• YAKHAK HOEJI
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• v.44 no.5
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• pp.424-431
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• 2000

A biopharmaceutics drug classification system for correlation between in vitro dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling the rate and extent of drug absorption. The objective of this study was to assess whether in vitro dissolution profiles of immediate-release beta-blocker tablets can be correlated with intestinal membrane permeability and/or in vivo bioavailability In vitro dissolution of the beta-blocker tablets was examined using KP VII Apparatus II methods at various pH. Intestinal membrane permeability was determined in vitro using the diffusion chamber method. Bioavailablity parameters were cited from literatures. The dissolution profiles did not accurately represent the in vivo bioavailablity However there were good correlations between intestinal membrane permeability and log P (noctanol/buffer). The correlations obtained in this study indicated that in vitro diffusion chamber method could be used to predict intestinal absorption in vivo.

• Journal of Cancer Prevention
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• v.21 no.2
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• pp.95-103
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• 2016

Background: Excess energy supply induces chronic low-grade inflammation in association with oxidative stress in various tissues including intestinal epithelium. The objective of this study was to investigate the effect of high-fat diet (HFD) on intestinal cell membrane integrity and intestinal tumorigenesis in $Apc^{Min/+}$ mice. Methods: Mice were fed with either normal diet (ND) or HFD for 12 weeks. The number of intestinal tumors were counted and biomarkers of endotoxemia, oxidative stress, and inflammation were determined. Changes in intestinal integrity was measured by fluorescein isothiocyanate (FITC)-dextran penetration and membrane gap junction protein expression. Results: HFD group had significantly higher number of tumors compared to ND group (P < 0.05). Blood total antioxidant capacity was lower in HFD group, while colonic 8-hydroxy-2'-deoxyguanosine level, a marker of oxidative damage, was higher in HFD group compared to that of ND group (P < 0.05). The penetration of FITC-dextran was substantially increased in HFD group (P < 0.05) while the expressions of membrane gap junction proteins including zonula occludens-1, claudin-1, and occludin were lower in HFD group (P < 0.05) compared to those in ND group. Serum concentration of lipopolysaccharide (LPS) receptor (CD14) and colonic toll-like receptor 4 (a LPS receptor) mRNA expression were significantly higher in HFD group than in ND group (P < 0.05), suggesting that significant endotoxemia may occur in HFD group due to the increased membrane permeability. Serum interleukin-6 concentration and myeloperoxidase activity were also higher in HFD group compared to those of ND group (P < 0.05). Conclusions: HFD increases oxidative stress disrupting intestinal gap junction proteins, thereby accelerating membrane permeability endotoxemia, inflammation, and intestinal tumorigenesis.

• Journal of Pharmaceutical Investigation
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• v.40 no.spc
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• pp.19-31
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• 2010

Orally administrated drugs permeate the biological membrane by various transport mechanisms. The oral absorption potential is closely related to the physicochemical properties of the drug and interaction with the physiological factors surrounding the site of absorption. Assessment of the drug membrane permeability is an integral part of the early stage drug developmental process. Appropriate selection of the permeability screening method at the right stage of drug development process is important in achieving successful developmental outcomes. This review aims at introducing currently available in vitro and in vivo screening methods for the membrane permeability assessment.

• Journal of Korean Medicine for Obesity Research
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• v.12 no.1
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• pp.33-47
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• 2012

Objectives This study was designed to investigate the effects of fermented soybean upon anti-inflammation, cytotoxicity, antioxidant and intestinal mucous membrane permeability by measuring the cell viability, NO (nitric oxide) production, DPPH, Polyphenol, HRP and TEER in cells like Raw 264.7 and HCT 116 using fermented soybean. Methods Raw 264.7 cell and HCT 166 cell were used in this study. And fermented soybean powders were used for the experimental group and soybean powders for the control group. There was inflammation response upon using lipopolysaccharide(LPS). Fermented soybean powders and soybean powders were in a respectively different dose added to the cells with LPS. MTT assay, NO, DPPH and Polyphenol measurement, TEER, HRP were conducted for each cell. The results of this study were presented in mean and standard deviation. Results 1. In Raw 254.7 cells added with $100{\mu}l/ml$ unfermented soybean powders, 104.95% higher than 62.59% was measured. In Raw 254.7 cells added with $100{\mu}l/ml$ fermented soybean powders, there was 74.90% measured higher than 62.59%, which was a significant result. 2. By a gradual increase of unfermented soybean powders like $0.1{\mu}l/ml$, $1.0{\mu}l/ml$, $10{\mu}l/ml$, $100{\mu}l/ml$, the measured NO were also gradually decreased $53.12{\mu}M$, $47.57{\mu}M$, $37.02{\mu}M$, $28.16{\mu}M$. In case of cells added with fermented soybean powders, $43.95{\mu}M$ NO was measured in $0.1{\mu}l/ml$ which is significant, and in other cases, mostly measured over$ 56.72{\mu}M$. 3. It was inferred that fermented soybean powders have anti-inflammatory effects of maintaining intestinal mucous membrane permeability because the measured values of cells in both groups were all higher than $133.62{\Omega}$ measured of cells added with only LPS. And measured values of cells in both groups were all lower than 2.26 measured of cells added with only LPS. 4. In case of experiment DPPH and polyphenol measurement, fermented group was all higher than unfermented group. Conclusion From the results of conducting MTT assay, NO measurement, and TEER, HRP by using cells Raw 264.7 and HCT-116, even though there was no significance in the correlation between cytotoxicity, anti-inflammatory effects, both unfermented soybean powders and fermented soybean powders were shown to have intestinal mucous membrane permeability improvement effects. This effects could be applicable for autoimmune diseases, chronic inflammatory diseases and so additional studies are expected in the future. From the results of conducting DPPH, Polyphenol measurement, Fermented soybean may be useful as potential antioxidant.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1997.04a
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• pp.119-119
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• 1997

Valacyclovir is a L-valyl ester prodrug of acyclovir which is a highly effective and selective antiviral agent in the treatment of herpes virus diseases. Valacyclovir is rapidly and almost completely converted to acyclovir and increases the oral bioavailability of acyclovir three to five fold. However, the intestinal absorption mechanism of valacyclovir is not clear. If the improved absorption mechanism of valacyclovir is fully understood, it will provide a rationale of designing the amino acid ester prodrugs of polar drugs containing hydroxyl group. The main objective of our present study is to characterize the membrane transport mechanism of valacyclovir. Methods : Intestinal absorption of valacyclovir was investigated by using in-situ rat perfusion study and its wall permeability was estimated by modified boundary layer model. The membrane transport mechanism was also investigated through the uptake study in Caco-2 cells and in CHO-hPepTl cells. Results : In the rat perfusion study, the wall permeability of valacyclovir was ten times higher than acyclovir and showed concentration dependency, Valacyclovir also demonstrated a D,L stereo-selectivity with L-isomer having an approximately five-fold higher permeability than D-isomer. Mixed dipeptides and cephalexin, which are transported by dipeptide carriers, strongly competed with valacyclovir for the intestinal absorption, while L-valine did not show any competition with valacyclovir. This indicated that the intestinal absorption of valacyclovir could be dipeptide carrier-mediated. In addition, the competitive uptake study in Caco-2 cells presented that dipeptides reduced the valacyclovir uptake but valine did not. Also, in IC$\sub$50/ study, valacyclovir showed strong inhibition on the $^3$H-gly-sar uptake in CHO-hPepTl cells over-expressing a human intestinal peptide transporter. Taken together, the result from our present study indicated that valacyclovir utilized the peptide transporter for the intestinal absorption.

• Journal of Korean Medicine for Obesity Research
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• v.13 no.1
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• pp.24-32
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• 2013

Objectives: The aim of this study is to investigate anti-imflammatory and protective effect for intestinal epithelial cells with Atractylodes macrocephae (AM), a traditional Korean Herbal medicine and fermented Atractylodes macrocephae (FAM) with Lactobacillus plantarum. Methods: HCT-116 and Raw 264.7 cells were used in this study. Using NO assay, we measured lipopolysaccharide (LPS)-induced anti-inflammatory effect. We measured permeability of intestinal epithelial cells with transepithelial electrical resistance and horseradish peroxide flux assay. Water soluble tetrazolium salt assay was used to see cell proliferation. All the results were presented in mean and standard deviation. We used Student's t-test for analyzing significance of results. Results: In Raw 264.7 cells NO production decreased 22.4% with pre-treatment of AM and FAM, especially with FAM in high concentration. In HCT-116 cells LPS-induced intestinal permeability had a protective effect with both AM and FAM, which was also tend to be proportional to the concentration. Cell viability increased up to 135.52% after treatment of high concentration of FAM in HCT-116, while there was no significant change in Raw 264.7 cells with herb treatments. Conclusions: These results show evidence that AM, especially fermented ones, significantly reduced intestinal membrane permeability. They also had a protective effect as well as an anti-inflammation effect for HCT-116 and Raw 264.7 cells. This suggest that FAM may be a therapeutic agent for Leaky gut syndrome by reducing intestinal permeability.

• Journal of Pharmaceutical Investigation
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• v.28 no.1
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• pp.25-33
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• 1998

Intestinal absorption of ${\beta}-lactam$ antibiotics and angiotensin converting enzyme(ACE) inhibitors has been shown to use the carrier-mediated transport system. In vitro experiments have established that the efficacy of uptake by enterocytes depends on an inwardly directed proton gradient. It was suggested that benazepril was mediated by tripeptide transport system and that amoxicillin was transported by dipeptide transport carrier. The aim of this study is to assess the influence of amoxicillin on the intestinal absorption of benazepril using in vitro diffusion chamber and in situ single pass perfusion technique in the rat in order to elucidate whether the above transport systems are competitive or not. We obtained the gastrointestinal pemeability coefficient of amoxicillin, benazepril and both of them using in vitro diffusion chamber. And also the gastrointestinal absorption clearance of amoxicillin, benazepril and both of them using in situ single-pass perfusion method at steady state were calculated. Amoxicillin and benazepril were analyzed by HPLC. The results by the use of diffusion chamber in vitro indicated that the apparent intestinal permeability coefficient of benazepril was significantly(p<0.01) decreased by amoxicillin(45.2%) and vice versa significantly(p<0.01) decreased(89.1%). The results by the in situ gastrointestinal single-pass perfusion method indicated that the intestinal absorption clearance of benazepril was significantly(p<0.05) decreased by amoxicillin (40.2%) and vice versa significantly(p<0.05) decreased(54.8%). These results might suggest that they share the same peptide carrier pathway for oral absorption.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1997.04a
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• pp.3-5
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• 1997

Properties of a good drug include safety, efficacy, half-life and bioavailability. With the current approach to drug discovery based on receptor-based and cell-based screening methods, compounds are frequently moved into development with poor bioavailability. With low bioavailability, drug administration is typically limited to parenteral routes, thus limiting the potential wide-spread utility of these therapeutic agents. The first and most important factor limiting a drug's bioavailability is the intestinal membrane permeability which in turn determines the maximum fi:action of the dose administered that can be absorbed. We have recently utilized new intubation methods for performing permeability measurements in humans and establishing a fundamental human data base for correlating intestinal jejunal membrane permeabilities with permeabilities determined in other systems, e.g., animals, tissue culture, as well as physical chemical properties.

• Journal of Applied Biological Chemistry
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• v.66
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• pp.311-319
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• 2023

Caveolin-1 (Cav-1) is the main structural component of the caveolae on the plasma membrane, which regulates various cellular processes, including cell growth, differentiation, and endocytosis. Although a recent study demonstrated that Cav-1 might be involved in diabetes-associated inflammation, its exact role in the intestine was unclear. In this study, we examined the intestinal expression of Cav-1 in diabetic conditions. We also investigated its effect on lipopolysaccharide (LPS)-induced inflammation by expressing this protein in human intestinal Caco-2 cells lacking Cav-1. We observed that increased Cav-1 levels and decreased expression of tight junction proteins affected intestinal permeability in high-fat diet-induced diabetic mice. When Caco-2 cells were treated with LPS, Cav-1 enhanced the NF-κB signaling. Moreover, LPS reduced the expression of tight junction proteins while it increased cell-cell permeability and reactive oxygen species generation in Caco-2 cells and this effect was amplified by cav-1 overexpression. LPS treatment promoted phosphorylation of tyrosine-14 (Y14) on Cav-1, and the LPS-induced NF-κB signaling was suppressed in cells expressing non-phosphorylatable Cav-1 (tyrosine-14 to phenylalanine mutant), which reduced intestinal barrier permeability. These results suggest that Cav-1 expression promotes LPS-induced inflammation in Caco-2 cells, and phosphorylation of Y14 on Cav-1 might contribute to the anti-inflammatory response in LPS-induced NF-κB signaling and cell permeability.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1996.04a
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• pp.273-273
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• 1996

Recently a novel in vivo approach in dogs, using a regional segmental intestinal perfusion technique, has been developed. The perfusion tube consists of a highly sophisticated multichannel tube with two inflatable occluding balloons, which are placed in 10cm apart. The tube was introduced orally from the stomach through the upper jejunum under the guidance of solid-state pH meter. In the present study, four healthy dogs were infused in the proximal jejunum on two periods. The two perfusion experiments used the same flow rate, 2 $m\ell$/min, and the same perfusion solution to determine the intrasubject variability. The mean (${\pm}$ S. E.) fractions of ranitidine absorbed calculated from the perfusion data were 21.32${\pm}$2.01% (n=3) (1st period), 27.88 ${\pm}$ 17.54% (n=4) (2nd period), respectively. The effective permeabilities (Peffs${\times}$10$\^$4/) of ranitidine were 1.51${\pm}$0.47cm/sec (n=3) (1st period), 1.50 ${\pm}$ 0.31 cm/sec (n=4) (2nd period), respectively. The pH and osmolarity of perfusion solution were 7.50 ${\pm}$ 0.03 and 300 ${\pm}$ 0.06 mOsm/L, There was no significant intrasubject variation. Mixing equilibrium (steady-state) was reached at about 50 min. l-Phenylalanine was absorbed almost completely. Intrinsic intestinal wall permeability of ranitidine showed low permeable characteristics, suggesting permeability-limited absorption. The absorption of 1-phenylalanine, an actively transported nutrient, was not inhibited by ranitidine. The low intestinal membrane permeability is one of the important factors responsible for the variable oral absorption of ranitidine. Supported by FDA Grant FD01462-04 and KOSEF Grant.