Details of a Researcher - ITAGAKI Shiro

Papers - ITAGAKI Shiro

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In vitro and in vivo antioxidant properties of ferulic acid: A comparative study with other natural oxidation inhibitors

Shirou Itagaki, Toshirnitsu Kurokawa, Chie Nakata, Yoshitaka Saito, Setsu Oikawa, Masaki Kobayashi, Takeshi Hirano, Ken Iseki

FOOD CHEMISTRY ( ELSEVIER SCI LTD ) 114 ( 2 ) 466 - 471 2009.05 [Refereed]

Ferulic acid exhibits a wide range of therapeutic effects that are attributed to its potent antioxidant capacity. However, in vitro antioxidant properties of ferulic acid have not been elucidated in detail. Evidence that polyphenols, including ferulic acid, act as antioxidants in vivo is also limited. In order to elucidate in more detail the scientific background of antioxidant activities of ferulic acid, we carried out in vitro and in vivo experiments. We focused on superoxide anion scavenging activity, xanthine oxidase inhibition activity, and chain-breaking activity. The combined antioxidant activity from radical scavenging and xanthine oxidase inhibition of ferulic acid was much weaker than that of (-)-epigallocatechin gallate (EGCG) and ascorbic acid. On the other hand, EGCG, ascorbic acid and ferulic acid exhibited chain-breaking activity and prevented ischaemia-reperfusion-associated intestinal injury. Chain-breaking activity may play a contributory role in the protective effect of ferulic acid on oxidative injury in humans and in in vivo studies. (C) 2008 Elsevier Ltd. All rights reserved.

DOI CiNii

Contribution of organic anion transporting polypeptide OATP2B1 to amiodarone accumulation in lung epithelial cells.

Seki S, Kobayashi M, Itagaki S, Hirano T, Iseki K

Biochimica et biophysica acta ( 5 ) 1788 ( 5 ) 911 - 917 2009.05 [Refereed] [International journal]

The accumulation mechanisms of amiodarone (AMD) involving transporters in lung alveolar epithelial type II cells were studied. The uptake of AMD was examined using human alveolar epithelial-derived cell line A549 as a model. AMD was transported by the carrier-mediated system, and the apparent K(m) and V(max) values were 66.8+/-30.3 muM and 49.7+/-9.7 nmol/mg protein/5 min, respectively. The uptake of AMD by A549 cells was Na(+)-independent and was inhibited by substrates of human organic anion transporting polypeptide (OATP). The inhibition profiles were similar to the inhibitory effects of several compounds on OATP2B1-mediated E-3-S transport, and RT-PCR analysis showed mRNA expression of OATP2B1 and 1B3 in A549 cells. SiRNAs targeted to the OATP2B1 gene decreased the OATP2B1 mRNA expression level in A549 cells up to about 50% and reduced the uptake of AMD up to about 40%. These results indicate that AMD uptake mediated by carriers, including OATP2B1, might lead to accumulation of AMD in the lung and AMD-induced pulmonary toxicity (AIPT).

DOI PubMed

Search for Antioxidative Compounds Capable of Preventing Stomatitis Induced by Chemotherapy

TAKANO Rumi, HIRANO Takeshi, NAKATA Chie, KASASHI Kumiko, SUGAWARA Mituru, KOBAYASHI Masaki, ITAGAKI Shirou, ISEKI Ken

Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences) ( Japanese Society of Pharmaceutical Health Care and Sciences ) 35 ( 4 ) 247 - 253 2009.04 [Refereed]

In the clinical setting,the frequency of adverse effects is directly linked to treatment results but during chemotherapy,they are unavoidable.One of them is stomatitis,a distressing toxic effect.In patients receiving myelosuppressive chemotherapy for solid tumors,the prevalence of stomatitis is 5-40% while its prevalence in patients receiving stem cell transplantation is 75-100%.Stomatitis-associated pain is the main source of cancer treatment-related pain and in some patients it is so severe that narcotic analgesia is required.
Oxidative stress may also be associated with chemotherapy-induced stomatitis and a mouthwash containing allopurinol,rebamipide and camostat for the removal of free radicals is widely used for the prevention and treatment of such stomatitis.However,such agents are not covered by the Japanese National Health Insurance scheme and there is little scientific evidence for their antioxidative properties and effectiveness in the prevention and treatment of chemotherapy-induced stomatitis.We therefore attempted to establish a more useful mouthwash.In the first part of this study,we investigated the antioxidant properties of various compounds.We then used H₂O₂-induced HO-1-N-1 cell injury as a model of stomatitis and found that epigallocatechin gallate had a strong preventive effect against it.Epigallocatechin gallate would therefore be a good component of a mouthwash for the prevention of stomatitis in patients undergoing cancer chemotherapy.

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薬物動態因子の発現変動を反映した肝切除患者に対する薬物治療の最適化に関する研究.

板垣史郎, 井関健

医療の広場 49 18 - 20 2009.04 [Invited]

Sodium-coupled transport of the short chain fatty acid butyrate by SLC5A8 and its relevance to colon cancer - Discussion

Stephen A. McClave, Gail Cresci

JOURNAL OF GASTROINTESTINAL SURGERY ( SPRINGER ) 12 ( 10 ) 1781 - 1782 2008.10 [Refereed]

DOI PubMed

Placental folate transport during pregnancy

Satoru Yasuda, Satoko Hasui, Chiaki Yamamoto, Chihiro Yoshioka, Masaki Kobayashi, Shirou Itagaki, Takeshi Hirano, Ken Iseki

BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY ( TAYLOR & FRANCIS LTD ) 72 ( 9 ) 2277 - 2284 2008.09 [Refereed]

The aim of this study was to elucidate the mechanism of folate transport in the placenta over the course of pregnancy. We found that folate receptor of (FR alpha) and reduced folate carrier (RFC) localized on the apical side of human placental villi. Since folate binding to placental brush-border membrane vesicles (BBMVs) was strongly inhibited by phosphatidylinositol-specific phospholipase C (PI-PLC) treatment, it is possible that FR alpha, a glycosyl phosphatidylinositol linked glycoprotein, is a candidate for folate uptake from maternal blood to the placenta. Moreover, additional inhibitory effects of thiamine pyrophosphate (TPP) and hemin on folate uptake after PI-PLC treatment suggested that not only FRa but also RFC and heme carrier protein I (HCPI) are involved in the folate transport mechanism in the human placenta. It was also found that accumulation of folate after intravenous injection increased with the progress of gestation in the rat placenta and the fetus. Furthermore, increases in the expression levels of mRNA of rFR alpha, rRFC, and rHCP1 in the rat placenta during pregnancy were observed. These findings suggest that FR alpha, RFC, and HCP1 are important carriers of folate in the placenta during pregnancy. The results of this study suggest that increases in the expression levels of FRa, REC, and HCP1 in the placenta play an important role in the response to increased need for folate for the placenta and fetus during development with the progress of gestation.

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Interaction of tryptophan derivatives with SLC6A14 (ATB(0,+)) reveals the potential of the transporter as a drug target for cancer chemotherapy

Senthil Karunakaran, Nagavedi S. Umapathy, Muthusarny Thangaraju, Takahiro Hatanaka, Shiro Itagaki, David H. Munn, Puttur D. Prasad, Vadivel Ganapathy

BIOCHEMICAL JOURNAL ( PORTLAND PRESS LTD ) 414 ( 3 ) 343 - 355 2008.09 [Refereed]

ATB(0,+) [SLC6A14 (Solute carrier family 6 member 14)] is an Na(+)/Cl(-)-coupled amino acid transporter whose expression is up-regulated in cancer. 1-Methyltryptophan is an inducer of immune surveillance against tumour Cells through its ability to inhibit indoleamine dioxygenase. fit the present Study, we investigated the role of ATB(0,+) in the uptake of 1-methyltryptophan as a potential mechanism for entry of this putative anticancer-drug into tumour cells. These Studies show that 1-methyltryptophan is a transportable substrate for ATB(0,+). The transport process is Na(+)/Cl(-)-dependent with an Na(+)/Cl(-)/1-methyltryptophan stoichiometry of 2:1:1. Evaluation of other derivatives of tryptophan has led to identification of (alpha-methyltryptophan as a blocker, not a transportable substrate, for ATB(0,+). ATB(0,+) can transport 18 of the 20 proteinogenic amino acids. alpha-Methyltryptophan blocks the transport function of ATB(0,+) with an IC(50) value of similar to 250 mu M under conditions simulating normal plasma concentrations of all these 18 amino acids. These results Suggest that a-methyltryptophan may induce amino acid deprivation in cells which depend on the transporter for their amino acid nutrition. Screening of several mammary epithelial cell lines shows that ATB(0,+) is expressed robustly in some cancer cell lines, but not in all; in contrast, non-malignant cell lines do not express the transporter. Treatment of ATB(0,+)-positive tumour cells with a-methyltryptophan leads to Suppression of their colony-forming ability, whereas ATB(0,+)-negative cell lines are not affected. The blockade of ATB(0,+) in these cells with alpha-methyltryptophan is associated with cell cycle arrest. These Studies reveal the potential of ATB(0,+) as a drug target for cancer chemotherapy.

DOI PubMed CiNii

Interaction of coenzyme Q10 with the intestinal drug transporter P-glycoprotein

Shirou Itagaki, Akiko Ochiai, Masaki Kobayashi, Mitsuru Sugawara, Takeshi Hiran, Ken Iseki

JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY ( AMER CHEMICAL SOC ) 56 ( 16 ) 6923 - 6927 2008.08 [Refereed]

In clinical trials, patients usually take many kinds of drugs at the same time. Thus, drug-drug interactions can often directly affect the therapeutic safety and efficacy of many drugs. Oral delivery is the most desirable means of drug administration. Changes in the activity of drug transporters may substantially influence the absorption of administered drugs from the intestine. However, there have been a few studies on food-drug interactions involving transporters. It is important to be aware of the potential of food-drug interactions and to act in order to prevent undesirable and harmful clinical consequences. Coenzyme Q10 (CoQ10) is very widely consumed by humans as a food supplement because of its recognition by the public as an important nutrient in supporting human health. Since intestinal efflux transporter P-glycoprotein (P-gp) is one of the major factors in drug-drug interactions, we focused on this transporter. We report here for the first time that CoQ10, which is widely used as a food supplement, affects the transport activity of P-gp.

DOI PubMed CiNii

Amiodarone increases the accumulation of DEA in a human alveolar epithelium-derived cell line

Satoru Seki, Shirou Itagaki, Masaki Kobayashi, Takeshi Hirano, Ken Iseki

BIOLOGICAL & PHARMACEUTICAL BULLETIN ( PHARMACEUTICAL SOC JAPAN ) 31 ( 7 ) 1449 - 1452 2008.07 [Refereed]

Amiodarone (AMD)-induced pulmonary toxicity (AIPT) is the most life-threatening side-effect of AMD treatment. N-Monodesethylamiodarone (DEA), an active metabolite of AMD, also exhibits cytotoxicity and tends to accumulate in the lung more intensively than AMD. In this study, we characterized the mechanism of DEA accumulation using A549 cells as a model of the alveolar epithelium. Typical ATP-depletion compounds caused an approximately 30% increase in the accumulation of DEA in A549 cells, although these effects were less than those in Caco-2 cells. Triiodothyronine (T3), which exhibited an inhibitory effect on DEA efflux in Caco-2 cells, did not affect the accumulation of DEA in A549 cells. On the other hand, 100uM AMD caused an approximately 200% increase in DEA content in A549 cells, although AMD accumulation was not affected by 100 um DEA. Since the reducing effect of AMD on cellular ATP levels and that of FCCP were similar, the mechanism by which DEA accumulation is increased by AMD might be different from the ATP-dependent DEA efflux mechanism. The decrease in cell viability by DEA in the presence of AMD (ICS value of DEA for A549 cell viability: 25.4 2.4 ELM) was more pronounced than that by DEA alone (IC5o value: 11.5 3.0 um). This further DEA accumulation by AMD might be a factor responsible for the greater accumulation of DEA than that of AMD in the lung in long-term AMD-treated patients.

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Alteration of Mrp2 and P-gp expression, including expression in remote organs, after intestinal ischemia-reperfusion

Jiro Ogura, Masaki Kobayashi, Shirou Itagaki, Takeshi Hirano, Ken Iseki

LIFE SCIENCES ( PERGAMON-ELSEVIER SCIENCE LTD ) 82 ( 25-26 ) 1242 - 1248 2008.06 [Refereed]

The present study was carried out in order to identify the changes in expression of multidrug resistance-associated protein (Mrp) 2 and P-glycoprotein (P-gp) in the intestine and remote organs after intestinal ischemia-reperfusion (I/R). Mrp2 expression in the jejunum and liver was decreased at 6 h after I/R. This decrease in Mrp2 expression was associated with an increase in the serum level of IL-6. These results suggest that the decreased Mrp2 expression after intestinal I/R was regulated by IL-6. The expression level of mdr1a in the ileum, which encodes P-gp, was decreased at 6 and 24 h after I/R, and the expression level of mdr1b, also encodes P-gp, was not altered at any time. P-gp protein expression in the ileum was decreased at 6 h after I/R. In the liver, mdr1a expression was decreased at 6 h after I/R, but mdr1b expression was increased at 6 h after I/R. Pgp protein was not altered at any time. In the kidney, mdr1a expression was decreased at 24 h after I/R, but mdr1b expression was not altered at any time. P-gp protein expression in the kidney was decreased at 24 h after I/R, as was mdr1a expression. These results suggest that P-gp expression after intestinal I/R differs in each organ. This is the first report to provide evidence that expression levels of transporters in remote organs are altered intestinal after I/R. (c) 2008 Elsevier Inc. All rights reserved.

DOI PubMed CiNii

Post-transcriptional regulation of breast cancer resistance protein after intestinal ischemia-reperfusion

Jiro Ogura, Masaki Kobayashi, Shirou Itagaki, Takeshi Hirano, Ken Iseki

BIOLOGICAL & PHARMACEUTICAL BULLETIN ( PHARMACEUTICAL SOC JAPAN ) 31 ( 5 ) 1032 - 1035 2008.05 [Refereed]

Breast cancer resistance protein (BCRP), the product of the ABCG2 gene, is a recently identified ATP binding cassette half-transporter. BCRP is expressed in a variety of tumor cells and many normal human tissues. In the small intestine, BCRP can limit the influx and facilitate the efflux to prevent intracellular accumulation of BCRP substrates. Ischemia-reperfusion (I/R) induces the release of reactive oxygen species, and organs are severely damaged by I/R. It has been shown that the expression of transporters was altered in the organ after I/R. The present study was undertaken to clarify the expression of BCRP after intestinal I/R. We showed that the expression level of Bcrp was significantly decreased at I h after I/R. Bcrp mRNA level was not altered at I h after I/R. These results suggest that Bcrp expression was regulated by a post-transcriptional regulation mechanism after intestinal I/R. Bcrp mRNA level was increased at 24 h after I/R, and the expression level of Bcrp protein was of the same level or slightly increased compared with sham operated-rats. Bcrp was slightly located at the intestinal membrane at 24 h after intestinal I/R. These results suggested that Bcrp was not translocated to the intestinal membrane after intestinal I/R. There is little information on post-transcriptional regulation compared with information on transcriptional regulation. In this study, it was shown that Bcrp expression is regulated by post-transcriptional regulation after intestinal I/R. These results of this study may provide important information for further studies aimed at revealing the biological function of Bcrp.

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Association between risk of myopathy and cholesterol-lowering effect: A comparison of all statins

Masaki Kobayashi, Ikumi Chisaki, Katsuya Narumi, Kazuhiro Hidaka, Toshiki Kagawa, Shirou Itagaki, Takeshi Hirano, Ken Iseki

LIFE SCIENCES ( PERGAMON-ELSEVIER SCIENCE LTD ) 82 ( 17-18 ) 969 - 975 2008.04 [Refereed]

In the present study, we examined the mechanisms underlying the cytotoxicity of pitavastatin, a new statin, and we compared the in vitro potencies of muscle cytotoxicity using a prototypic embryonal rhabdomyosarcoma cell line (RD cells), a typical side effect of statins and compared the cholesterol-lowering effects of statins using Hep G2 hepatoma cells. Pitavastatin reduced the number of viable cells and caused caspase-9 and -3/7 activation in a time- and concentration-dependent manner. The comparison of cytotoxities of statins showed that statins significantly reduced cell viability and markedly enhanced activity of caspase-3/7 in concentration-dependent manner. On the other hand, the effects of hydrophilic statins, pravastatin, rosuvastatin were very weak. The rank order of cytotoxicity was cerivastatin > sinavastatin acid> fluvastatin > atorvastatin > lovastatin acid > pitavastatin >> rosuvastatin, pravastatin. Statin-induced cytotoxicity is associated with these partition coefficients. On the other hand, the cholesterol-lowering effect of statins did not correlate with these partition coefficients and cytotoxicity. Thus, it is necessary to consider the association between risk of myopathy and cholesterol-lowering effect of a statin for precise use of statins. (c) 2008 Elsevier Inc. All rights reserved.

DOI PubMed

Sodium-coupled monocarboxylate transporters in normal tissues and in cancer

Vadivel Ganapathy, Muthusamy Thangaraju, Elangovan Gopal, Pamela M. Martin, Shiro Itagaki, Seiji Miyauchi, Puttur D. Prasad

AAPS JOURNAL ( SPRINGER ) 10 ( 1 ) 193 - 199 2008.03 [Refereed] [Invited]

SLC5A8 and SLC5A12 are sodium-coupled monocarboxylate transporters (SMCTs), the former being a high-affinity type and the latter a low-affinity type. Both transport a variety of monocarboxylates in a Na+-coupled manner. They are expressed in the gastrointestinal tract, kidney, thyroid, brain, and retina. SLC5A8 is localized to the apical membrane of epithelial cells lining the intestinal tract and proximal tubule. In the brain and retina, its expression is restricted to neurons and the retinal pigment epithelium. The physiologic functions of SLC5A8 include absorption of short-chain fatty acids in the colon and small intestine, reabsorption of lactate and pyruvate in the kidney, and cellular uptake of lactate and ketone bodies in neurons. It also transports the B-complex vitamin nicotinate. SLC5A12 is also localized to the apical membrane of epithelial cells lining the intestinal tract and proximal tubule. In the brain and retina, its expression is restricted to astrocytes and Muller cells. SLC5A8 also functions as a tumor suppressor; its expression is silenced in tumors of colon, thyroid, stomach, kidney, and brain. The tumor-suppressive function is related to its ability to mediate concentrative uptake of butyrate, propionate, and pyruvate, all of which are inhibitors of histone deacetylases. SLC5A8 can also transport a variety of pharmacologically relevant monocarboxylates, including salicylates, benzoate, and gamma-hydroxybutyrate. Non-steroidal anti-inflammatory drugs such as ibuprofen, ketoprofen, and fenoprofen, also interact with SLC5A8. These drugs are not transportable substrates for SLC5A8, but instead function as blockers of the transporter. Relatively less is known on the role of SLC5A12 in drug transport.

DOI PubMed

A new method for determination of both thalidomide enantiomers using HPLC systems

Kaname Sgmbongi, Masanori Tanaka, Kelsuke Sakurada, Masakl Kobayasfi, Shlrou Itagaki, Takeshi Hirano, Ken Iseki

BIOLOGICAL & PHARMACEUTICAL BULLETIN ( PHARMACEUTICAL SOC JAPAN ) 31 ( 3 ) 497 - 500 2008.03 [Refereed]

Although thalidomide was withdrawn due to teratogenicity and neuropathy, there is now growing clinical interest in this compound because of its immunomodulatory and anti-angiogenic properties. In 1998, thalidomide was approved by the U.S. Food and Drug Administration for the treatment of erythema nodosum leprosum (ENL), an inflammatory complication of Hansen's disease, through a restricted-use program. Thalidomide was approved for the treatment of relapsed or refractory multiple myeloma (MM) as an orphan drug in Japan. Direct deproteinization method was shown to be useful for quantitation of enantioselective thalidomide blood level. Stabilized blood was deproteinized with methanol and 2 m trichloroacetic acid. The supernatant was injected onto reverse-phase column (CHIRALPAK AD-RH). The mobile phase consisted of 10% acetonitrile, 70% methanol and 20% 0.025 M citrate buffer (pH 3.0), and the flow rate was 0.5 ml/min. Wavelength of detection was 220 nm. (-)-(S)-thalidomide and (+)-(R)-thalidomide were separated at 13.5 min and 17.6 min, respectively. The accuracy of this method was almost the same as that of the measurement technique with extraction and concentration. In clinical practice, MM patients usually take many kinds of drugs at the same time. Actually, this patient takes a lot of drugs with thalidomide. However, we found no interference of these drugs and thalidomide on the chromatogram. This simple and reliable HPLC determination method for both enantiomers of thalidomide is thought to be very useful for thalidomide studies.

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The inhibitory effects of fluoroquinolones on L-carnitine transport in placental cell line BeWo

Takeshi Hirano, Satoru Yasuda, Yuki Osaka, Masaru Asari, Masaki Kobayashi, Shirou Itagaki, Ken Iseki

INTERNATIONAL JOURNAL OF PHARMACEUTICS ( ELSEVIER SCIENCE BV ) 351 ( 1-2 ) 113 - 118 2008.03 [Refereed]

L-Carnitine plays an important role in lipid metabolism by facilitating the transport of long-chain fatty acids across the mitochondrial inner membrane followed by fatty acid beta-oxidation. It is known that members of the OCTN family play an important role in L-carnitine transport in the placenta. Investigation of drug-drug or drug-nutrient interaction in the placenta is important for establishment of safety drug medication during pregnancy. The aim of this study was to determine the effects of fluoroquinolones, inhibitors of OCTN2, on L-carnitine transport in the placenta which is known to have a high expression level of OCTN2. We investigated the inhibitory effect of five fluoroquinolones, ciprofloxacin (CPFX), gatifloxacin (GFLX), ofloxacin (OFLX), levofloxacin (LVFX) and grepafloxacin (GPFX), on L-carnitine transport mediated by OCTN2 in placental cell line BeWo cells. We found that all of the fluoroquinolones inhibited L-carnitine transport, GPFX being the strongest inhibitor. We also found that the inhibitory effects of LVFX and GPFX depended on their existence ratio of zwitterionic forms as, we reported previously. Furthermore, we elucidated the LVFX transport mechanism in BeWo cells. LVFX was transported actively by transporters. However, we found that LVFX transport was Na+-independent and L-carnitine had no inhibitory effect on LVFX transport, suggesting that LVFX acts as inhibitor of OCTN2, not as a substrate for OCTN2. (C) 2007 Elsevier B.V. All rights reserved.

DOI PubMed

The mechanism of carrier-mediated transport of folates in BeWo cells: The involvement of heme carrier protein 1 in placental folate transport

Satoru Yasuda, Satoko Hasui, Masaki Kobayashi, Shirou Itagaki, Takeshi Hirano, Ken Iseki

BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY ( TAYLOR & FRANCIS LTD ) 72 ( 2 ) 329 - 334 2008.02 [Refereed]

The aim of this study was to elucidate the mechanism of folate transport in the placenta. A study of folate was carried out to determine which carriers transport folates in the human choriocarcinoma cell line BeWo, a model cell line for the placenta. We investigated the effects of buffer pH and various compounds on folate uptake. In the first part of the study, the expression levels of the mRNA of the folate receptor alpha (FR alpha), the reduced folate carrier (RFC), and heme carrier protein 1 (HCP1) were determined in BeWo cells by RT-PCR analysis. Folate uptake into BeWo cells was greater under an acidic buffer condition than under a neutral one. Structure analogs of folates inhibited folate uptake under all buffer pH conditions, but anion drugs (e.g., pravastatin) inhibited folate uptake only under an acidic buffer condition. Although thiamine pyrophosphate (TPP), a substrate of RFC, had no effect on folate uptake, hemin (a weak inhibitor of folate uptake via HCPI) decreased folate uptake to about 80% of the control level under an acidic buffer condition. Furthermore, kinetic analysis showed that hemin inhibited the low-affinity phase of folate uptake under an acidic buffer condition. We conclude that pH-dependent folate uptake in BeWo cells is mediated by at least two carriers. RFC is not involved in folate uptake, but FR alpha (high affinity phase) and HCP1 (low affinity phase) transport folate in BeWo cells.

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Contribution of multidrug resistance-associated protein 2 to secretory intestinal transport of organic anions

Shirou Itagaki, Makoto Chiba, Masaki Kobayashi, Takeshi Hirano, Ken Iseki

BIOLOGICAL & PHARMACEUTICAL BULLETIN ( PHARMACEUTICAL SOC JAPAN ) 31 ( 1 ) 146 - 148 2008.01 [Refereed]

Various mechanisms can influence the intestinal absorption and oral bioavailability of drugs. The barrier effects of efflux transporters may be one of the critical factors limiting the bioavailability of certain drugs. It has been reported that multidrug resistance-associated protein 2 (Mrp2) is expressed in the mucosal membrane of the epithelium of the small intestine and secretes various drugs into the jejunum lumen. However, it is possible that total intestinal secretion of Mrp2 substrates is accounted for the contribution of Mrp2 and other transporter(s) to the intestinal secretion of Mrp2 substrates. In this study, we found that phenolsulfonphthalein and pravastatin, both Mrp2 substrates, are transported by different transport systems in the intestine. These results suggest that contribution of transporters to the drug transport may be a critical factor affecting drug disposition and drug-drug interaction. In addition to evaluating the substrate specificity of a transporter, it is important to be aware of the contribution of a transporter to drug disposition.

DOI CiNii

Functional analysis of phenolsulfonphthalein transport system in Long-Evans Cinnamon rats.

Itagaki S, Chiba M, Kobayashi M, Sugawara M, Kobayashi M, Hirano T, Iseki K

Biochimica et biophysica acta ( 1 ) 1778 ( 1 ) 270 - 275 2008.01 [Refereed] [International journal]

It has been reported that the transport function for organic anions on the kidney is maintained in multidrug resistance-associated protein 2 (Mrp2)-deficient rats. Different from Mrp2-deficient rats, Long-Evans Cinnamon (LEC) rats have impaired urinary excretion of Mrp2-substrate, phenolsulfonphthalein (PSP). PSP is transported by the potential-sensitive urate transport system in rat brush-border membranes. We analyzed the function of PSP transport system in LEC rats. Unlike Long-Evans Agouti (LEA) rats, the initial uptake of PSP and urate into the renal brush-border membrane vesicles of LEC rats were not significantly enhanced in the presence of positive intravesicular potential, suggesting that the potential-sensitive urate transport system is impaired in LEC rats. LEC rats should be useful for elucidating the potential-sensitive urate transport system in rats at the molecular level.

DOI PubMed

Functional analysis of phenolsulfonphthalein transport system in Long-Evans Cinnamon rats

Shirou Itagaki, Makoto Chiba, Masaki Kobayashi, Mitsuru Sugawara, Michlya Kobayashi, Takeshi Hirano, Ken Iseki

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES ( ELSEVIER SCIENCE BV ) 1778 ( 1 ) 270 - 275 2008.01 [Refereed]

It has been reported that the transport function for organic anions on the kidney is maintained in multidrug resistance-associated protein 2 (Mrp2)-deficient rats. Different from Mrp2-deficient rats, Long-Evans Cinnamon (LEC) rats have impaired urinary excretion of Mrp2-substrate, phenolsulfonphthalein (PSP). PSP is transported by the potential-sensitive urate transport system in Tat brush-border membranes. We analyzed the function of PSP transport system in LEC rats. Unlike Long-Evans Agouti (LEA) rats, the initial uptake of PSP and urate into the renal brush-border membrane vesicles of LEC rats were not significantly enhanced in the presence of positive intravesicular potential, suggesting that the potential-sensitive urate transport system is impaired in LEC rats. LEC rats should be useful for elucidating the potential-sensitive urate transport system in rats at the molecular level. (c) 2007 Elsevier B.V. All rights reserved.

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Functional characterization of human monocarboxylate transporter 9 (SLC16A9)

Masaki Kobayashi, Toshiki Kagawa, Katsuya Narumi, Kazuhiro Hidaka, Shirou Itagaki, Takeshi Hirano, Ken Iseki

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN ( PHARMACEUTICAL SOC JAPAN ) 128 47 - 48 2008 [Refereed]

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Papers - ITAGAKI Shiro