67 results on '"Mikio Tomita"'
Search Results
2. Intestinal Absorption of Alogliptin Is Mediated by a Fruit-Juice-Sensitive Transporter
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Mikio Tomita, Makoto Ishii, Momona Sasaki, Takuo Ogihara, Kaori Morimoto, Erika Oikawa, Tatsuro Kikuchi, and Maho Abe
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0301 basic medicine ,Male ,Pharmaceutical Science ,Administration, Oral ,Organic Anion Transporters ,4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid ,Intestinal absorption ,03 medical and health sciences ,chemistry.chemical_compound ,Food-Drug Interactions ,0302 clinical medicine ,Piperidines ,medicine ,Animals ,Humans ,Carnitine ,Uracil ,Pharmacology ,Organic cation transport proteins ,biology ,Peptide transporter 1 ,Transporter ,General Medicine ,Rats ,Organic anion-transporting polypeptide ,Fruit and Vegetable Juices ,030104 developmental biology ,HEK293 Cells ,Biochemistry ,chemistry ,Diabetes Mellitus, Type 2 ,Intestinal Absorption ,DIDS ,030220 oncology & carcinogenesis ,Malus ,biology.protein ,Terfenadine ,Caco-2 Cells ,Alogliptin ,medicine.drug ,Citrus paradisi ,Citrus sinensis ,Half-Life - Abstract
Alogliptin (ALG), an inhibitor of dipeptidylpeptidase-4, is used in the management of type 2 diabetes mellitus, and has a high absorption rate (>60-71%), despite its low lipophilicity (logP=-1.4). Here, we aimed to clarify the mechanism of its intestinal absorption. ALG uptake into Caco-2 cells was time-, temperature-, and concentration-dependent, but was not saturated at concentrations up to 10 mmol/L. The uptake was significantly inhibited by the organic anion transporting polypeptide (OATP) substrate fexofenadine and by the OATP inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), but was not inhibited by organic cation transporter (OCT)/organic cation/carnitine transporter (OCTN) or peptide transporter 1 (PEPT1) substrates. Grapefruit, orange, and apple juices and their constituents, which are known to strongly inhibit intestinal OATPs, significantly inhibited ALG uptake into Caco-2 cells. The pH dependence was bell-shaped, indicating the involvement of a pH-sensitive transporter. However, ALG uptake by HEK293 cells overexpressing OATP2B1, a key intestinal OATP transporter of amphiphilic drugs, was not different from that of mock cells. In a rat in vivo study, apple juice reduced systemic exposure to orally administered ALG without changing the terminal half-life. These observations suggest that intestinal absorption of ALG is carrier-mediated, and involves a fruit-juice-sensitive transporter other than OATP2B1.
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- 2021
3. Increased membrane permeation and blood concentration of 6-carboxyfluorescein associated with dysfunction of paracellular route barrier in the small intestine of ulcerative colitis model rats
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Kaori Morimoto, Maho Kumagai, Makoto Ishii, and Mikio Tomita
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Male ,medicine.medical_specialty ,Cell Membrane Permeability ,Colon ,Pharmaceutical Science ,Administration, Oral ,Ileum ,Absorption (skin) ,digestive system ,030226 pharmacology & pharmacy ,Tight Junctions ,Jejunum ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Intestine, Small ,medicine ,Animals ,Pharmacology (medical) ,Intestinal Mucosa ,Rats, Wistar ,Barrier function ,Pharmacology ,Tight junction ,Chemistry ,digestive, oral, and skin physiology ,Dextran Sulfate ,General Medicine ,medicine.disease ,Fluoresceins ,Ulcerative colitis ,digestive system diseases ,Small intestine ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,030220 oncology & carcinogenesis ,Paracellular transport ,Administration, Intravenous ,Colitis, Ulcerative - Abstract
In the colon of patients with ulcerative colitis (UC), decreased function of the paracellular barrier, especially hypofunction of the tight junction, is associated with pathological conditions. However, there has been no report to date on the function of tight junctions in the small intestine. Here, we focused on the barrier function of the small intestine, especially in tight junctions, and compared it with that of the colon. Dextran sulfate sodium (DSS) was used to induce ulcerative colitis in rats in order to evaluate the function of the paracellular barrier in the jejunum, ileum, and colon. An in vitro diffusion chamber method was used to evaluate membrane resistance, which is an index of tight junction function and mucosal permeability, using 6-carboxyfluorescein (6-CF), a paracellular marker. In the jejunum and colon, with decrease of membrane resistance in the DSS group, mucosal permeability increased, whereas no marked difference was observed in the ileum. In the in situ closed-loop method, absorption of 6-CF from the jejunum was higher than that from the ileum. Immunohistochemical staining of claudin-4 showed heterogeneous attenuation of claudin-4 in the jejunum. Pharmacokinetic parameters were calculated from the blood concentration after intravenous injection and oral administration of 6-CF. In the DSS group, there was a delay in the elimination phase, suggesting a decrease in renal function, and an increase in maximum blood concentration, associated with an increased absorption rate constant. The increased absorption and decreased renal function due to decreased paracellular barrier function in the small intestine and colon may cause fluctuations in drug efficacy and side effects.
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- 2019
4. Retraction Note to: Changes of Absorptive and Secretory Transporting System of (1 → 3) β-D-glucan Based on Efflux Transporter in Indomethacin-induced Rat
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Toshio Oda, Jun Aketagawa, Yasuhiko Ito, Shohei Ouchi, Mikio Tomita, Yusuke Takizawa, Masahiro Hayashi, and Aiko Iida
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Pharmacology ,Chemistry ,Pharmacology toxicology ,Pharmacology (medical) ,Christian ministry ,Transporter ,Human physiology ,Efflux ,1 3 β d glucan - Abstract
The Editor-in-Chief has retracted this article [1] based on an investigation by the Ministry of Education, Culture, Sports, Science and Technology, Japan, which found that the article contained overlap with a previously published article by Kalitsky-Szirtes J, et al. [2].
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- 2018
5. Intestinal secretion of indoxyl sulfate as a possible compensatory excretion pathway in chronic kidney disease
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Masanari Miyamoto, Yuuta Tominaga, Yoshimi Sano, Kentaro Yano, Shota Kashiwagura, Yuta Agatsuma, Kaori Morimoto, Takuo Ogihara, Mikio Tomita, Akira Takahashi, and Chihaya Kakinuma
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0301 basic medicine ,Male ,medicine.medical_specialty ,Cell ,030232 urology & nephrology ,Pharmaceutical Science ,Excretion ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,Internal medicine ,medicine ,ATP Binding Cassette Transporter, Subfamily G, Member 2 ,Animals ,Humans ,Pharmacology (medical) ,Secretion ,Renal Insufficiency, Chronic ,Pharmacology ,Lucifer yellow ,Intestinal Secretions ,Chemistry ,Multidrug resistance-associated protein 2 ,Transporter ,General Medicine ,medicine.disease ,Multidrug Resistance-Associated Protein 2 ,Neoplasm Proteins ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Jejunum ,Caco-2 Cells ,Multidrug Resistance-Associated Proteins ,Indican ,Kidney disease ,Sodium-Phosphate Cotransporter Proteins, Type I - Abstract
Indoxyl sulfate (IS) is a protein-bound uremic toxin that progressively accumulates in plasma during chronic kidney disease (CKD), and its accumulation is associated with the progression of CKD. This study examined the intestinal secretion of IS using in situ single-pass intestinal perfusion in a rat model of renal insufficiency, MRP2- and BCRP-overexpressing Sf9 membrane vesicles, and Caco-2 cell monolayers. An in situ single-pass perfusion study in CKD model rats demonstrated that a small amount of IS is secreted into intestinal lumen after iv administration of IS, and the clearance increased AUC-dependently. An excess amount of IS (3 mm) partially inhibited the MRP2- and BCRP-mediated uptake of specific fluorescent substrates, CDCF and Lucifer yellow, respectively, into the membrane vesicles, although IS was not taken up at a physiological concentration, 10 μm. In the Caco-2 cell monolayers, the IS transport was higher in the absorptive direction than in the secretory direction (p < 0.05). p-Aminohippuric acid (PAH) strongly inhibited IS transport in both directions (absorptive, p = 0.142; secretory, p < 0.01). Given that the blood IS levels are much higher than those in the intestinal lumen, it is possible that this unknown PAH-sensitive system contributes to the intestinal IS secretion. Although in situ inhibition study is needed to confirm that this unknown transporter mediates the in vivo intestinal secretion of IS, we speculate that this unknown active efflux system works as a compensatory excretion pathway for excess organic anions such as IS especially in end-stage renal disease.
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- 2018
6. RETRACTED ARTICLE: Changes of Absorptive and Secretory Transporting System of (1 → 3) β-D-glucan Based on Efflux Transporter in Indomethacin-induced Rat
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Mikio Tomita, Yusuke Takizawa, Yasuhiko Ito, Aiko Iida, Toshio Oda, Jun Aketagawa, Masahiro Hayashi, and Shohei Ouchi
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Pharmacology ,medicine.medical_specialty ,Abcg2 ,biology ,Multidrug resistance-associated protein 2 ,Ileum ,ATP-binding cassette transporter ,Intestinal absorption ,Jejunum ,medicine.anatomical_structure ,Endocrinology ,Paracellular transport ,Internal medicine ,medicine ,biology.protein ,Pharmacology (medical) ,Efflux - Abstract
Infection and inflammation suppress the expression and activity of several drug transporters in liver. In the intestine, P-glycoprotein (P-gp/MDR1), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP) are important barriers to the absorption of many clinically important drugs. The expression and activity of these proteins were examined under inflammation. Drug transport was determined in jejunum and ileum segments isolated from 1.0 mg/kg, 5.0 mg/kg, and 7.5 mg/kg indomethacin-treated or control rats in diffusion chambers. Transport of laminaran, used as a model compound of (1-3) β-D-glucan, was measured for 120 min in the presence or absence of inhibitors. Reverse transcription-polymerase chain reaction was used to measure mRNA levels. Compared with controls, levels of Mdr1a mRNA were significantly decreased in the jejunum and ileum of 7.5 mg/kg indomethacin-treated rats. Both reductions in the basolateral to apical efflux of laminaran and increases in the apical to basolateral influx of laminaran were observed, resulting in significant increases in the apical to basolateral absorption of laminaran in 7.5 mg/kg indomethacin-treated rats. The inhibitory effect of verapamil on laminaran transport was observed in control rats but not in indomethacin-treated rats. Fluorescein isothiocyanate dextran 40,000 permeability, membrane resistance, and claudin-4 mRNA level were not altered, indicating no change in the paracellular pathway. These results indicate that indomethacin-induced inflammation reduces the intestinal expression and activity of P-gp in rats, which elicits corresponding changes in the intestinal transport of laminaran. Hence, inflammatory diseases may impose variability in drug bioavailability through alterations in the intestinal expression and activity of drug transporters.
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- 2014
7. Impact of Intestinal Drug Absorption Enhancement in Drug Delivery System
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Mikio, TOMITA, 総説, Review, 東北薬科大学, and Tohoku Pharmaceutical University
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- 2012
8. RETRACTED: Suppression of efflux transporters in the intestines of endotoxin-treated rats
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Megumi Hatanaka, Mariko Nakaike, Mikio Tomita, Yusuke Takizawa, Atsushi Kanbayashi, Ayako Tanaka, Masahiro Hayashi, Tomomi Kai, and Hiroyuki Murata
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Lipopolysaccharide ,business.industry ,Multidrug resistance-associated protein 2 ,Pharmaceutical Science ,Inflammation ,Transporter ,ATP-binding cassette transporter ,Pharmacology ,chemistry.chemical_compound ,chemistry ,Paracellular transport ,medicine ,Efflux ,medicine.symptom ,business ,Fluorescein isothiocyanate - Abstract
Infection and inflammation suppress the expression and activity of several drug transporters in the liver. In the intestine, P-glycoprotein (PGP/mdr1) and the multidrug resistance-associated protein 2 (MRP2) are important barriers to the absorption of many clinically important drugs. The protein expression and activity of these transporters were examined during inflammation induced by lipopolysaccharide (LPS). The transport of rhodamine123 (Rho123) and 5-carboxyfluorescein (5-CF) was determined in isolated ileal segments from endotoxin-treated or control rats in the presence or absence of inhibitors. The reverse transcription-polymerase chain reaction was used to measure mRNA levels. Compared with the controls, the mRNA levels of mdr1a and mrp2 were significantly decreased by approximately 50% in the ilea of the LPS-treated rats. Corresponding reductions in the basolateral-apical efflux of Rho123 and 5-CF were observed, resulting in significant increases in the apical-basolateral absorption of these compounds. Neither the permeability of fluorescein isothiocyanate labeled dextran 4000 (FD-4), a paracellular marker, nor membrane resistance was altered. These results indicate that endotoxin-induced inflammation reduces the intestinal expression and activity of PGP and MRP2 in rats, which eliciting corresponding changes in the intestinal transport of their substrates. Hence, infection and inflammatory diseases may induce variability in drug bioavailability through alterations in the intestinal expression and activity of drug transporters.
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- 2012
9. Effects of nitric oxide on mucosal barrier dysfunction during early phase of intestinal ischemia/reperfusion
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Takuya Kitazato, Masahiro Hayashi, Yusuke Takizawa, Hisanao Kishimoto, and Mikio Tomita
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Male ,Pathology ,medicine.medical_specialty ,Blotting, Western ,Ischemia ,Pharmaceutical Science ,Pharmacology ,Nitric Oxide ,Permeability ,Nitric oxide ,chemistry.chemical_compound ,Intestinal mucosa ,In vivo ,medicine ,Animals ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Intestinal Mucosa ,Rats, Wistar ,Claudin ,P-glycoprotein ,biology ,Tight junction ,medicine.disease ,Rats ,chemistry ,Reperfusion Injury ,biology.protein ,Reperfusion injury - Abstract
Ischemia/reperfusion (I/R) injury must be overcome for successful small intestinal transplantation. During intestinal I/R, the expression level of nitric oxide (NO) is increased, and vermiculation of the mucosal tract is induced by NO. Although NO has many beneficial effects on intestinal I/R injury, its role in intestinal I/R injury is controversial. Therefore, in the present study, we examined changes in the tight junctions (TJ) and P-glycoprotein (P-gp) by aminoguanidine (AG), which can be considered a selective inducible NO synthase inhibitor during intestinal I/R, to clarify the effect of NO on mucosal barrier dysfunction during intestinal I/R. A mucosal lesion was induced by intestinal I/R. The protein expression levels of the claudin family organizing TJ and P-gp, were decreased, and their functions were also decreased. Through the inhibition of NO generation by AG in the above mucosal lesion, TJ and P-gp dysfunction was significantly inhibited. NO participated in opening TJ and decreasing P-gp function and expression induced during intestinal I/R. Therefore, it is important to consider the level of NO generation in the ileal mucosa in drug therapy for intestinal I/R injury.
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- 2011
10. Nonlinear Intestinal Absorption of Fluorescein Isothiocyanate Dextran 4, 000 Caused by Absorptive and Secretory Transporting System
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Chise Kawahata, Masahiro Hayashi, Shohei Ouchi, Mikio Tomita, and Rie Ohkubo
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Fluorescein isothiocyanate dextran ,Reaction rate constant ,Chromatography ,Chemistry ,Intestinal loops ,Efflux ,Permeation ,Flux (metabolism) ,Intestinal absorption ,In vitro - Abstract
The mechanism of the nonlinear concentration dependence of the intestinal absorption of fluorescein isothiocyanate dextran 4,000 (FD-4) was studied using in situ rat intestinal loops and the in vitro Ussing-type chamber method. The intestinal absorption rate constant of FD-4, as evaluated by the intestinal loop method, increased significantly in a nonlinear fashion as the FD-4 concentration increased up to 0.2 mM and tended to decrease at concentrations higher than 0.2 mM. The mucosal-to-serosal permeation of FD-4 across rat ileal sheets, as evaluated by the in vitro Ussing-type chamber method, also increased in a nonlinear fashion in the low concentration range (0.01 - 0.02 mM), before decreasing as the concentration increased further, whereas serosal-to-mucosal permeation decreased in a concentration-dependent manner. In addition, mucosal-to-serosal flux and serosal-to-mucosal flux were increased and reduced in the presence of the metabolic inhibitor 2, 4-dinitrophenol, respectively. These results suggest that FD-4 is predominantly secreted into the intestinal lumen by an efflux transport system.
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- 2011
11. Effect of Aminoguanidine on Ischemia/Reperfusion Injury in Rat Small Intestine
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Yusuke Takizawa, Naomi Kamiya, Mikio Tomita, Masahiro Hayashi, Takuya Kitazato, and Haruka Ishizaka
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Male ,Survival ratio ,Ischemia ,Nitric Oxide Synthase Type II ,Pharmaceutical Science ,Pharmacology ,Nitric Oxide ,Guanidines ,Rat Small Intestine ,Nitric oxide ,chemistry.chemical_compound ,Inducible no synthase ,Intestine, Small ,medicine ,Animals ,Enzyme Inhibitors ,Rats, Wistar ,chemistry.chemical_classification ,Reactive oxygen species ,Chemistry ,General Medicine ,medicine.disease ,Rats ,Area Under Curve ,Reperfusion Injury ,Anesthesia ,Paracellular transport ,Reactive Oxygen Species ,Reperfusion injury - Abstract
Ischemia/reperfusion (I/R) injury is induced by reactive oxygen species (ROS). During intestinal I/R, the amount of nitric oxide (NO), which is a ROS, is increased. In this study, we examined the protection against I/R injury by inhibition of NO generation. Wistar/ST rats were exposed to 1 h of ischemia, followed by reperfusion for 4 h. The rats were intravenously injected with 100 mg/kg aminoguanidine (AG), which is a selective inducible NO synthase (iNOS) inhibitor, for 5 min before ischemia. The increase in NO(2)(-) by intestinal I/R was significantly inhibited by AG 1 h after reperfusion. Moreover, the increase in area under curve of 0 to 1 h after reperfusion (AUC(0-1)) of paracellular marker was inhibited. However, 3 h after reperfusion, the survival ratio of rats was significantly decreased in the intestinal I/R condition with AG. The amount of NO(2)(-) and AUC of 3 to 4 h after reperfusion (AUC(3-4)) of paracellular marker in intestinal I/R groups were increased by AG compared with those in the I/R condition without AG 3 h after reperfusion. These data indicated that AG, which was given by single pre-administration, can clearly inhibit intestinal I/R injury 1 h after reperfusion. However, the injury occurs again 3 h after reperfusion and grows worse.
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- 2011
12. Effects of antioxidants on drug absorption in in vivo intestinal ischemia/reperfusion
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Hisanao Kishimoto, Mikio Tomita, Yusuke Takizawa, Takuya Kitazato, and Masahiro Hayashi
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Male ,Ischemia ,Xanthophylls ,Pharmacology ,Antioxidants ,Catechin ,Intestinal absorption ,Lipid peroxidation ,chemistry.chemical_compound ,Intestinal mucosa ,In vivo ,medicine ,Animals ,Pharmacology (medical) ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Intestinal Mucosa ,Rats, Wistar ,Tiron ,Dextrans ,medicine.disease ,Rats ,Intestines ,Transplantation ,Intestinal Absorption ,Biochemistry ,chemistry ,Reperfusion Injury ,1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt ,Reperfusion injury ,Fluorescein-5-isothiocyanate - Abstract
Ischemia/reperfusion (I/R) injury must be overcome in order to succeed in small intestinal transplantation. Reactive oxygen species (ROS) are generated by I/R, and they induce lipid peroxidation which is one of the causes of mucosal lesion. We previously reported the protection effects of antioxidants to I/R injury in the in vitro study. In the present study, we examined the inhibitive effect of antioxidants on intestinal I/R injury in the in vivo study. Intestinal ischemia was induced in Wistar/ST rats using the spring scale and the surgical suture for 1 h, followed by reperfusion for 1 h. We used 4,5-dihydroxy-1,3-benzene-disulfonic acid (Tiron), astaxanthin (ATX) and epigallocatechin gallate (EGCG) as antioxidants. The inhibitive effects on mucosal lesion, opening of TJ and decrease in protein expression level of P-gp by in vivo intestinal I/R were admitted by three kinds of antioxidant. Tiron and EGCG inhibited P-gp function but ATX did not. Therefore, for the use of P-gp substrate like immunosuppressants after the intestinal transplantation, ATX, which does not inhibit P-gp is considered to be effective for intestinal I/R injury.
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- 2010
13. Effect of lipopolysaccharide on P-glycoprotein-mediated intestinal and biliary excretion of rhodamine123 in rats
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Mariko Nakaike, Hiroyuki Murata, Ayako Tanaka, Masahiro Hayashi, Mikio Tomita, Megumi Hatanaka, and Atsushi Kanbayashi
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Lipopolysaccharides ,Male ,medicine.medical_specialty ,ATP Binding Cassette Transporter, Subfamily B ,Lipopolysaccharide ,Blotting, Western ,Gene Expression ,Pharmaceutical Science ,ATP-binding cassette transporter ,Ileum ,Biliary excretion ,chemistry.chemical_compound ,Increased lipid ,Internal medicine ,medicine ,Animals ,Bile ,Rhodamine 123 ,Rats, Wistar ,P-glycoprotein ,Messenger RNA ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Rats ,Blot ,Endocrinology ,medicine.anatomical_structure ,Liver ,chemistry ,Inactivation, Metabolic ,biology.protein ,lipids (amino acids, peptides, and proteins) - Abstract
The effects of lipopolysaccharide (LPS) on the ileal and biliary excretion of rhodamine123 were investigated in rats at different times after intraperitoneal (i.p.) injection (1 mg/kg and 5 mg/kg of body weight). P-gp protein decreased 8h after injection of LPS and returned to the control level 24h after i.p. injection of LPS in the ileum. There was a marked decrease in the expression level of mdr1a mRNA in the ileum and liver 8h after i.p. injection of LPS when compared with the control condition. Also, the ileal and biliary clearance of rhodamine123 significantly decreased 8h after i.p. injection of LPS, but returned to the control levels 24h after i.p. injection of LPS. These results suggest that LPS-induced decreases in P-gp-mediated ileal and biliary excretion of rhodamine123 were probably due to impaired P-gp-mediated transport ability. The levels of iNOS and IL-1beta mRNA in the ileum and liver increased 2 and 8h after i.p. injection of LPS, respectively, and returned to the control levels 24h after injection of LPS. These findings suggest that LPS markedly decreases P-gp-mediated ileal and biliary excretion of rhodamine123, probably by partly decreasing the expression of P-gp protein levels, likely due to increased lipid peroxidation levels through iNOS mRNA and inflammatory mediators such as IL-1beta.
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- 2010
14. Effects of Intestinal Ischemia/Reperfusion on P-Glycoprotein Mediated Biliary and Renal Excretion of Rhodamine123 in Rat
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Mikio Tomita, Hisanao Kishimoto, Yusuke Takizawa, and Masahiro Hayashi
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Male ,medicine.medical_specialty ,Urinary system ,Nitric Oxide Synthase Type II ,Pharmaceutical Science ,Nitric Oxide Synthase Type I ,Kidney ,Lipid peroxidation ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Rhodamine 123 ,Pharmacology (medical) ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Rats, Wistar ,Biliary Tract ,P-glycoprotein ,Pharmacology ,biology ,Intestinal ischemia ,business.industry ,Tetraethylammonium ,Kidney metabolism ,Rats ,Endocrinology ,medicine.anatomical_structure ,Liver ,Verapamil ,chemistry ,Reperfusion Injury ,Renal physiology ,Inos mrna ,Cyclosporine ,biology.protein ,Cimetidine ,business - Abstract
To analyze the effects of I/R on P-gp function in liver and kidney, biliary and urinary excretions of rhodamine123 as a substrate of P-gp were examined in rats. The effects of reperfusion time on change and recovery of P-gp function were also examined. The biliary and renal clearance of rhodamine123 significantly decreased at 3 hr after reperfusion, but returned to control levels at 24 hr after reperfusion. These results suggest that intestinal I/R-induced decrease in P-gp-mediated biliary and renal excretion of rhodamine123 is litely due to impairment of P-gp-mediated transport ability. The level of P-gp protein in liver decreased and that of iNOS mRNA increased at 3 hr after reperfusion and both levels returned to control levels at 24 hr after reperfusion. No marked change in the levels of P-gp protein and iNOS mRNA was observed in kidney at 3 hr and 24 hr after reperfusion. Thus, decrease in biliary excretion of rhodamine123 would appear due in part to decrease in expression of P-gp, caused by increase in lipid peroxidation levels through iNOS mRNA.
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- 2009
15. Assessment of Ileal Epithelial P-Glycoprotein Dysfunction Induced by Ischemia/Reperfusion using in vivo Animal Model
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Masahiro Hayashi, Mikio Tomita, Hisanao Kishimoto, and Yusuke Takizawa
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Male ,medicine.medical_specialty ,ATP Binding Cassette Transporter, Subfamily B ,Ischemia ,Pharmaceutical Science ,Thiobarbituric Acid Reactive Substances ,Lipid peroxidation ,chemistry.chemical_compound ,Mesenteric Veins ,Ileum ,Mesenteric Artery, Superior ,In vivo ,Internal medicine ,medicine.artery ,medicine ,Animals ,Rhodamine 123 ,Pharmacology (medical) ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,RNA, Messenger ,Superior mesenteric artery ,Intestinal Mucosa ,Rats, Wistar ,Vein ,Survival rate ,Pharmacology ,business.industry ,Membrane Proteins ,medicine.disease ,In vitro ,Rats ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Reperfusion Injury ,Anesthesia ,Claudins ,Models, Animal ,Lipid Peroxidation ,business ,Blood vessel - Abstract
We presented the ischemia/reperfusion (I/R) model which can evaluate changes in P-glycoprotein (P-gp) function induced by lipid peroxidation using surgical-sutures connected with the spring balance. The superior mesenteric artery and vein was occluded by hanging itself using surgical-sutures connected with the spring balance for 60 min (ischemia), followed by reperfusion by cutting of sutures. To determine the hanging force of blood vessel during ischemia, treatment at the hanging force of 50g load, 100g load and 150g load for 60 min was carried out and survival rate was evaluated. Although our 150g load group had some effect on survival, the survival was 100% in the case of 50g and 100g load groups. Thiobarbituric acid-reactive substance (TBA-RS) as an indicator of lipid peroxidation and P-gp expression level after I/R was increased and decreased in a load-dependent manner during ischemia, respectively. Also, the decrease in the level of mdr1a mRNA and function of P-gp by I/R depended on load during ischemia. The changes in TBA-RS, P-gp expression level and P-gp function observed in this study corresponded with our in vitro I/R model reported previously. In conclusion, it was shown that this in vivo I/R model can evaluate the function of P-gp through lipid peroxidation.
- Published
- 2008
16. Ischemia/Reperfusion Injury in the Monolayers of Human Intestinal Epithelial Cell Line Caco-2 and Its Recovery by Antioxidants
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Satoshi Mizuno, Mayuko Nagira, Masahiro Hayashi, Toshiyuki Ayabe, Mikio Tomita, and Miyuki Kumata
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Lutein ,Cell Membrane Permeability ,Antioxidant ,medicine.medical_treatment ,Blotting, Western ,Pharmaceutical Science ,Xanthophylls ,Pharmacology ,Antioxidants ,Lipid peroxidation ,chemistry.chemical_compound ,tert-Butylhydroperoxide ,medicine ,Humans ,Vitamin E ,Rhodamine 123 ,Pharmacology (medical) ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Intestinal Mucosa ,Fluorescent Dyes ,Biliverdin ,Dose-Response Relationship, Drug ,Tight junction ,Superoxide ,Biliverdine ,Epithelial Cells ,medicine.disease ,Intestines ,chemistry ,Biochemistry ,Caco-2 ,Reperfusion Injury ,1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt ,Indicators and Reagents ,Lipid Peroxidation ,Caco-2 Cells ,Reperfusion injury - Abstract
We previously established a in vitro system for assessing early ischemia/reperfusion injury using monolayers of human intestinal epithelial cell line Caco-2, in which lipid peroxidation caused by tertiary-butylhydroperoxide (t-BuOOH), a lipid peroxidation inducer, acts as a trigger of the injury. By now, we have shown that superoxide anion participates in the opening of tight junctions (TJ) induced by reoxygenation following the induction of lipid peroxidation by t-BuOOH at a low concentration. The present objectives are to elucidate the dysfunction of P-glycoprotein (P-gp) in addition to the opening of TJ by t-BuOOH at a high concentration condition using rhodamine123 (Rho123) as a P-gp substrate and cyclosporine A (CyA) as a P-gp inhibitor. Also, we compared the inhibition effect of lutein and other compounds such as biliverdin as a radical scavenger on the opening of TJ and the dysfunction of P-gp. t-BuOOH at a high concentration increased the permeability of Rho123 in the apical to basal direction and decreased basal to apical direction when compared with control conditions. t-BuOOH at a high concentration showed no significant difference between directional transport of Rho123 and no inhibition was observed in the permeability of both directions by CyA. The staining intensity of Western blot was decreased by t-BuOOH at a high concentration. Although lutein and the other compounds had recovery effects on the opening of TJ and P-gp dysfunction induced by t-BuOOH, lutein is more advantageous than other compounds since it has effective effects at the lower concentration. In conclusion, the barrier dysfunction such as the inhibition of P-gp in addition to the opening of TJ was induced by t-BuOOH at a high concentration condition. The above two barrier dysfunctions was ameliorated by antioxidant such as lutein and biliverdin.
- Published
- 2006
17. The Novel Formulation Design of Self-emulsifying Drug Delivery Systems (SEDDS) Type O/W Microemulsion III: The Permeation Mechanism of a Poorly Water Soluble Drug Entrapped O/W Microemulsion in Rat Isolated Intestinal Membrane by the Ussing Chamber Method
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Masahiro Hayashi, Mikio Tomita, and Hiroshi Araya
- Subjects
Male ,Taurocholic Acid ,Cell Membrane Permeability ,Chemistry, Pharmaceutical ,Drug Compounding ,Sodium ,Pharmaceutical Science ,Salt (chemistry) ,chemistry.chemical_element ,Ibuprofen ,In Vitro Techniques ,Mass Spectrometry ,Permeability ,Rats, Sprague-Dawley ,Drug Delivery Systems ,medicine ,Animals ,Pharmacology (medical) ,Microemulsion ,Intestinal Mucosa ,Chromatography, High Pressure Liquid ,Micelles ,Pharmacology ,chemistry.chemical_classification ,Membranes ,Chromatography ,Ussing chamber ,Anti-Inflammatory Agents, Non-Steroidal ,Mucins ,Permeation ,Acetylcysteine ,Rats ,Pharmaceutical Preparations ,chemistry ,Permeability (electromagnetism) ,Drug Design ,Drug delivery ,Diffusion Chambers, Culture ,Emulsions ,medicine.drug - Abstract
We used ibuprofen as a poorly water soluble model drug, to examine the influence of bile salts and mucin layers on the permeability of that entrapped in an O/W microemulsion, in a rat isolated intestinal membrane by the Ussing chamber method. Under the presence of 3 kinds of the primary bile salts such a sodium taurocholate, etc., or a secondary bile salt such a sodium taurochenodeoxycholate at 0.01 mmol/L concentration, a significant difference was not demonstrated in the permeation clearance of the ibuprofen entrapped O/W microemulsion, as compared with the case without the bile salts. Thus, the bile salts did not have a remarkable influence on the permeability of the drug entrapped in the O/W microemulsion, and it was verified that this O/W microemulsion was hardly influenced by the flow of the bile secretion. On the other hand, when N-acetyl-L-cysteine (NAC) with the removal ability of a mucin layer was combined with the ibuprofen entrapped O/W microemulsion at the concentration of 3 and 10 mmol/L, it was shown that the permeation clearance of free ibuprofen did not decrease, but that of ibuprofen entrapped in the O/W microemulsion decreased with the increase of the NAC concentration. Therefore, it is confirmed that the mucin layer participates in the permeability of the drug entrapped in the O/W microemulsion. From these results, the mechanism in which the drug entrapped in the O/W microemulsion is released in a mucin layer, without passing through the route of the mixed micelle formation by bile, thereafter the drug permeates an intestinal membrane, is supposed.
- Published
- 2006
18. Improvement of transmucosal absorption of drugs in drug delivery system (DDS) 2. Improvement of intestinal drug absorption based on structural changes of tight junction and functional changes of P-glycoprotein
- Author
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Mikio Tomita and Masahiro Hayashi
- Subjects
Absorption (pharmacology) ,biology ,Tight junction ,Chemistry ,Drug delivery ,biology.protein ,Biophysics ,Pharmaceutical Science ,Pharmacology ,P-glycoprotein - Abstract
各種吸収促進剤による腸管粘膜透過改善の生理学的な作用機構について検討した. カプリン酸ナトリウムは細胞内カルシウムを上昇させ, カルモジュリン依存的なアクチンフィラメントの収縮により, また, デカノイルカルニチンと酒石酸はATPの枯渇と細胞内アシドーシスにより, 細胞間隙ルートを拡大した. 一方, 酒石酸およびピロチオデカンはP-糖蛋白質(P-gp)の機能抑制により, P-gp基質の吸収を改善した. 以上から, 各種吸収促進剤による細胞間隙ルートと細胞内ルートそれぞれにおける薬物吸収制御機構が明らかとなった.
- Published
- 2005
19. The Novel Formulation Design of Self-emulsifying Drug Delivery Systems (SEDDS) Type O/W Microemulsion II: Stable Gastrointestinal Absorption of a Poorly Water Soluble New Compound, ER-1258 in Bile-fistula Rats
- Author
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Masahiro Hayashi, Hiroshi Araya, and Mikio Tomita
- Subjects
Male ,Biliary Fistula ,Common Bile Duct Diseases ,Pharmaceutical Science ,Absorption (skin) ,Rats, Sprague-Dawley ,Surface-Active Agents ,Castor wax ,chemistry.chemical_compound ,Drug Delivery Systems ,Estrogen Receptor Modulators ,Pulmonary surfactant ,Animals ,Bile ,Pharmacology (medical) ,Microemulsion ,Medium chain fatty acid ,Triacetin ,Pharmacology ,Chromatography ,Triglyceride ,Chemistry ,Rats ,Disease Models, Animal ,Intestinal Absorption ,Solubility ,Area Under Curve ,Drug Design ,Drug delivery ,Cyclosporine ,Emulsions - Abstract
The stabilization effect of the novel self-emulsifying drug delivery systems (SEDDS) type O/W microemulsion on the gastrointestinal absorption of a poorly water soluble new compound, ER-1258 was examined by bile-fistula model rats. In the components of this formulation, medium chain fatty acid triglyceride (MCT), diglyceryl monooleate (DGMO-C), polyoxyethylene hydrogenated castor oil 40 (HCO-40) and ethanol were used as an oil, a lipophilic surfactant, a hydrophilic surfactant and a solubilizer at the mixture ratio of 25/5/45/25 w/w%, respectively. The ratios of AUC in the non-treated rats to that in the bile-fistula rats were 5.1, 12.1 and 3.0 for the suspension, the oily solution and the SEDDS type O/W microemulsion, respectively. The risk from which the difference between individuals of the compound absorption amounts resulting from the flow of the bile secretion serves as the maximum was high in order of oily solution>suspension>SEDDS type O/W microemulsion. Therefore, it was verified that the SEDDS type O/W microemulsion was able to reduce this risk, compared with the other formulations. When short chain fatty acid triglyceride (Triacetin) was used as an oil, the similar effect was demonstrated in the formulation composed of sorbitan sesquioleate (SO-15) as a lipophilic surfactant and polyoxyethylene hydrogenated castor oil 60 (HCO-60) or polyoxyethylene 20 sorbitan monooleate (TO-10M) as a hydrophilic surfactant.
- Published
- 2005
20. Effect of aminated gelatin on the nasal absorption of insulin in rats
- Author
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Kazuhiro Morimoto, Yasuhiko Tabata, Toshinobu Seki, Mikio Tomita, Sumio Chono, Hiroshi Kanbayashi, Masahiro Hayashi, and Tomonobu Nagao
- Subjects
Male ,aminated gelatin ,insulin ,food.ingredient ,medicine.medical_treatment ,Pharmaceutical Science ,Peptide ,Absorption (skin) ,Gelatin ,food ,medicine ,absorption enhancer ,Animals ,Rats, Wistar ,Administration, Intranasal ,Amination ,Pharmacology ,chemistry.chemical_classification ,Insulin ,General Medicine ,nasal absorption ,Rats ,Nasal Mucosa ,Nasal Absorption ,Isoelectric point ,Biochemistry ,chemistry ,Paracellular transport ,Nasal administration - Abstract
Absorption enhancers, which increase the permeability of drugs through epithelial membranes without damaging them, are especially useful for intranasal administration of peptide drugs. In this study, aminated gelatins, candidate enhancers, having different numbers of amino groups were prepared from gelatin (H-gelatin, isoelectric point = 9.0, MW 100 kDa) and a partial gelatin hydrolysate (L-gelatin, isoelectric point = 8.0, MW 5 kDa), and the enhancing effects on the nasal absorption of insulin, used as a model peptide drug, and 5(6)-carboxyfluorescein (CF), a paracellular marker, were examined in rats. The enhancing effect on insulin and CF depends on the MW and number of amino groups. A high correlation between the enhancing effects on insulin and CF was observed and this suggests that an increase in the paracellular permeability is the mechanism governing the nasal absorption-enhancement of aminated gelatins, at least as far as insulin and CF are concerned. The enhancing mechanism might be shared with other cationic polymers having absorption-enhancing effects.
- Published
- 2005
21. Regional Difference in P-glycoprotein Punction in Rat Intestine
- Author
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Mikio Tomita, Aiko Iida, and Masahiro Hayashi
- Subjects
Male ,Absorption (pharmacology) ,medicine.medical_specialty ,Colon ,Pharmaceutical Science ,Ileum ,digestive system ,Rhodamine 123 ,Gastroenterology ,Intestinal absorption ,Jejunum ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Pharmacology (medical) ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Intestinal Mucosa ,Rats, Wistar ,P-glycoprotein ,Pharmacology ,biology ,digestive, oral, and skin physiology ,Water ,Intestinal epithelium ,Rats ,Intestines ,medicine.anatomical_structure ,Endocrinology ,Intestinal Absorption ,Verapamil ,chemistry ,biology.protein ,medicine.drug - Abstract
It has been reported that inhibition of the P-glycoprotein (P-gp) results in the improved absorption of P-gp substrate in the intestinal tract. In fact, the increased permeability of P-gp substrate across the intestinal epithelium was observed following inhibition of P-gp in in vitro experiments. To develop the formulation containing P-gp inhibitor and P-gp substrate for practical use, it is necessary to know whether the results obtained in the in vitro experiments are reproducible at whole body level. It is also important to find out the regional difference of the P-gp activity in the intestinal tract. In this study, we examined whether verapamil, a specific inhibitor of P-gp, improves the absorption of rhodamine123 (Rho123), a substrate of P-gp, from the jejunum, ileum, and colon of rats using the in situ loop method. The water content in the loop decreased during the experiment, resulting in a significant change of the Rho123 concentration in the loop. Thus, to accurately determine the absorption rate of Rho123, it was necessary to measure the water movement. It was found that there was a regional difference in the water movement, i.e., greatest in colon, followed by ileum. Verapamil did not change the water movement in any intestinal regions. When the concentration of Rho123 in the loop was corrected by water movement, the Rho123 clearance was in the order of ileum (1.15 microL/min/cm), colon (0.83 microL/min/cm) and jejunum (0.47 microL/min/cm). In the presence of verapamil, the Rho123 clearance was significantly increased at jejunum and ileum but not in colon (ileum: 2.08 microL/min/cm, colon: 1.14 microL/min/cm, jejunum: 1.28 microL/min/cm). These results suggest that P-gp inhibits the drug absorption in jejunum and ileum. From these results, it is possible to evaluate the role of P-gp and its regional difference in the in situ experiments. In particular, the inhibition of P-gp results in an increase in absorption of the P-gp substrate limited to jejunum and ileum.
- Published
- 2005
22. The Novel Formulation Design of Self-emulsifying Drug Delivery Systems (SEDDS) Type O/W Microemulsion I: Enhancing Effects on Oral Bioavailability of Poorly Water Soluble Compounds in Rats and Beagle Dogs
- Author
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Masahiro Hayashi, Mikio Tomita, Hiroshi Araya, and Shunsuke Nagao
- Subjects
Male ,Ketoprofen ,Indoles ,Biological Availability ,Pharmaceutical Science ,Ibuprofen ,Rats, Sprague-Dawley ,Surface-Active Agents ,Castor wax ,Dogs ,Drug Delivery Systems ,Pulmonary surfactant ,Oral administration ,medicine ,Animals ,Pharmacology (medical) ,Microemulsion ,Particle Size ,Solubility ,Benzofurans ,Pharmacology ,Chromatography ,Chemistry ,Lipids ,Rats ,Bioavailability ,Gastric Mucosa ,Area Under Curve ,Drug Design ,Drug delivery ,Emulsions ,medicine.drug - Abstract
We examined the design of the versatile novel self-emulsifying drug delivery systems (SEDDS) type O/W microemulsion formulation which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds. Namely, seven kinds of poorly water soluble compounds such as disopyramide, ibuprofen, ketoprofen, tolbutamide, and other new compounds, as the model compounds were used to compare the plasma concentration profile of the compound following single oral administration of each compound to rats and beagle dogs as a solution, an oily solution, a suspension (or a powder), an O/W microemulsion, and a SEDDS type O/W microemulsion. And the enhancing effect of the SEDDS type O/W microemulsion on the gastrointestinal absorption of these compounds was evaluated. In the components of the SEDDS type O/W microemulsion, medium chain fatty acid triglyceride (MCT), diglyceryl monooleate (DGMO-C), polyoxyethylene hydrogenated castor oil 40 (HCO-40), and ethanol were used as an oil, a lipophilic surfactant, a hydrophilic surfactant, and a solubilizer, at the mixture ratio of 25/5/45/25 (w/w%), respectively. Thereby, to six kinds of the model compounds except disopyramide, the solubility was from 340 to 98,000 times that in water, and the AUCs in plasma concentration of the compound were equivalent to that of solution or O/W microemulsion administration, or was increased by 1.5 to 78 times that of suspension administration. Accordingly, this novel SEDDS type O/W microemulsion is the versatile, useful formulation which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds.
- Published
- 2005
23. Effectiveness of Pirotiodecane, Absorption Enhancer, on Nasal Absorption in Rabbits
- Author
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Mikio Tomita, Hiroshi Otake, Masahiro Hayashi, Mariko Sugimoto, Michinori Sakai, Yoshihiro Idota, Makoto Haga, and Koji Okuma
- Subjects
Pharmacology ,Chromatography ,Ussing chamber ,Chemistry ,Pharmaceutical Science ,Mucous membrane of nose ,Absorption (skin) ,Permeation ,Kinetics ,Nasal Mucosa ,Nasal Absorption ,medicine.anatomical_structure ,In vivo ,Area Under Curve ,Nasal septum ,medicine ,Animals ,Pyrroles ,Pharmacology (medical) ,Nasal administration ,Rabbits ,Administration, Intranasal - Abstract
The absorption enhancing effect of 1-[2-(decylthio) ethyl] azacyclopentan-2-one (Pirotiodecane), on drug permeation across rabbit nasal mucosa was studied. The nasal epithelial mucosa was isolated from rabbit nasal septum and mounted in an Ussing chamber to allow for monitoring of the membrane resistance (Rm), and the permeation of fluorescein isothiocyanate-labeled dextran (FD-4, M.W. 4,400 Da). Treatment with 0.05, 0.1, and 0.2% Pirotiodecane for 60 min decreased Rm, and increased the cumulative amount of FD-4 permeated in a concentration-dependent manner, suggesting that Pirotiodecane possesses passively a disassembly of tight junction to enable the enhanced FD-4 permeation. The remarkable increase in plasma concentration of FD-4 was also observed in intranasal co-administration with 1% Pirotiodecane in rabbits. The Rm was virtually maintained after the removal of Pirotiodecane, although recovery of Rm was not seen. On the other hand, the increase in plasma concentration of FD-4 with intranasal co-administration of 1% Pirotiodecane in rabbits in vivo was not observed in FD-4 administration at 15-60 min after administration of 1% Pirotiodecane alone. It was concluded that Pirotiodecane possesses a relatively short absorption enhancing effect through nasal epithelial.
- Published
- 2005
24. Lipopolysaccharide Transport System across Colonic Epithelial Cells in Normal and Infective Rat
- Author
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Masahiro Hayashi, Rie Ohkubo, and Mikio Tomita
- Subjects
Lipopolysaccharides ,Male ,Pathology ,medicine.medical_specialty ,Cell Membrane Permeability ,Lipopolysaccharide ,Colon ,CD14 ,Lipopolysaccharide Receptors ,Pharmaceutical Science ,Receptors, Cell Surface ,Substrate Specificity ,Rats, Sprague-Dawley ,Lipopolysaccharide transport ,chemistry.chemical_compound ,medicine ,Animals ,Pharmacology (medical) ,Intestinal Mucosa ,Receptor ,Escherichia coli Infections ,Pharmacology ,Membrane Glycoproteins ,biology ,Toll-Like Receptors ,Biological Transport ,Molecular biology ,Rats ,Toll-Like Receptor 4 ,Electrophysiology ,chemistry ,Permeability (electromagnetism) ,biology.protein ,TLR4 ,lipids (amino acids, peptides, and proteins) ,Antibody ,Fluorescein-5-isothiocyanate ,Injections, Intraperitoneal - Abstract
To clarify whether lipopolysaccharide (LPS) is transported in rat intestinal epithelial cells, the transport of FITC-LPS across colonic epithelial cells in normal and LPS-exposured rats using a diffusion chamber was examined. The expression of CD14 and Toll-like receptor 4 (TLR4) was also examined. Rats were given 10 mg/kg LPS i.p. injection at 4 hr prior to the isolation of colonic epithelial tissues. The permeation rate across colonic mucosa by FITC-LPS was several times greater in the mucosal to serosal (M to S) direction than in the opposite direction in both normal and LPS-exposured rats. Increased M to S permeation by FITC-LPS was evident at 37 degrees C, but not at 4 degrees C. The permeability of FITC-LPS in both the M to S and S to M directions was inhibited by unlabeled LPS, anti-CD14 antibody or anti-TRL4 antibody in normal rat. In LPS-exposured rat, the inhibition in the M to S direction was observed by anti-TLR4 antibody, but not by unlabeled LPS and anti- CD14 antibody. In contrast, the permeability in the S to M direction was decreased only by unlabeled LPS in LPS-exposured rat. In normal rat, the expression of CD14 and TLR4 was found in the mucosal and serosal sides. In LPS-exposured rat, the expression of CD14 was not observed in the mucosal side. The electrophysiological parameters by LPS exposure remain unchanged. These findings suggest the possibility that colonic epithelial cells contain specific transport systems for LPS, one of which shows some degree of substrate specificity with the interaction of CD14 and/or that of TLR4.
- Published
- 2004
25. Clarification of the Mechanism of Structural Change Induced by Reoxygenation following the Induction of Lipid Peroxidation in Caco-2 Cell Monolayers
- Author
-
Masahiro Hayashi, Makoto Haga, Mayuko Nagira, and Mikio Tomita
- Subjects
Pharmacology ,Tiron ,Tight junction ,Superoxide ,Pharmaceutical Science ,Glutathione ,medicine.disease ,Lipid peroxidation ,Deferoxamine ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Biophysics ,medicine ,Pharmacology (medical) ,Reperfusion injury ,Barrier function ,medicine.drug - Abstract
Recently, we established a system for assessing ischemia/reperfusion injury, specifically the opening of tight junctions (TJ), caused by reoxygenation following the induction of lipid peroxidation by tertiary-butylhydroperoxide (t-BuOOH), using the human intestinal epithelial cell line Caco-2 in order to focus on the barrier function of the epithelium independent of the vascular compartment. In the present study, we attempted to identify factors involved in the structural changes induced by reoxygenation using 0.5 mM t-BuOOH in Caco-2 cell monolayers. Glutathione (GSH) and N-acetylcystein, a precursor of GSH, inhibited the opening of TJ evoked by reoxygenation following the induction of lipid peroxidation by 0.5 mM of t-BuOOH. Tiron, as a cell permeable superoxide anion scavenger and deferoxamine, an iron-chelating agent ameliorated the opening in a dose-dependent manner. Also, Tiron suppressed the apical-to-basal and basal-to-apical permeability of the increased Rhodamine123 by reoxygenation in a concentration-dependent manner. These results collectively suggest that superoxide anion and iron ions play an important role or contribute to structural changes such as the opening of TJ induced by reoxygenation following the induction of lipid peroxidation by 0.5 mM t-BuOOH.
- Published
- 2002
26. Electrophysiological Evaluation for Conditions of Preservation of Isolated Human Colon Tissues
- Author
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Rie Ohkubo, Shoji Awazu, Sotaro Sadahiro, Masahiro Hayashi, Yoshiyuki Hotta, Tatsuya Shimazaki, Mikio Tomita, and Mayuko Nagira
- Subjects
Electrophysiology ,Membrane permeability ,Viability assay ,Biology ,Human colon ,Cell biology - Published
- 2001
27. Polarized transport of hydrophilic compounds across rat colonic mucosa from serosa to mucosa is temperature dependent
- Author
-
Mitchell P. Fink, Russell L. Delude, Michael J. Menconi, and Mikio Tomita
- Subjects
Male ,Colon ,In Vitro Techniques ,Permeability ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Serous Membrane ,Gastrointestinal Agents ,Intestinal mucosa ,medicine ,Animals ,Mannitol ,Intestinal Mucosa ,Fluorescein ,Fluorescein isothiocyanate ,Fluorescent Dyes ,Gastrointestinal agent ,Hepatology ,Chemistry ,Temperature ,Gastroenterology ,Biological Transport ,Permeation ,Lactulose ,Rats ,Dextran ,Biochemistry ,Biophysics ,Efflux ,medicine.drug - Abstract
Background & Aims: In both clinical and experimental studies, intestinal epithelial barrier function is routinely assessed by measuring mucosal permeability to various hydrophilic compounds. We performed experiments to determine whether permeation of several hydrophilic compounds across rat colonic mucosa is polarized. Methods: Sheets of colonic mucosa, stripped of the underlying seromuscular coats, were mounted in Ussing chambers. Results: The rates of permeation across colonic mucosa by numerous hydrophilic compounds (fluorescein isothiocyanate [FITC]-dextrans with molecular weights of 4000 [FD4] and 70,000 [FD70] daltons, fluorescein disulfonic acid [FS], lucifer yellow [LY], lactulose, and mannitol) were several times greater in the serosal-to-mucosal (S→M) direction than in the opposite direction. Increased S→M permeation by FD4, lactulose, and mannitol was evident at 37°C, but not at 4°C. Efflux of FD4 and FS in the S→M direction was dose-dependently inhibited by verapamil, an inhibitor of the P-glycoprotein efflux system. Indomethacin, an anion transporter inhibitor, showed no effect on the S→M permeation of FD4, FD70, FS, or LY. Adding an excess of unlabeled dextran (mol wt, 10,000 daltons) dose-dependently decreased the S→M efflux of FD4, but not FS or LY. Conclusions: The transport across rat colonic mucosa of a number of hydrophilic substances, including some compounds that are commonly used to measure intestinal permeability in clinical practice, is greater in the S→M than in the M→S direction. S→M transport of these hydrophilic solutes is temperature dependent, suggesting that the process is an active one. S→M transport of FD4 may occur via a process that manifests some degree of substrate specificity for polysaccharides. GASTROENTEROLOGY 2000;118:535-543
- Published
- 2000
28. Mesenteric dysfunction after cardiopulmonary bypass: role of complement C5a
- Author
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Cesario Bianchi, Caroline Metais, Mitchell P. Fink, Gregory L. Stahl, Motohisa Tofukuji, Frank W. Sellke, Mikio Tomita, and Azin Agah
- Subjects
Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Swine ,medicine.medical_treatment ,Complement C5a ,Ileum ,Vascular permeability ,law.invention ,Capillary Permeability ,Postoperative Complications ,law ,Internal medicine ,medicine ,Cardiopulmonary bypass ,Animals ,Splanchnic Circulation ,Intestinal Mucosa ,Saline ,Phenylephrine ,Cardiopulmonary Bypass ,biology ,business.industry ,Mesenteric Arteries ,Nitric oxide synthase ,surgical procedures, operative ,medicine.anatomical_structure ,Endocrinology ,Myeloperoxidase ,Immunology ,biology.protein ,Female ,Surgery ,Cardiology and Cardiovascular Medicine ,business ,Perfusion ,circulatory and respiratory physiology ,medicine.drug - Abstract
Background . We investigated the effects of cardiopulmonary bypass (CPB) on ileal homeostasis, and the influence of functional inhibition of complement C5a on CPB-induced mesenteric injury. Methods . Pigs were perfused on CPB for 1 hour and then perfused off CPB for an additional 2 hours. Antiporcine C5a monoclonal antibody (C5a MAb) was administered 20 minutes before onset of CPB to 6 pigs; 6 controls received saline vehicle. Total complement activity, ileal myeloperoxidase, and indices of ileal integrity were examined. Results. Treatment with C5a MAb ameliorated CPB-induced abnormalities in endothelium-dependent relaxation to ADP and substance P, and the hypercontractile response to phenylephrine of ileal microvessels (88 to 168 μm). Ileal myeloperoxidase activity [units/g protein] was 41 ± 11 in the C5a MAb group, compared to 83 ± 13 in the saline group (19 ± 10 base line). Total hemolytic complement activity was similar in the C5a MAb and saline groups (0.6 ± 0.2 and 0.7 ± 0.2 CH 50 units). During CPB, ileal mucosal blood flow and mucosal pH, edema formation, and epithelial permeability deteriorated similarly in saline and C5a MAb groups. Inducible nitric oxide synthase (iNOS) mRNA expression was similar before and after CPB. Conclusions. CPB is associated with significant physiologic alterations in mucosal perfusion, epithelial permeability, edema formation, and blood flow regulation. Inhibition of C5a limits neutrophil-mediated impairment of ileal microvascular regulation after bypass, but does not improve extravascular mesenteric dysfunction after CPB.
- Published
- 2000
29. Nonlinear Intestinal Absorption of (1.RAR.3)-.BETA.-D-Glucan Caused by Absorptive and Secretory Transporting System
- Author
-
Mitsutaka Miwa, Masahiro Hayashi, Shohei Ouchi, Mikio Tomita, Toshio Oda, Yuko Goto, and Jun Aketagawa
- Subjects
Male ,beta-Glucans ,Pharmaceutical Science ,Ileum ,In Vitro Techniques ,Biology ,Beta-glucan ,Intestinal absorption ,chemistry.chemical_compound ,Serous Membrane ,Polysaccharides ,medicine ,Animals ,Intestinal Mucosa ,Rats, Wistar ,Glucans ,Pharmacology ,Dose-Response Relationship, Drug ,Biological Transport ,Transporter ,General Medicine ,Permeation ,In vitro ,Rats ,Dose–response relationship ,medicine.anatomical_structure ,Intestinal Absorption ,Nonlinear Dynamics ,Biochemistry ,chemistry ,Biophysics ,Proteoglycans ,Efflux ,2,4-Dinitrophenol - Abstract
The mechanism of the nonlinear concentration dependence of intestinal absorption of (1-->3)-beta-D-glucan was studied using in situ rat intestinal perfusion, as well as the in vitro Ussing-type chamber method mounted with rat intestinal tissue. The intestinal absorption rate constant of a (1-->3)-beta-D-glucan, laminaran, evaluated by the loop method increased significantly with increasing concentration of laminaran up to 0.5 muM in a nonlinear fashion and tended to decrease at higher concentrations. Mucosal-to-serosal directed permeation of the laminaran across rat ileal sheets evaluated by the in vitro Ussing-type chamber method also decreased in a dose-dependent fashion. Serosal-to-mucosal directed permeation decreased in a concentration-dependent manner. In addition, the serosal-to-mucosal flux was reduced in the presence of metabolic inhibitor, 2,4-di-nitrophenol. These results suggest that laminaran is secreted into the intestinal lumen predominantly by the efflux transporting system. We conclude that intestinal transport of (1-->3)-beta-D-glucan involves specialized transporter or something similar in both absorptive and secretory directions, and complex nonlinear intestinal absorption characteristics can be ascribed to the participation of multiple transport mechanism.
- Published
- 2009
30. [Untitled]
- Author
-
Sotaro Sadahiro, Tatsuya Shimazaki, Shoji Awazu, Mikio Tomita, and Masahiro Hayashi
- Subjects
Contraction (grammar) ,Calmodulin ,biology ,Tight junction ,Physiology ,Chemistry ,Gastroenterology ,Permeation ,digestive system diseases ,chemistry.chemical_compound ,Membrane ,Biochemistry ,Paracellular transport ,biology.protein ,Biophysics ,medicine ,Carnitine ,Palmitoylcarnitine ,medicine.drug - Abstract
We examined the enhancing action of sodium caprate and palmitoylcarnitine on the permeability of fluorescein isothiocyanate dextran 4000 as a paracellular permeant compound in isolated rat and human colon samples using the Ussing-type chamber method. In the absence of an enhancer, the permeation clearance of fluorescein isothiocyanate dextran 4000 was not significantly different in the rat and human colons, but the electric membrane resistance was smaller in the rat colon than in the human colon. Sodium caprate and palmitoylcarnitine increased permeation clearance and decreased electric membrane resistance in both types of colonic membrane, showing that the rat colon can be used as a model of the human colon for studies of enhancer effects. A calmodulin antagonist significantly inhibited the action of sodium caprate in both colonic membranes. However, it tended to promote the effects of palmitoylcarnitine on permeation clearance and electric membrane resistance. These results suggest that sodium caprate induces the contraction of the perijunctional actomyosin ring to widen the tight junction and that the mechanism of palmitoylcarnitine is different from that of sodium caprate in the human colon, as reported previously for Caco-2 cell monolayers.
- Published
- 1998
31. Transcellular and paracellular contribution to transport processes in the colorectal route
- Author
-
Mikio Tomita, Masahiro Hayashi, and Shoji Awazu
- Subjects
Absorption (pharmacology) ,Membrane potential ,Tight junction ,urogenital system ,Chemistry ,Pharmaceutical Science ,Membrane transport ,complex mixtures ,digestive system ,Biochemistry ,Mechanism of action ,In vivo ,Paracellular transport ,medicine ,Biophysics ,lipids (amino acids, peptides, and proteins) ,Transcellular ,medicine.symptom ,tissues - Abstract
The two permeation pathways for colorectal drug absorption, the transcellular and paracellular pathways, were examined. The transcellular pathway is generally a principal route for drugs with some degree of lipophilicity. The contribution of the paracellular pathway to drug absorption is significant when absorption enhancers such as capric acid (C10) and decanoylcarnitine (DC) are used. The action mechanism of C10 on the transcellular pathway was examined by membrane perturbation. The following in vitro effects of C10 on the paracellular pathway were observed: (i) an increase in the equivalent pore radius; (ii) an increase in the permeabilities of water-soluble non-electrolytes and ionic drugs; (iii) a decrease in the junctional resistance and an increase in the membrane capacitance. The action mechanism of C10 in the paracellular pathway was especially elucidated by stimulation to the contraction of the perijunctional actomyosin ring. Finally, an in vivo C10 effect was also observed, as an enhancement of rectal drug absorption from suppositories in rats.
- Published
- 1997
32. Changes of Absorptive and Secretory Transporting System of (1 → 3) β-D-glucan Based on Efflux Transporter in Indomethacin-induced Rat
- Author
-
Aiko, Iida, Shohei, Ouchi, Toshio, Oda, Jun, Aketagawa, Yasuhiko, Ito, Yusuke, Takizawa, Mikio, Tomita, and Masahiro, Hayashi
- Subjects
Inflammation ,Male ,ATP Binding Cassette Transporter, Subfamily B ,Time Factors ,beta-Glucans ,Indomethacin ,Down-Regulation ,Biological Transport ,Disease Models, Animal ,Jejunum ,Intestinal Absorption ,Ileum ,ATP Binding Cassette Transporter, Subfamily G, Member 2 ,Animals ,ATP-Binding Cassette Transporters ,Proteoglycans ,RNA, Messenger ,Rats, Wistar ,Glucans - Abstract
Infection and inflammation suppress the expression and activity of several drug transporters in liver. In the intestine, P-glycoprotein (P-gp/MDR1), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP) are important barriers to the absorption of many clinically important drugs. The expression and activity of these proteins were examined under inflammation. Drug transport was determined in jejunum and ileum segments isolated from 1.0 mg/kg, 5.0 mg/kg, and 7.5 mg/kg indomethacin-treated or control rats in diffusion chambers. Transport of laminaran, used as a model compound of (1-3) β-D-glucan, was measured for 120 min in the presence or absence of inhibitors. Reverse transcription-polymerase chain reaction was used to measure mRNA levels. Compared with controls, levels of Mdr1a mRNA were significantly decreased in the jejunum and ileum of 7.5 mg/kg indomethacin-treated rats. Both reductions in the basolateral to apical efflux of laminaran and increases in the apical to basolateral influx of laminaran were observed, resulting in significant increases in the apical to basolateral absorption of laminaran in 7.5 mg/kg indomethacin-treated rats. The inhibitory effect of verapamil on laminaran transport was observed in control rats but not in indomethacin-treated rats. Fluorescein isothiocyanate dextran 40,000 permeability, membrane resistance, and claudin-4 mRNA level were not altered, indicating no change in the paracellular pathway. These results indicate that indomethacin-induced inflammation reduces the intestinal expression and activity of P-gp in rats, which elicits corresponding changes in the intestinal transport of laminaran. Hence, inflammatory diseases may impose variability in drug bioavailability through alterations in the intestinal expression and activity of drug transporters.
- Published
- 2013
33. Effects of pharmaceutical excipients on membrane permeability in rat small intestine
- Author
-
Mikio Tomita, Nasa Sakamoto, Minami Nakagawa, Takahito Furuya, Yusuke Takizawa, Yoshifusa Tobe, Masahiro Hayashi, and Hisanao Kishimoto
- Subjects
Male ,Cell Membrane Permeability ,Membrane permeability ,Pharmaceutical Science ,Ileum ,In Vitro Techniques ,Intestinal absorption ,Jejunum ,Excipients ,Intestinal mucosa ,medicine ,Animals ,Intestinal Mucosa ,Rats, Wistar ,Fluorescent Dyes ,Chromatography ,Chemistry ,Permeation ,Fluoresceins ,Small intestine ,Rats ,medicine.anatomical_structure ,Intestinal Absorption ,Paracellular transport - Abstract
Pharmaceutical excipients should not disturb the effects of drug therapy. In recent years, however, it has been reported that excipients induce some changes to the tight junction (TJ) and P-glycoprotein (P-gp), which can affect drug disposition. In this study, we examined the effects of 20 common pharmaceutical excipients from different classes on mucosal membrane and the differences of such effects among regions of the small intestine. We used the in vitro sac method in rat jejunum and ileum to study the effects of excipients on the membrane permeation of 5(6)-carboxyfluorescein (5-CF). 5-CF was used as a model of water-soluble compounds. In some dosage conditions of methyl-β-cyclodextrin, the membrane permeability of 5-CF was significantly increased in the jejunum, but such change was not observed in the ileum. Similarly, in the cases of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and croscarmellose sodium, the membrane permeability of 5-CF was significantly increased in the jejunum, but no change was observed in the ileum. On the other hand, in both the jejunum and the ileum, the membrane permeation of 5-CF was decreased with 0.02% (w/v) hydroxypropyl cellulose, but significantly increased with it at 0.20% (w/v). It was shown that excipients affected the membrane permeability of water-soluble compounds via the paracellular route, and these effects on absorption differed among regions of the small intestine. Moreover, in the case of 20 excipients, not only an increase in membrane permeability but also a decrease was observed. Therefore, it was suggested that a more effective formulation could be designed by changing the combination of excipients.
- Published
- 2013
34. Characteristics of reversible absorption-enhancing effect of sodium nitroprusside in rat small intestine
- Author
-
Hisanao Kishimoto, Masahiro Hayashi, Naomi Kamiya, Yusuke Takizawa, Yasuhiko Ito, Haruka Ishizaka, Mikio Tomita, and Takuya Kitazato
- Subjects
Male ,Nitroprusside ,Pharmaceutical Science ,Ileum ,Absorption (skin) ,Nitric oxide ,chemistry.chemical_compound ,Lactate dehydrogenase ,medicine ,Animals ,Nitric Oxide Donors ,Viability assay ,Intestinal Mucosa ,Rats, Wistar ,Claudin ,Nitrites ,Phospholipids ,Chemistry ,Cell Membrane ,Molecular biology ,Rats ,medicine.anatomical_structure ,Intestinal Absorption ,Paracellular transport ,Claudins ,Sodium nitroprusside ,medicine.drug - Abstract
Nitric oxide (NO) donors increase the permeability of water-soluble compounds with neither loss of cell viability nor lactate dehydrogenase release. In addition, the rectal absorption of insulin has been reported to be remarkably enhanced in the presence of NO donors such as 1-Hydroxy-3-(3-aminopropyl)-3-isopropyltriazene 2-oxide (NOC5) and N-Ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino) ethanamine (NOC12). In this study, we examined the effect of sodium nitroprusside (SNP), which is used in clinical situations as a vasodilator, as a model NO donor on the ileal mucosa of rats. We used an in situ closed loop method in rat ileum to study changes in the permeability of fluorescein isothiocyanate dextran 4000 (FD-4) as a paracellular marker. The effect of SNP (1 and 10 mg/kg) on the protein expression level of the claudin family was examined by Western blotting. The membrane permeation of FD-4 was increased but no mucosal lesion was observed upon the administration of SNP. Moreover, the protein expression level of the claudin family was not changed by the administration of SNP. When SNP was removed 2 h after its administration, no significant change in the membrane permeation of FD-4 was observed. Moreover, no decrease of ileal membrane resistance or disruption of membrane structure was observed. The absorption-enhancing effect of SNP was associated with low injury and low toxicity. The reversibility of the effect of SNP was observed. Consequently, it was shown that SNP can be a useful absorption enhancer.
- Published
- 2013
35. Changes in the expression levels of tight junction components during reconstruction of tight junction from mucosal lesion by intestinal ischemia/reperfusion
- Author
-
Hisanao Kishimoto, Masahiro Hayashi, Yusuke Takizawa, and Mikio Tomita
- Subjects
Scaffold protein ,Male ,Pathology ,medicine.medical_specialty ,Time Factors ,Blotting, Western ,Biology ,Real-Time Polymerase Chain Reaction ,Cell junction ,Permeability ,Tight Junctions ,Ileum ,Cell polarity ,medicine ,Animals ,Pharmacology (medical) ,RNA, Messenger ,Intestinal Mucosa ,Rats, Wistar ,Claudin ,Pharmacology ,Regulation of gene expression ,Messenger RNA ,Tight Junction Proteins ,Tight junction ,Reverse Transcriptase Polymerase Chain Reaction ,Intracellular Signaling Peptides and Proteins ,Cell biology ,Blot ,Disease Models, Animal ,Gene Expression Regulation ,Reperfusion Injury ,Claudins ,Carrier Proteins - Abstract
Tight junction (TJ) is composed of the most apical components of the intercellular junctional complex in epithelial cells; TJ has cell polarity and functions as a major determinant of epithelial barrier function. In this study, to clarify the components of TJ required for its reconstruction and functional acquisition, we examined the changes in intestinal mucosal structure that depended on mucosal lesion by intestinal I/R, that is, the changes in mRNA and protein expression of the claudin family and scaffold proteins. We used an in vivo intestinal I/R model made using the spring scale and surgical sutures, and examined the mRNA and protein expression levels of TJ components by real-time RT-PCR and Western blotting, respectively. Changes in mRNA and protein expression levels of TJ components by intestinal I/R were observed. Among them, characteristic changes were observed in claudin-2 and claudin-4. In addition, the expression behavior of multi-PDZ domain protein (MPDP) mRNA was similar to that of claudin-4. In conclusion, in the recovery process of TJ from mucosal lesion by intestinal I/R, it was suggested that claudin-2 and claudin-4 strongly participate in the reconstruction and functional acquisition of TJ, respectively. Furthermore, it was suggested that MPDZ, which is scaffold protein, also has an important role in these processes.
- Published
- 2013
36. Absorption-Enhancing Mechanism of EDTA, Caprate, and Decanoylcarnitine in Caco-2 Cells
- Author
-
Shoji Awazu, Mikio Tomita, and Masahiro Hayashi
- Subjects
Intracellular Fluid ,Cell Membrane Permeability ,Calmodulin ,Pharmaceutical Science ,chemistry.chemical_element ,Calcium ,Microfilament ,Epithelium ,Calcium in biology ,Carnitine ,Electric Impedance ,Humans ,Intestinal Mucosa ,Egtazic Acid ,Protein kinase C ,biology ,Dextrans ,Apical membrane ,Calmodulin dependent protein kinase ,Intestinal Absorption ,chemistry ,Biochemistry ,Paracellular transport ,biology.protein ,Biophysics ,Caco-2 Cells ,Decanoic Acids ,Fluorescein-5-isothiocyanate - Abstract
The mechanism of paracellular expansion by absorption enhancers, e.g., EDTA, sodium caprate (C10), and decanoylcarnitine (DC), was studied, the focus being on the process of actin microfilament contraction in the tight junction. The effects of various inhibitors such as KN-62 (a specific inhibitor of Ca2+/calmodulin dependent protein kinase), H7 (a protein kinase C (PKC) inhibitor), and W7 (a calmodulin antagonist) were examined on the paracellular expansion by the enhancers in Caco-2 cells. From the experimental results, the following mechanisms were suggested. EDTA activates PKC by depletion of extracellular calcium via chelation resulting in expansion of the paracellular route. C10 increases the intracellular calcium level by an interaction with the cell membrane independent of cell polarity resulting in contraction with actin microfilament. DC interacts specifically with the apical membrane to increase the intracellular calcium level, but the mechanistic details subsequent to the increase of calcium are not clear.
- Published
- 1996
37. Changes in absorption and excretion of rhodamine 123 by sodium nitroprusside
- Author
-
Mikio Tomita, Hisanao Kishimoto, Takuya Kitazato, Naomi Kamiya, Yusuke Takizawa, Masahiro Hayashi, Haruka Ishizaka, and Yasuhiko Ito
- Subjects
Male ,Nitroprusside ,medicine.medical_specialty ,Pharmaceutical Science ,Absorption (skin) ,Rhodamine 123 ,Nitric oxide ,Absorption ,Excretion ,chemistry.chemical_compound ,Ileum ,Lactate dehydrogenase ,Internal medicine ,medicine ,Animals ,Nitric Oxide Donors ,Viability assay ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Transcellular ,Rats, Wistar ,Fluorescent Dyes ,Rats ,Endocrinology ,Biochemistry ,chemistry ,Sodium nitroprusside ,medicine.drug - Abstract
Nitric oxide (NO) donors increase the permeability of water-soluble compounds with neither loss of cell viability nor lactate dehydrogenase release, but the involved mechanism is not fully understood. In this study, we focused on permeation via the transcellular route and P-glycoprotein, which is a typical ABC transporter. We examined the effect of sodium nitroprusside (SNP), which is an NO donor, on the membrane permeation of rhodamine 123 (Rho123), a representative P-gp substrate, and the change in expression level of ileal P-gp. We used an in situ closed loop method in rat ileum to study changes in the permeation of Rho123. The effects of SNP (1 and 10mg/kg) on the mdr-1a mRNA and P-gp protein expression levels were examined by real-time RT-PCR and Western blotting, respectively. The absorption and excretion of Rho123 were significantly increased in an SNP dose-dependent manner when compared with those with no addition, but no changes in protein expression level of P-gp in ileal BBM were observed by SNP administration. The relative activity of P-gp was not changed by SNP administration. On the other hand, the expression level of mdr-1a mRNA was induced by SNP administration. We indicated that SNP could increase the mucosal permeation of Rho123 via the transcellular route without an influence on P-gp, and we showed that this effect is temporary. SNP has no influence on P-gp function and protein expression level in the short term, but they may change in the long term.
- Published
- 2012
38. IMPROVEMENT OF GASTROINTESTINAL DRUG ABSORPTION BASED ON OPENING THE TIGHT JUNCTION
- Author
-
Nobuyuki Tanaka, Mikio Tomita, and Shoji Awazu
- Subjects
Materials science ,Tight junction ,Gastrointestinal drug absorption ,Biophysics - Published
- 1995
39. [Examination of involuntary admissions in relations of CRPD]
- Author
-
Mikio, Tomita
- Subjects
Patient Rights ,Japan ,Commitment of Mentally Ill - Abstract
When we examine the problems of involuntary admissions, CRPD (the convention on the rights of persons with disabilities-2006) must be considered within the context of the problems. The principle of the convention is based on enjoyment of legal capacity of persons with disabilities. So, it is necessary to recognize the relation and the contradiction between disease-disorder-disability spectrum and capacity-ability spectrum. The two spectrums have been developed after the Second World War with development of societies of the world. Author presents the recognition of involuntary admissions of Japan. So, Japanese psychiatry must select the road to community psychiatry to solve the problems.
- Published
- 2012
40. Increases in bioavailability of poorly absorbed drug by acylcarnitine
- Author
-
Mikio Tomita, Nobuyuki Doi, Aoi Kimura, and Masahiro Hayashi
- Subjects
Drug ,Male ,medicine.medical_specialty ,Colon ,media_common.quotation_subject ,Pharmaceutical Science ,Administration, Oral ,Biological Availability ,Pharmacology ,Jejunum ,chemistry.chemical_compound ,Internal medicine ,Carnitine ,medicine ,Animals ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Claudin-4 ,Rats, Wistar ,Palmitoylcarnitine ,P-glycoprotein ,media_common ,Fluorescent Dyes ,Lucifer yellow ,biology ,L-Lactate Dehydrogenase ,Transporter ,Isoquinolines ,Bioavailability ,Rats ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Intestinal Absorption ,Lauroylcarnitine ,Injections, Intravenous ,biology.protein ,Laurates - Abstract
We examined the effect of acylcarnitines on the in situ bioavailability of lucifer yellow (LY) from the loops of small and large intestines of rats. The area under the blood concentration of LY versus time curve (AUC) from the jejunum was significantly increased by the treatments of the loop with 100 µM lauroylcarnitine (LC) or 100 µM palmitoylcarnitine (PC) (fourfold and 17-fold, respectively). No marked change in the expression of claudin-4 protein was observed by the treatments. On the contrary, the expression of P-glycoprotein (P-gp) was decreased by the treatment, more greatly by PC than by LC, suggesting that increases in the bioavailability of LY by LC and PC are associated with the decreased expression of P-gp in jejunum. The increase in the bioavailability was also observed for colon by the treatment of LC, but not that of PC. LC decreased the expression of claudin-4 protein, whereas PC decreased the expression of P-gp in colon. Therefore, LC and PC appear to have different impact on the intestinal transporters depending on the site (i.e., jejunum and colon). © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association
- Published
- 2012
41. Suppression of efflux transporters in the intestines of endotoxin-treated rats
- Author
-
Mikio, Tomita, Yusuke, Takizawa, Atsushi, Kanbayashi, Hiroyuki, Murata, Ayako, Tanaka, Mariko, Nakaike, Megumi, Hatanaka, Tomomi, Kai, and Masahiro, Hayashi
- Subjects
Inflammation ,Lipopolysaccharides ,Male ,ATP Binding Cassette Transporter, Subfamily B ,Gene Expression ,Membrane Transport Proteins ,Biological Transport ,Fluoresceins ,Infections ,Drug Resistance, Multiple ,Rats ,Endotoxins ,Ileum ,Animals ,ATP-Binding Cassette Transporters ,Rhodamine 123 ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,RNA, Messenger ,Rats, Wistar - Abstract
Infection and inflammation suppress the expression and activity of several drug transporters in the liver. In the intestine, P-glycoprotein (PGP/mdr1) and the multidrug resistance-associated protein 2 (MRP2) are important barriers to the absorption of many clinically important drugs. The protein expression and activity of these transporters were examined during inflammation induced by lipopolysaccharide (LPS). The transport of rhodamine123 (Rho123) and 5-carboxyfluorescein (5-CF) was determined in isolated ileal segments from endotoxin-treated or control rats in the presence or absence of inhibitors. The reverse transcription-polymerase chain reaction was used to measure mRNA levels. Compared with the controls, the mRNA levels of mdr1a and mrp2 were significantly decreased by approximately 50% in the ilea of the LPS-treated rats. Corresponding reductions in the basolateral-apical efflux of Rho123 and 5-CF were observed, resulting in significant increases in the apical-basolateral absorption of these compounds. Neither the permeability of fluorescein isothiocyanate labeled dextran 4000 (FD-4), a paracellular marker, nor membrane resistance was altered. These results indicate that endotoxin-induced inflammation reduces the intestinal expression and activity of PGP and MRP2 in rats, which eliciting corresponding changes in the intestinal transport of their substrates. Hence, infection and inflammatory diseases may induce variability in drug bioavailability through alterations in the intestinal expression and activity of drug transporters.
- Published
- 2011
42. Changes in protein and mRNA expression levels of claudin family after mucosal lesion by intestinal ischemia/reperfusion
- Author
-
Hisanao Kishimoto, Yusuke Takizawa, Mikio Tomita, Masahiro Hayashi, and Takuya Kitazato
- Subjects
Male ,medicine.medical_specialty ,Pathology ,Ischemia ,Pharmaceutical Science ,Administration, Oral ,Ileum ,Biology ,Cell junction ,Intestinal absorption ,Permeability ,Tight Junctions ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Intestinal Mucosa ,Rats, Wistar ,Claudin ,Phospholipids ,Fluorescent Dyes ,Tight junction ,Dextrans ,medicine.disease ,Rats ,Transplantation ,Disease Models, Animal ,Endocrinology ,medicine.anatomical_structure ,Gene Expression Regulation ,Intestinal Absorption ,Paracellular transport ,Area Under Curve ,Reperfusion Injury ,Claudins ,Fluorescein-5-isothiocyanate - Abstract
Ischemia/reperfusion (I/R) injury of the intestine is the leading cause of organ dysfunction after restoration of blood flow after diverse events, including shock and intestinal transplantation. I/R injury must be overcome for successful small intestinal transplantation. Tight junctions (TJ) are the most apical component of the intercellular junctional complex in epithelial cells; they establish cell polarity and functioning as major determinants of epithelial barrier function. Among the proteins that comprise TJ, the claudin family is thought to play a crucial role in homeostasis in multicellular organisms. Therefore, the aim of this study was to examine the changes in function of TJ and behavior of the claudin family during intestinal I/R. Wistar/ST rats underwent intestinal ischemia by using the spring scale and surgical suture for 1h, followed by 24h of reperfusion. We examined the changes in area under the blood concentration curve (AUC) after oral administration of FD-4, which is a paracellular marker, and claudin-1, -2, -4, and -7 mRNA and protein expression levels in ileum. The structure of ileal mucosa was partly damaged and its function was diminished by intestinal I/R until 3h after reperfusion, but were almost recovered 24h after reperfusion. However, a time difference was shown between the recoveries of mucosal structure and function. Furthermore, a difference in the expression among various kinds of claudin was found. It was suggested that claudin-4 and multi-PDZ domain protein, which is a scaffolding protein, regulate intestinal paracellular permeability during intestinal I/R. Moreover, the changes in the expression level of claudin-2 were unique.
- Published
- 2011
43. Effects of acylcarnitines on efflux transporting system in Caco-2 cell monolayers
- Author
-
Nobuyuki Doi, Masahiro Hayashi, and Mikio Tomita
- Subjects
Pharmacology ,Lucifer yellow ,L-Lactate Dehydrogenase ,Chemistry ,Palmitoylcarnitine ,ATP-binding cassette transporter ,Biological Transport ,Dextrans ,Membrane transport ,Isoquinolines ,chemistry.chemical_compound ,Biochemistry ,Caco-2 ,Carnitine ,Moiety ,Humans ,Pharmacology (medical) ,Efflux ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Caco-2 Cells ,Cytotoxicity ,Fluorescein-5-isothiocyanate ,Laurates ,Fluorescent Dyes - Abstract
This study examined the effects of the absorption enhancers, acylcarnitines, on efflux transporting systems, including P-glycoprotein (P-gp) and other efflux transporters, and elucidated the importance of acyl chain length and the concentration of acylcarnitine on the activity of efflux transport. The effects of two acyl (lauroyl and palmitoyl) carnitines on the influx and efflux of lucifer yellow and fluorescein isothiocyanate dextran 4,000, which have characteristic vectorial transport, were examined in Caco-2 cell monolayers. Lauroylcarnitine and palmitoylcarnitine increased influx and decreased efflux of these substrates, in a manner dependent on their concentration and acyl chain lengths by increasing influx and inhibiting efflux of the substrates. The results indicated that both the acyl moiety and long acyl chains play important roles in the modification of influx and efflux transport. Because no marked changes in the levels of P-gp protein or the leakage of LDH were observed at 1 h after the application of acylcarnitines, it was concluded that these acylcarnitines had an effect on modulation of the function of P-gp or other efflux transporters without cytotoxicity.
- Published
- 2011
44. Changes in the localization of ileal P-glycoprotein induced by intestinal ischemia/reperfusion
- Author
-
Takuya Kitazato, Yusuke Takizawa, Hisanao Kishimoto, Masahiro Hayashi, and Mikio Tomita
- Subjects
Male ,medicine.medical_specialty ,Brush border ,medicine.medical_treatment ,Ischemia ,Pharmaceutical Science ,Nitric Oxide ,Proinflammatory cytokine ,Nitric oxide ,chemistry.chemical_compound ,Ileum ,Internal medicine ,medicine ,Animals ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,RNA, Messenger ,Intestinal Mucosa ,Rats, Wistar ,Epithelial polarity ,P-glycoprotein ,Pharmacology ,biology ,Biological Transport ,General Medicine ,Organ Transplantation ,medicine.disease ,Rats ,Transplantation ,Endocrinology ,Cytokine ,Biochemistry ,chemistry ,Reperfusion ,biology.protein ,Cytokines ,Inflammation Mediators ,Immunosuppressive Agents - Abstract
P-glycoprotein is one of the most important transporters in the ATP binding cassette transporter. Moreover, it is well known that the efficacy of immunosuppressants, which are used after organ transplantation, is controlled by P-glycoprotein (P-gp). We investigated how ischemia/reperfusion (I/R), which occurs after transplantation, influences the expression level and function of P-gp. To clarify the influence of intestinal I/R on the localization of P-gp, an intestinal ischemia model was produced using a spring scale and surgical sutures for 1 h, followed by reperfusion for 24 h. The expression levels of mRNA and protein of P-gp were examined. The protein expression levels of P-gp in ileal homogenate and the brush border membrane (BBM) were significantly decreased until 3 h after reperfusion. While the protein expression level of P-gp in homogenate showed a tendency to increase, that in the BBM continued to significantly decrease until 24 h after reperfusion. In contrast, the protein expression level of P-gp in the basolateral membrane (BLM) increased significantly until 24 h after reperfusion. While no significant change in multidrug resistance (mdr)-1a mRNA was found, the levels of mdr-1b and mdr-2 significantly increased during intestinal I/R. In addition, the levels of inflammatory cytokines mRNA and nitric oxide (NO) also significantly increased. It was shown that mdr-1b and mdr-2 mRNA strongly participate in the recovery of P-gp protein level after intestinal I/R. We detected the abnormal localization of P-gp in the ileal membrane during intestinal I/R, suggesting NO and/or inflammatory cytokines participate in the abnormal localization of P-gp.
- Published
- 2011
45. [Now is the time to abolish the law concerning medical observation of medically insane and drastically revise the psychiatric care]
- Author
-
Mikio, Tomita
- Subjects
Psychiatry ,Jurisprudence ,Japan ,Insanity Defense - Published
- 2010
46. Effect of intestinal ischaemia/reperfusion on P-glycoprotein-mediated ileal excretion of rhodamine 123 in the rat
- Author
-
Hisanao Kishimoto, Masahiro Hayashi, Yusuke Takizawa, and Mikio Tomita
- Subjects
Male ,medicine.medical_specialty ,Ischemia ,Pharmaceutical Science ,Gene Expression ,Nitric Oxide Synthase Type II ,Ileum ,Nitric Oxide Synthase Type I ,Rhodamine 123 ,Excretion ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Rats, Wistar ,P-glycoprotein ,Pharmacology ,biology ,Chemistry ,Membrane Transport Proteins ,medicine.disease ,Small intestine ,Rats ,Nitric oxide synthase ,Oxidative Stress ,medicine.anatomical_structure ,Endocrinology ,Biochemistry ,Verapamil ,Reperfusion Injury ,biology.protein ,medicine.drug - Abstract
Objectives We have shown that ischaemia/reperfusion in the small intestine at an early phase, such as 1 h after reperfusion, induced not only functional changes in the membrane, such as P-glycoprotein (P-gp) dysfunction, but also decreased expression of P-gp protein and mdr1a mRNA. In the present study we examined whether intestinal ischaemia/reperfusion modifies the P-gp-mediated ileal excretion transport system in rats beyond 1 h after reperfusion. Methods To evaluate the contribution of P-gp-mediated transport to the ileal excretion of rhodamine 123, we used Western blotting to measure the expression of P-gp protein levels isolated from the ileum at different reperfusion times after 60 min of ischaemia. We also measured the expression of inducible nitric oxide synthase (iNOS) mRNA using real-time RT-PCR. Key findings Ileal excretion of rhodamine 123 decreased at 3 h after reperfusion and had recovered at 24 h. Changes in villi structure at 3 h and its recovery at 24 h were also observed. Verapamil, a competitive inhibitor of P-gp, significantly inhibited ileal clearance of rhodamine 123 to the lumen at 24 h after reperfusion, suggesting that P-gp was working at this time. These results suggest that intestinal ischaemia/reperfusion-induced decrease in P-gp-mediated ileal excretion of rhodamine 123 was probably due to impaired P-gp-mediated transport. Levels of P-gp protein and iNOS mRNA in the ileum decreased 3 h after ischaemia/reperfusion and returned to control levels after 24 h. Conclusions These findings suggest that intestinal ischaemia/reperfusion markedly decreases P-gp-mediated ileal excretion of rhodamine 123, probably by decreasing the expression of P-gp protein, which is likely to be due to increased lipid peroxidation via iNOS.
- Published
- 2009
47. Nonlinear absorption of methylprednisolone by absorptive and secretory transporters
- Author
-
Tomoko Yamakawa, Mikio Tomita, Atsuko Watanabe, Masahiro Hayashi, and Ikue Fujinaga
- Subjects
Absorption (pharmacology) ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Cell ,Pharmaceutical Science ,Methylprednisolone ,Intestinal absorption ,Pharmacokinetics ,Internal medicine ,medicine ,Animals ,Humans ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Intestinal Mucosa ,Rats, Wistar ,Glucocorticoids ,Dose-Response Relationship, Drug ,Chemistry ,Transporter ,Biological Transport ,Permeation ,Rats ,Steroid hormone ,medicine.anatomical_structure ,Endocrinology ,Jejunum ,Intestinal Absorption ,Nonlinear Dynamics ,Biophysics ,Caco-2 Cells ,medicine.drug - Abstract
The intestinal absorption rate constant of methylprednisolone (MP) evaluated by the loop method increased significantly with increasingly higher concentrations of the drug up to 500 microM in a nonlinear fashion but did not increase further at higher concentrations. Mucosal-to-serosal directed permeation of MP across rat jejunal sheets also increased in a nonlinear fashion in a low concentration range (100-150 microM), followed by a decrease as the concentration increased further, whereas serosal-to-mucosal directed permeation decreased in a concentration-dependent manner. Vectorial transport of MP across Caco-2 cell monolayers was observed, with greater transport in the basolateral-to-apical direction at 37 degrees C. These observations suggest that MP is taken up in the intestinal epithelial cells by a carrier-mediated transport mechanism. The absorptive and secretory clearance of MP increased and decreased with P-glycoprotein (P-gp) inhibitors, respectively. These results strongly suggest that MP is secreted into the intestinal lumen predominantly by P-gp. We conclude that intestinal transport of MP involves P-gp or some other transporters in both the absorptive and secretory directions, and complex nonlinear intestinal absorption characteristics can be ascribed to the existence of multiple transport mechanisms.
- Published
- 2009
48. [Untitled]
- Author
-
Masahiro Hayashi, Takahiro Ogawa, Toyohiro Sawada, Mikio Tomita, and Shoji Awazu
- Subjects
Pharmacology ,Chromatography ,Chemistry ,Organic Chemistry ,Pharmaceutical Science ,Erythritol ,Permeation ,Cell junction ,chemistry.chemical_compound ,Thiourea ,Permeability (electromagnetism) ,Paracellular transport ,medicine ,Molecular Medicine ,Pharmacology (medical) ,Mannitol ,Transcellular ,Biotechnology ,medicine.drug - Abstract
The enhancing effects of 0.25% sodium caprate (C10) and sodium caprylate (C8) on the paracellular permeation of seven water-soluble nonelectrolytes (inulin, polyethylene glycol 900, mannitol, erythritol, glycerol, thiourea, and urea) across the isolated rat colonic epithelium were examined using the Ussing-type chamber technique. The paracellular changes were also measured by impedance analysis. In both the presence and the absence of enhancers, the permeation clearances (Pm) for inulin (12–15 A in molecular radius) to erythritol (3.2 A) increased linearly with the increase in their free diffusion coefficients (Dfr), showing the existence of a paracellular shunt pathway unrestricted to any molecular size. Glycerol (2.9 A), thiourea (2.6 A), and urea (2.3 A) had higher clearances than the expected linear values, showing the existence of a restricted paracellular or transcellular pathway. Both C10 and C8 increased the permeabilities in the two pathways, but C10 was more effective than C8. The increase in the permeabilities via the shunt pathway caused by the enhancers was greater than that via the restricted pathway, and thus, the two-phase pattern in the relationship of Pm and Dfr was similar to that in the absence of enhancers. The transcellular permeabilities for urea and thiourea, which were obtained from the efflux experiments, were increased by the enhancers. However, the relative increase caused by C10 was smaller than that of the paracellular-restricted permeabilities. The paracellular changes probably were due to the increase in pore area per unit diffusive path length. A decrease in the resistance of the intercellular junctions involving a simultaneous increase of membrane capacitance was observed in the presence of C10, corresponding to an increase of pore area per unit path length. The effect of C10 on the paracellular permeability was reversible, and the junctional resistance, membrane capacitance, and Pm of mannitol returned to the control level following the removal of C10.
- Published
- 1991
49. Mechanistic analysis for drug permeation through intestinal membrane
- Author
-
Mikio Tomita and Masahiro Hayashi
- Subjects
Lipopolysaccharides ,Cell Membrane Permeability ,Intracellular pH ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,chemistry.chemical_element ,Biology ,Calcium ,Rhodamine 123 ,Calcium in biology ,Intestinal absorption ,Tight Junctions ,chemistry.chemical_compound ,Carnitine ,Animals ,Humans ,Pharmacology (medical) ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Transcellular ,Intestinal Mucosa ,Tartrates ,Pharmacology ,Bacterial Infections ,Inflammatory Bowel Diseases ,Intestines ,Intestinal Diseases ,chemistry ,Biochemistry ,Intestinal Absorption ,Pharmaceutical Preparations ,Paracellular transport ,Reperfusion Injury ,Biophysics ,Lipid Peroxidation ,Caco-2 Cells ,Decanoic Acids ,Intracellular - Abstract
For drug absorption, intestinal drug permeability's through both the paracellular and transcellular routes were analyzed. Absorption enhancers, such as sodium caprate (C10), decanoylcarnitine (DC) and tartaric acid (TA), increased the paracellular permeability of water-soluble, low lipophilic and poorly absorbable drugs by enlargement of tight junction (TJ) adhering to the intercellular portion; that is, expansion of the paracellular routes. C10 increased the intracellular calcium level to induce contraction of calmodulin-dependent actin filaments. Although DC also increased the intracellular calcium level, the action was independent of calmodulin, and thus the action mechanism of DC was considered to differ from that of C10. DC and TA decreased the intracellular ATP level and the intracellular pH, suggesting that intracellular acidosis increases the calcium level through decrease in ATP level followed by opening TJ. TA had no effect on Western blot analysis, but TA significantly inhibited excretion of rhodamine 123, one of the P-glycoprotein (P-gp) substrates, from the serosal to mucosal side, suggesting that TA increases the intestinal absorption of P-gp substrates, possibly by inhibiting the P-gp function without changing the expression of P-gp. During ischemia/reperfusion (I/R) injury during small intestine grafting, TJ opening and decrease in P-gp function simultaneously occurred. The in vitro model of I/R showed that lipid peroxidation is a trigger of the injury, and superoxide and iron ion participate in TJ opening and decrease in P-gp function. Colonic epithelial cells have the specific transcellular transport systems for lipopolysaccharide (LPS), one of which shows substrate specificity in the interaction with CD14 and/or that of TLR4. In the infective disease induced by LPS, the mucosal LPS sensitive transport capability was decreased and in the secretory direction, the receptor-mediated uptake mechanism disappeared. LPS taken up into the cells can be excreted by P-gp or mrp. The expression levels and function of the secretory transporters were considered to be increased in the infective condition. In conclusion, changes in TJ as the membrane structure and P-gp as the membrane function are important factors controlling intestinal membrane transport.
- Published
- 2007
50. Improvement of intestinal absorption of P-glycoprotein substrate by D-tartaric acid
- Author
-
Yusuke Takizawa, Aiko Iida, Masahiro Hayashi, Yoko Idota, and Mikio Tomita
- Subjects
Absorption (pharmacology) ,Male ,Daunorubicin ,Colon ,Blotting, Western ,Pharmaceutical Science ,Ileum ,Intestinal absorption ,Jejunum ,medicine ,Animals ,Pharmacology (medical) ,Rhodamine 123 ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Rats, Wistar ,Tartrates ,P-glycoprotein ,Fluorescent Dyes ,Pharmacology ,Antibiotics, Antineoplastic ,Tight junction ,biology ,Chemistry ,Biological Transport ,Cardiovascular Agents ,Molecular biology ,Rats ,medicine.anatomical_structure ,Biochemistry ,Intestinal Absorption ,Verapamil ,Paracellular transport ,Injections, Intravenous ,biology.protein ,Diffusion Chambers, Culture ,medicine.drug - Abstract
The purpose of the present experiment was to examine the effects of D-tartaric acid (TA) on intestinal drug absorption under both in situ and in vitro experimental conditions. In the in vitro diffusion chamber experiments, TA (10 mM) added to the mucosal side of rat colon significantly decreased rhodamine123 (Rho 123) transport from the serosal to mucosal side. Since TA has been shown to change the integrity of the epithelial tight junctions in rat colon at low pH conditions, resulting in improved paracellular drug transport, the effect of TA on membrane resistance was examined at pH 7.4 in the present study. It was found that membrane resistance, an indicator of paracellular integrity, did not change at pH 7.4. In the in situ loop method, TA (20 mM) increased the absorption of Rho123 in both ileum and colon but not in jejunum. TA (20 mM) also increased the absorption of daunorubicin in the ileum, but TA (20 mM) did not change the expression level of P-glycoprotein (P-gp). TA (20 mM) significantly inhibited excretion of i.v.-administered Rho123 and daunorubicin into the ileal lumen. In conclusion, for the first time we demonstrated that TA increases the intestinal absorption of P-gp substrates Rho123 and daunorubicin, possibly by modulating the P-gp function without changing the expression level of P-gp in the rat intestine.
- Published
- 2006
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