 was detected in the rat small intestine, colon, and feces during the feeding trial. The bacterial levels remained high even after the administration of lactic acid bacteria had been stopped for 2 weeks. These results suggest that administration of L. acidophilus ATCC 4356 can protect against atherosclerosis through the inhibition of intestinal cholesterol absorption. Therefore, L. acidophilus ATCC 4356 may be a potential therapeutic material for preventing the progression of atherosclerosis. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Intestinal Parasitic Infections in Human Immunodeficiency Virus-Infected and Noninfected Persons in a High Human Immunodeficiency Virus Prevalence Region of Cameroon.

PubMed

Nkenfou, Céline Nguefeu; Tchameni, Sandrine Mboula; Nkenfou, Carine Nguefeu; Djataou, Patrice; Simo, Ulrich Florian; Nkoum, Alexandre Benjamin; Estrin, William

2017-09-01

The problem of intestinal parasitic infection in human immunodeficiency virus (HIV)-infected people requires careful consideration in the developing world where poor nutrition is associated with poor hygiene and several coinfecting diseases. Studies have addressed this issue in Cameroon, especially in the low HIV prevalence area. The current study was conducted to determine the prevalence of intestinal parasitosis in people living with HIV (PLHIV) in Adamaoua and to identify associated risk factors. Stool and blood specimens from study participants were screened for intestinal parasites and anti-HIV antibodies, respectively. Of 235 participants, 68 (28.9%) were HIV positive, 38 of them on antiretroviral treatment (ART). The overall prevalence of intestinal parasites was 32.3%. Of 68 PLHIV, 32.3% (22/68) were infected with intestinal parasites, compared with 32.3% (54/167) of the HIV-negative patients. Univariate analysis showed no difference between the prevalence of intestinal parasites among PLHIV and HIV-negative patients ( P = 0.69). ART was not associated with the prevalence of intestinal parasites. Multivariate analysis showed that the quality of water and the personal hygiene were the major risk factors associated to intestinal parasitosis. The level of education was associated with HIV serostatus: the higher the level of education, the lower the risk of being infected with HIV ( P = 0.00). PLHIV and the general population should be screened routinely for intestinal parasites and treated if infected.

A Review on Phytosome Technology as a Novel Approach to Improve The Bioavailability of Nutraceuticals

NASA Astrophysics Data System (ADS)

Amin, Tawheed; Bhat, Suman Vikas

2012-08-01

The bioavailability and absorption of water soluble phytoconstituents is erratic due to poor solubility of these constituents in gastrointestinal tract. This can be overcome by a novel delivery system known as phytosome technology in which water soluble phytoconstituents are allowed to react with phospholipids. For better and improved bioavailability, natural phytoconstituents must have a good balance between hydrophilicity (helps in dissolution in gastro-intestinal fluids) and hydrophobicity (helps to cross lipid rich cell membranes). This is achieved through phytosome technology. Phospholipids have a dual solubility and acts as an emulsifier. Phytosome technology acts as a bridge between novel and conventional delivery systems. Many products are available in the market based on this phytosome technology which include popular herbal extracts such as Ginkgo biloba, Silybum marianum, grape seed, olive oil flavonoids etc.

Jejunal and ileal absorption of oxprenolol in man: influence of nutrients and digestive secretions on jejunal absorption and systemic availability.

PubMed Central

Godbillon, J; Vidon, N; Palma, R; Pfeiffer, A; Franchisseur, C; Bovet, M; Gosset, G; Bernier, J J; Hirtz, J

1987-01-01

1 Study I evaluated the absorption of oxprenolol in the ileum, compared to jejunum, in healthy volunteers by an intestinal perfusion technique. Around 80 mg of drug were delivered as a saline solution directly in the small bowel. 2 Samples taken 30 cm distally to the site of perfusion showed that 63% of perfused oxprenolol was absorbed in the jejunum and 48% in the ileum; the differences were significant. 3 The plasma concentration-time profiles were similar for the two perfusions. The AUC and Cmax values of free and conjugated oxprenolol for the jejunal perfusion were significantly lower than those of ileum. They showed large but consistent intersubject variations in the two treatments. 4 Study II investigated, using the same technique, the influence of nutrients and digestive secretions on jejunal absorption and systemic availability of this drug. A saline (in treatments A and B) or a nutrient (in treatment C) solution containing oxprenolol was perfused into the jejunum below a balloon either inflated (A) or deflated (B and C). 5 The disappearance rate of oxprenolol from the jejunum was unaffected by endogenous secretions. The mean amount of drug absorbed along a 30-cm jejunal segment accounted for 52 (A) and 57% (B) of the total amount perfused. The intestinal absorption rate was markedly increased in the presence of nutrients (mean amount absorbed 96% for C). 6 The change in the rate of disappearance from the intestine had no effect on the systemic availability of oxprenolol (mean AUC values 8740, 8250 and 8020 nmol l-1 h for A, B and C, respectively) or its elimination from plasma.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3663450

Effect of proinflammatory interleukins on jejunal nutrient transport

PubMed Central

Hardin, J; Kroeker, K; Chung, B; Gall, D

2000-01-01

AIM—We examined the effect of proinflammatory and anti-inflammatory interleukins on jejunal nutrient transport and expression of the sodium-glucose linked cotransporter (SGLT-1).
METHODS—3-O-methyl glucose and L-proline transport rates were examined in New Zealand White rabbit stripped, short circuited jejunal tissue. The effects of the proinflammatory cytokines interleukin (IL)-1α, IL-6, and IL-8, IL-1α plus the specific IL-1 antagonist, IL-1ra, and the anti-inflammatory cytokine IL-10 were investigated. In separate experiments, passive tissue permeability was assessed and brush border SGLT-1 expression was measured by western blot in tissues exposed to proinflammatory interleukins.
RESULTS—The proinflammatory interleukins IL-6, IL-1α, and IL-8 significantly increased glucose absorption compared with control levels. This increase in glucose absorption was due to an increase in mucosal to serosal flux. IL-1α and IL-8 also significantly increased L-proline absorption due to an increase in absorptive flux. The anti-inflammatory IL-10 had no effect on glucose transport. The receptor antagonist IL-1ra blocked the ability of IL-1α to stimulate glucose transport. IL-8 had no effect on passive tissue permeability. SGLT-1 content did not differ in brush border membrane vesicles (BBMV) from control or interleukin treated tissue.
CONCLUSIONS—These findings suggest that intestinal inflammation and release of inflammatory mediators such as interleukins increase nutrient absorption in the gut. The increase in glucose transport does not appear to be due to changes in BBMV SGLT-1 content.


Keywords: glucose transport; small intestine; intestinal inflammation; inflammation PMID:10896908

In silico prediction of drug dissolution and absorption with variation in intestinal pH for BCS class II weak acid drugs: ibuprofen and ketoprofen.

PubMed

Tsume, Yasuhiro; Langguth, Peter; Garcia-Arieta, Alfredo; Amidon, Gordon L

2012-10-01

The FDA Biopharmaceutical Classification System guidance allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms only for BCS class I. Extensions of the in vivo biowaiver for a number of drugs in BCS class III and BCS class II have been proposed, in particular, BCS class II weak acids. However, a discrepancy between the in vivo BE results and in vitro dissolution results for BCS class II acids was recently observed. The objectives of this study were to determine the oral absorption of BCS class II weak acids via simulation software and to determine if the in vitro dissolution test with various dissolution media could be sufficient for in vitro bioequivalence studies of ibuprofen and ketoprofen as models of carboxylic acid drugs. The oral absorption of these BCS class II acids from the gastrointestinal tract was predicted by GastroPlus™. Ibuprofen did not satisfy the bioequivalence criteria at lower settings of intestinal pH of 6.0. Further the experimental dissolution of ibuprofen tablets in a low concentration phosphate buffer at pH 6.0 (the average buffer capacity 2.2 mmol l (-1) /pH) was dramatically reduced compared with the dissolution in SIF (the average buffer capacity 12.6 mmol l (-1) /pH). Thus these predictions for the oral absorption of BCS class II acids indicate that the absorption patterns depend largely on the intestinal pH and buffer strength and must be considered carefully for a bioequivalence test. Simulation software may be a very useful tool to aid the selection of dissolution media that may be useful in setting an in vitro bioequivalence dissolution standard. Copyright © 2012 John Wiley & Sons, Ltd.

In Silico Prediction of Drug Dissolution and Absorption with variation in Intestinal pH for BCS Class II Weak Acid Drugs: Ibuprofen and Ketoprofen§

PubMed Central

Tsume, Yasuhiro; Langguth, Peter; Garcia-Arieta, Alfredo; Amidon, Gordon L.

2012-01-01

The FDA Biopharmaceutical Classification System guidance allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms only for BCS class I. Extensions of the in vivo biowaiver for a number of drugs in BCS Class III and BCS class II have been proposed, particularly, BCS class II weak acids. However, a discrepancy between the in vivo- BE results and in vitro- dissolution results for a BCS class II acids was recently observed. The objectives of this study were to determine the oral absorption of BCS class II weak acids via simulation software and to determine if the in vitro dissolution test with various dissolution media could be sufficient for in vitro bioequivalence studies of ibuprofen and ketoprofen as models of carboxylic acid drugs. The oral absorption of these BCS class II acids from the gastrointestinal tract was predicted by GastroPlus™. Ibuprofen did not satisfy the bioequivalence criteria at lower settings of intestinal pH=6.0. Further the experimental dissolution of ibuprofen tablets in the low concentration phosphate buffer at pH 6.0 (the average buffer capacity 2.2 mmol L-1/pH) was dramatically reduced compared to the dissolution in SIF (the average buffer capacity 12.6 mmol L -1/pH). Thus these predictions for oral absorption of BCS class II acids indicate that the absorption patterns largely depend on the intestinal pH and buffer strength and must be carefully considered for a bioequivalence test. Simulation software may be very useful tool to aid the selection of dissolution media that may be useful in setting an in vitro bioequivalence dissolution standard. PMID:22815122

D-Lactic acidosis in a boy with short bowel syndrome.

PubMed Central

Schoorel, E P; Giesberts, M A; Blom, W; van Gelderen, H H

1980-01-01

Metabolic acidosis in a 3-year-old child with short bowel syndrome led to the discovery of massive D-lactic aciduria. After normalisation of the intestinal bacterial flora, D-lactate disappeared together with the acidosis. Dysbacteriosis with excessive production of D-lactate by intestinal bacteria (unidentified) and subsequent absorption explains this unusual cause of metabolic acidosis. PMID:7436446

Safety concerns over the use of intestinal permeation enhancers: A mini-review.

PubMed

McCartney, Fiona; Gleeson, John P; Brayden, David J

2016-01-01

Intestinal permeation enhancers (PEs) are key components in ∼12 oral peptide formulations in clinical trials for a range of molecules, primarily insulin and glucagon-like-peptide 1 (GLP-1) analogs. The main PEs comprise medium chain fatty acid-based systems (sodium caprate, sodium caprylate, and N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC)), bile salts, acyl carnitines, and EDTA. Their mechanism of action is complex with subtle differences between the different molecules. With the exception of SNAC and EDTA, most PEs fluidize the plasma membrane causing plasma membrane perturbation, as well as enzymatic and intracellular mediator changes that lead to alteration of intestinal epithelial tight junction protein expression. The question arises as to whether PEs can cause irreversible epithelial damage and tight junction openings sufficient to permit co-absorption of payloads with bystander pathogens, lipopolysaccharides and its fragment, or exo- and endotoxins that may be associated with sepsis, inflammation and autoimmune conditions. Most PEs seem to cause membrane perturbation to varying extents that is rapidly reversible, and overall evidence of pathogen co-absorption is generally lacking. It is unknown however, whether the intestinal epithelial damage-repair cycle is sustained during repeat-dosing regimens for chronic therapy.

Bile Acid Metabolism and Signaling

PubMed Central

Chiang, John Y. L.

2015-01-01

Bile acids are important physiological agents for intestinal nutrient absorption and biliary secretion of lipids, toxic metabolites, and xenobiotics. Bile acids also are signaling molecules and metabolic regulators that activate nuclear receptors and G protein-coupled receptor (GPCR) signaling to regulate hepatic lipid, glucose, and energy homeostasis and maintain metabolic homeostasis. Conversion of cholesterol to bile acids is critical for maintaining cholesterol homeostasis and preventing accumulation of cholesterol, triglycerides, and toxic metabolites, and injury in the liver and other organs. Enterohepatic circulation of bile acids from the liver to intestine and back to the liver plays a central role in nutrient absorption and distribution, and metabolic regulation and homeostasis. This physiological process is regulated by a complex membrane transport system in the liver and intestine regulated by nuclear receptors. Toxic bile acids may cause inflammation, apoptosis, and cell death. On the other hand, bile acid-activated nuclear and GPCR signaling protects against inflammation in liver, intestine, and macrophages. Disorders in bile acid metabolism cause cholestatic liver diseases, dyslipidemia, fatty liver diseases, cardiovascular diseases, and diabetes. Bile acids, bile acid derivatives, and bile acid sequestrants are therapeutic agents for treating chronic liver diseases, obesity, and diabetes in humans. PMID:23897684

Canine gastrointestinal physiology: Breeds variations that can influence drug absorption.

PubMed

Oswald, Hayley; Sharkey, Michele; Pade, Devendra; Martinez, Marilyn N

2015-11-01

Although all dogs belong to Canis lupus familiaris, the physiological diversity resulting from selective breeding can lead to wide interbreed variability in drug pharmacokinetics (PK) or in oral drug product performance. It is important to understand this diversity in order to predict the impact of drug product formulation attributes on in vivo dissolution and absorption characteristics across the canine population when the dog represents the targeted patient population. Based upon published information, this review addresses breed differences in gastrointestinal (GI) physiology and discusses the in vivo implications of these differences. In addition to the importance of such information for understanding the variability that may exist in the performance of oral dosage forms in dogs for the purpose of developing canine therapeutics, an appreciation of breed differences in GI physiology can improve our prediction of oral drug formulation performance when we extrapolate bioavailability results from the dog to the humans, and vice versa. In this literature review, we examine reports of breed associated diversity in GI anatomy and morphology, gastric emptying time (GET), oro-cecal transit time (OCTT), small intestinal transit time (SITT), large intestinal transit time (LITT), intestinal permeability, sodium/potassium fecal concentrations, intestinal flora, and fecal moisture content. Published by Elsevier B.V.

Effect of dietary phosphorus on intestinal phosphorus absorption in growing Holstein steers.

PubMed

Feng, X; Ronk, E; Hanigan, M D; Knowlton, K F; Schramm, H; McCann, M

2015-05-01

The effect of dietary P intake on intestinal P absorption was evaluated in growing Holstein steers. Diets varying in P content (0.15, 0.27, 0.36, and 0.45%, DM basis) were fed to 8 steers (174±10kg of BW) fitted with permanent duodenal and ileal cannulas in a replicated 4×4 Latin square with 14-d periods. Ytterbium-labeled corn silage and cobalt-EDTA were used as particulate and liquid phase markers, respectively, to measure digesta flow. Duodenal and ileal samples and spot urine samples were collected every 9 h from d 11 to 14. Total fecal collection was conducted on d 11 to 14 with fecal bags. Blood samples were collected from the coccygeal vessel on d 14. Feed, digesta, and fecal samples were analyzed for total P and inorganic P. Data were analyzed using PROC GLIMMIX in SAS with a model including treatment, square, period, and interaction of treatment and square. Preplanned contrasts were used to evaluate linear and quadratic treatment effects. Results were reported as least squares means. Dry matter intake (mean=4.90kg/d, 2.8% of BW) and apparent DM digestibility (mean=78.1%) were unaffected by treatment. Duodenal and ileal flow of total P increased linearly with increasing P intake (13.4, 18.5, 23.0, and 27.4g/d; 6.80, 7.87, 8.42, and 10.4g/d). Increasing P intake increased the quantity of P absorbed from the small intestine linearly (6.96, 11.1, 14.6, and 17.2g/d), but absorption efficiency was unchanged (mean=59.6%). Phosphorus was absorbed on a net basis from the large intestine, but this was not affected by treatment and was a small proportion of total P absorption. Blood inorganic P increased linearly with increased dietary P (4.36, 6.31, 7.68, and 8.5mg/dL) and salivary P secretion was unchanged (mean=5.79g/d), suggesting that rumen function was prioritized during short-term P deficiency. These data showing an absence of change in absorption efficiency and salivary P secretion in the face of short-term P deficiency may be used to improve published models of P digestion, absorption, and metabolism. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Proteins involved in uptake, intracellular transport and basolateral secretion of fat-soluble vitamins and carotenoids by mammalian enterocytes.

PubMed

Reboul, Emmanuelle; Borel, Patrick

2011-10-01

Our understanding of the molecular mechanisms responsible for fat-soluble vitamin uptake and transport at the intestinal level has advanced considerably over the past decade. On one hand, it has long been considered that vitamin D and E as well as β-carotene (the main provitamin A carotenoid in human diet) were absorbed by a passive diffusion process, although this could not explain the broad inter-individual variability in the absorption efficiency of these molecules. On the other hand, it was assumed that preformed vitamin A (retinol) and vitamin K1 (phylloquinone) absorption occurred via energy-dependent processes, but the transporters involved have not yet been identified. The recent discovery of intestinal proteins able to facilitate vitamin E and carotenoid uptake and secretion by the enterocyte has spurred renewed interest in studying the fundamental mechanisms involved in the absorption of these micronutrients. The proteins identified so far are cholesterol transporters such as SR-BI (scavenger receptor class B type I), CD36 (cluster determinant 36), NPC1L1 (Niemann-Pick C1-like 1) or ABCA1 (ATP-Binding Cassette A1) displaying a broad substrate specificity, but it is likely that other membrane proteins are also involved. After overviewing the metabolism of fat-soluble vitamins and carotenoids in the human upper gastrointestinal lumen, we will focus on the putative or identified proteins participating in the intestinal uptake, intracellular transport and basolateral secretion of these fat-soluble vitamins and carotenoids, and outline the uncertainties that need to be explored in the future. Identifying the proteins involved in intestinal uptake and transport of fat-soluble vitamins and carotenoids across the enterocyte is of great importance, especially as some of them are already targets for the development of drugs able to slow cholesterol absorption. Indeed, these drugs may also interfere with lipid vitamin uptake. A better understanding of the molecular mechanisms involved in fat-soluble vitamin and carotenoid absorption is a priority to better optimize their bioavailability. Copyright © 2011 Elsevier Ltd. All rights reserved.

A randomized, double-blind, placebo-controlled trial of Rifaximin, a nonabsorbable antibiotic, in the treatment of tropical enteropathy

USDA-ARS?s Scientific Manuscript database

Tropical enteropathy is characterized by an increased urinary lactulose-to-mannitol (L:M) ratio on a site-specific sugar absorption test and is associated with increased intestinal permeability and decreased nutrient absorptive capacity. The etiology of tropical enteropathy is postulated to be intes...

Glucagon-like peptide 2 therapy reduces negative effects of diarrhea on calf gut

USDA-ARS?s Scientific Manuscript database

Damage to the intestinal epithelium caused by diarrhea reduces nutrient absorption and growth rate, and may have long-term effects on the young animal. Glucagon-like peptide 2 (GLP-2) is an intestinotropic hormone that improves gut integrity and nutrient absorption, and has antioxidant effects in th...

Glucagon-like peptide 2 therapy reduces the negative impacts the proinflammatory response in the gut of calves with coccidiosis

USDA-ARS?s Scientific Manuscript database

Damage to the intestinal epithelium reduces nutrient absorption and animal growth, and can have negative long-term health effects on livestock. The intestinotropic hormone glucagon-like peptide 2 (GLP-2) contributes to gut integrity, reduces inflammation, and improves nutrient absorption. The presen...

Enhancement of lymphatic transport of lutein by oral administration of a solid dispersion and a self-microemulsifying drug delivery system.

PubMed

Sato, Yuki; Joumura, Tatsuru; Nashimoto, Shunsuke; Yokoyama, Sayaka; Takekuma, Yoh; Yoshida, Hideto; Sugawara, Mitsuru

2018-06-01

Lutein is located in the macula lutea in the human eye. Since humans cannot synthesize lutein de novo, it must be digested as food. Some studies including our previous study showed very low absorption of lutein after oral administration. These studies also suggested that the absorption route of lutein from the small intestine involves not only the blood but also the lymph. The aim of this study was to clarify the transfer of lutein into lymph and the tissue distribution after oral administration of a solid dispersion (SD) and a self-microemulsifying drug delivery system (SMEDDS) for improvement of the absorption. We used thoracic lymph-cannulated rats. It was shown that the plasma concentrations of lutein in the SD and SMEDDS groups were increased compared with that in the powder group. The absorption of lutein after oral administration of each formulation was clearly evaluated by its cumulative amount in lymph. Our data clearly showed that lutein is transferred into the lymph stream from the small intestine. Copyright © 2018 Elsevier B.V. All rights reserved.