Tomohiro Nishimura

Teikyo Heisei University, Edo, Tōkyō, Japan

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Publications (28)59.2 Total impact

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    ABSTRACT: Ezrin is a membrane-associated cytoplasmic protein that serves to link cell-membrane proteins with the actin-based cytoskeleton, and also plays a role in regulation of the functional activities of some transmembrane proteins. It is expressed in placental trophoblasts. We hypothesized that placental ezrin is involved in the supply of nutrients from mother to fetus, thereby influencing fetal growth. The aim of this study was firstly to clarify the effect of ezrin on fetal growth and secondly to determine whether knockout of ezrin is associated with decreased concentrations of serum and placental nutrients. Ezrin knockout mice (Ez-/-) were confirmed to exhibit fetal growth retardation. Metabolome analysis of fetal serum and placental extract of ezrin knockout mice by means of capillary electrophoresis-time-of-flight mass spectrometry revealed a markedly decreased concentration of hypotaurine, a precursor of taurine. However, placental levels of cysteine and cysteine sulfinic acid (precursors of hypotaurine) and taurine were not affected. Lack of hypotaurine in Ez-/- mice was confirmed by liquid chromatography with tandem mass spectrometry. Administration of hypotaurine to heterogenous dams significantly decreased the placenta-to-maternal plasma ratio of hypotaurine in wild-type fetuses but only slightly decreased it in ezrin knockout fetuses, indicating that the uptake of hypotaurine from mother to placenta is saturable and that disruption of ezrin impairs the uptake of hypotaurine by placental trophoblasts. These results indicate that ezrin is required for uptake of hypotaurine from maternal serum by placental trophoblasts, and plays an important role in fetal growth.
    PLoS ONE 08/2014; 9(8):e105423. DOI:10.1371/journal.pone.0105423 · 3.53 Impact Factor
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    ABSTRACT: The purpose of this study is to assess the role of the protein kinase A (PKA) in regulating uptake of dehydroepiandrosterone sulfate (DHEAS), an estrogen precursor, by syncytiotrophoblasts. Forskolin, a PKA activator, significantly increased [3H]DHEAS uptake and the mRNA expression levels of organic anion transporter (OAT) 4 and CYP19A1 in choriocarcinoma JEG-3 cells, while other steroid sulfate transporters present in the placenta showed no change in expression level. KT5720, a PKA inhibitor, attenuated these effects of forskolin. Accordingly, the PKA pathway appears to play an important role in estrogen synthesis by cooperatively regulating OAT4 and steroidogenic enzymes in syncytiotrophoblasts.
    Placenta 08/2014; 35(8). DOI:10.1016/j.placenta.2014.06.003 · 3.29 Impact Factor
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    ABSTRACT: Betaine uptake is induced by hypertonic stress in a placental trophoblast cell line, and involvement of amino acid transport system A was proposed. Here, we aimed to identify the subtype(s) of system A that mediates hypertonicity-induced betaine uptake. Measurement of [(14)C]betaine uptake by HEK293 cells transiently transfected with human or rat SNAT1, SNAT2 and SNAT4 revealed that only human and rat SNAT2 have betaine uptake activity. The Michaelis constants (Km) of betaine uptake by human and rat SNAT2 were estimated to be 5.3mM and 4.6mM, respectively. Betaine exclusively inhibited the uptake activity of SNAT2 among the rat system A subtypes. We found that rat SNAT1, SNAT2 and SNAT4 were expressed at the mRNA level under isotonic conditions, while expression of SNAT2 and SNAT4 was induced by hypertonicity in TR-TBT 18d-1 cells. Western blot analyses revealed that SNAT2 expression on plasma membrane of TR-TBT 18d-1 cells was more potently induced by hypertonicity than that in total cell lysate. Immunocytochemistry confirmed that the induction of SNAT2 expression in TR-TBT 18d-1 cells exposed to hypertonic conditions and indicated that SNAT2 was localized on the plasma membrane in these cells. Our results indicate that SNAT2 transports betaine, and that tonicity-sensitive SNAT2 expression may be involved in regulation of betaine concentration in placental trophoblasts.
    Biochimica et Biophysica Acta 01/2014; 1838(5). DOI:10.1016/j.bbamem.2014.01.004 · 4.66 Impact Factor
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    ABSTRACT: Endothelial progenitor cells (EPC) can differentiate into both endothelial cells and contractile smooth muscle cells (SMC). Previously we reported that TR-BME2 cells, a model for EPC, developed contractile SMC-like characteristics in culture medium deprived of endothelial cell growth factors (ECGF). The aim of the present study was to clarify the effect of one of these factors, basic fibroblast growth factor (bFGF) on differentiation of EPC. First it was confirmed that bFGF receptor (FGFR-1) mRNA is expressed in TR-BME2 cultured in both ECGF-rich and ECGF-deprived medium. When TR-BME2 cells were cultured in ECGF-deprived medium, they differentiated into contractile SMC. Expression of an undifferentiated state marker, CD133, and proliferation of TR-BME2 were both reduced by ECGF deprivation, but these changes were diminished in the presence of bFGF. mRNA expression of smooth muscle α-actin (SMA) and smooth muscle protein 22 (SM22), which are contractile SMC markers, was induced by deprivation of ECGF and the induction was suppressed by bFGF. In vascular endothelial cell growth factor (VEGF)-induced tube formation assay, TR-BME2 cells formed tube structures in the presence of bFGF, but not in its absence. Our results indicate that bFGF is essential for the maintenance of EPC phenotype, serving to suppress differentiation to contractile SMC.
    Biological & Pharmaceutical Bulletin 01/2014; 37(4):688-93. DOI:10.1248/bpb.b13-00841 · 1.85 Impact Factor
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    ABSTRACT: Substrate-induced upregulation of ATP-binding cassette subfamily G member 2 (ABCG2) has been well studied in cancer cells, but it is also important to understand whether ABCG2 is upregulated by its substrates in tissues in which it is constitutively expressed. In the present study, we aimed to clarify the regulatory mechanism of Abcg2 expression by its substrate, mitoxantrone, in placental cells. Abcg2 mRNA expression in rat placental TR-TBT 18d-1 cells treated with 10 μM mitoxantrone for 24 h was increased, compared with that in nontreated cells, whereas 10 μM pheophorbide-a had no effect. Methylated CpG level in the promoter region of the Abcg2 gene was low and was not altered by mitoxantrone. On the contrary, mitoxantrone markedly increased the expression of estrogen receptor (ER) α and progesterone receptor (PR) B. Fulvestrant, an ER antagonist, attenuated the mitoxantrone-induced increase of Abcg2 mRNA expression, whereas mifepristone, a PR antagonist, had little effect. 17β-estradiol, an ER ligand, positively regulated the mitoxantrone-induced increase of Abcg2 expression. DNA demethylation by 5-aza-2-deoxycytidine treatment increased ERα expression, but mitoxantrone failed to facilitate the demethylation of ERα promoter in TR-TBT 18d-1 cells. In conclusion, Abcg2 expression is induced by mitoxantrone via the induction of ERα in TR-TBT 18d-1 cells. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
    Journal of Pharmaceutical Sciences 09/2013; 102(9). DOI:10.1002/jps.23549 · 3.13 Impact Factor
  • Placenta 09/2013; 34(9):A46. DOI:10.1016/j.placenta.2013.06.139 · 3.29 Impact Factor
  • Placenta 09/2013; 34(9):A94. DOI:10.1016/j.placenta.2013.06.279 · 3.29 Impact Factor
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    ABSTRACT: It is important to address the tissue permeability of drugs, particularly in tissues that have a blood-tissue barrier, in terms of both lipophilicity and the contribution of transporters. Here, we employed umbilical perfusion in rats to evaluate in vivo fetal-to-maternal transfer clearances of various xenobiotics. We measured fetal-to-maternal clearance (CLfm ) of 23 compounds, which have a broad range of lipophilicity. Drugs for which CLfm was more than 300 µL/(mL min) belonged exclusively to Biopharmaceutical Drug Disposition Classification System (BDDCS) class 1 (highly permeable) and those for which CLfm was less than 50 µL/(mL min) belonged exclusively to BDDCS class 3 (poorly permeable). For most drugs, CLfm values were broadly consistent with lipophilicity. However, CLfm of digoxin was saturable and was inhibited by verapamil, suggesting that P-glycoprotein (P-gp)-mediated efflux has a substantially effect on measured clearance. CLfm of mitoxantrone continued to increase slightly at high concentrations of mitoxantrone, but placental-to-maternal clearance of mitoxantrone was saturable, implying that Bcrp1 contributes to mitoxantrone efflux across the placenta. Thus, we measured CLfm by umbilical perfusion and examined the relationship between CLfm and lipophilicity of xenobiotics. Fetal-to-maternal transport clearances measured in this study will be helpful to understand the characteristics of the blood-placental barrier. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
    Journal of Pharmaceutical Sciences 04/2013; 102(9). DOI:10.1002/jps.23551 · 3.13 Impact Factor
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    ABSTRACT: The purpose of this study was to clarify the transport characteristics of nucleosides in rat placenta and the changes of functional expression of nucleoside transporters in rat placenta with experimental diabetes mellitus. Placental uptake clearances of [(3)H]adenosine and [(3)H]zidovudine from maternal blood was much higher than that of [(14)C]mannitol. Xenopus oocytes injected with rat ENT1 and ENT2 cRNA took up [(3)H]adenosine with K(m) values of 6.1 and 26 µM, respectively. [(3)H]Adenosine transport by rat placental brush-border membrane vesicles (BBMV) was saturable and was inhibited by nitrobenzylthioinosine (NBMPR), a specific ENT inhibitor, in a manner consistent with involvement of both rat ENT1 and ENT2. [(3)H]Didanosine was modestly taken up by placenta, and the inhibitory effect of 100 µM NBMPR on [(3)H]ddI uptake by BBMV suggested a role of ENT2-mediated transport. Expression of ENT1, ENT2, ENT3, CNT2, and CNT3 mRNAs was detected in placenta of control and streptozotocin (STZ)-induced diabetic pregnant rats, and CNT2 (SLC28A2) expression was significantly increased in STZ-induced diabetic rats. Consistently, Na(+)-dependent adenosine uptake by BBMV from STZ-induced diabetic pregnant rats was higher than that from control rats. These results suggest the involvement of placental ENT2 as well as ENT1 in nucleoside uptake from maternal blood, and the induction of CNT2 in experimental diabetes mellitus.
    Drug Metabolism and Pharmacokinetics 02/2012; 27(4). DOI:10.2133/dmpk.DMPK-11-RG-103 · 2.07 Impact Factor
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    ABSTRACT: The purpose of this research was to noninvasively evaluate the influence of aromatherapy on work performance in 14 healthy young adults. Participants in a room filled with the fragrance of lavender completed a self-reported questionnaire and multi-dimensional fatigue inventory-20 (MFI-20). Further, as an objective measure, blood flow in the inferior frontal cortex was evaluated via near-infrared spectroscopy (NIRS) as a parameter of working memory capacity. Compared to the control stage (no aromatherapy), exposure to aromatherapy achieved a significant reduction in general and mental fatigue according to MFI-20. Self-reported questionnaires also indicated improvement, but the differences were not statistically significant. NIRS measurement during the task performance of an N-back program indicated that regional blood flow in the inferior frontal cortex was significantly increased through exposure to aromatherapy, compared to without. The prefrontal area in the brain is involved in working memory, attention concentration and judgment. These results suggest that lavender may improve both cognitive ability and mood. A larger study with more aroma oils seems warranted.
    01/2012; 38(4):265-271. DOI:10.5649/jjphcs.38.265
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    Masatoshi Tomi, Tomohiro Nishimura, Emi Nakashima
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    ABSTRACT: Administration of antiviral drugs to pregnant women with influenza, human immunodeficiency virus (HIV), and herpes simplex virus (HSV) infections is widely accepted as an effective treatment to safeguard the health of the mother and fetus. This review deals with the transfer of antiviral drugs to the fetus across the placental barrier, which is formed by an epithelial layer of syncytiotrophoblasts. First, the structure, function, and developmental change of the placenta and the placental barrier are briefly presented. We then review the transplacental permeability of antiviral drugs, such as oseltamivir for influenza, antiretrovirals (e.g., zidovudine, didanosine, and saquinavir) for HIV, and acyclovir for HSV, focusing on the involvement of ATP-binding cassette, organic anion/cation, and nucleoside transporters. The increasing evidence that is becoming available about transport mechanisms operating at the placental barrier is expected to be useful in the development of techniques to control fetal and placental transfer of antiviral drugs, and thereby to obtain maximum therapeutic benefit while minimizing potential fetal toxicity.
    Journal of Pharmaceutical Sciences 09/2011; 100(9):3708-18. DOI:10.1002/jps.22642 · 3.13 Impact Factor
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    ABSTRACT: A possible approach to improve antiretroviral therapy with nucleoside reverse transcriptase inhibitors is to enhance inhibitor delivery to CD4-positive T cells. We previously showed that dehydroepiandrosterone sulfate (DHEAS) enhances zidovudine (AZT) transfer into syncytiotrophoblast. Here, we investigated whether DHEAS also enhances AZT transfer into a cellular model of human T lymphocytes, and whether AZT is taken up by a specific transport system. The effects of DHEAS and related compounds on the uptake of [(3) H]AZT and other nucleosides by Molt-4 cells (a model of human CD4-positive T cells) were measured. [(3) H]AZT uptake by Molt-4 cells was nitrobenzylthioinosine insensitive and pH dependent, and the uptake was significantly inhibited by 1 mM ethylisopropylamiloride. [(3) H]AZT uptake by Molt-4 cells was increased in the presence of DHEAS, whereas uptake of other nucleosides was reduced. Kinetic study revealed that the maximum uptake velocity (up to 30 min) was increased in the presence of DHEAS. The structural requirements for AZT uptake-enhancing activity were studied using structural analogues of DHEAS. Estrone-3-sulfate and 16α-hydroxy DHEAS also enhanced AZT uptake into Molt-4 cells. The use of uptake enhancers may be a good strategy to improve the efficacy of antiretroviral therapy.
    Journal of Pharmaceutical Sciences 05/2011; 100(9):3959-67. DOI:10.1002/jps.22624 · 3.13 Impact Factor
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    ABSTRACT: Recent studies indicate that various members of the organic anion transporting polypeptide (OATP) family are expressed on apical membranes of the small intestine. In the present study, we investigated possible interaction of Oatp with the PDZ protein PDZK1 in mouse small intestine, using [³H]estrone-3-sulfate (E3S) as a typical substrate. After intraduodenal administration, the level of [³H]E3S appearing in the portal vein of pdzk1 gene knockout (pdzk1(-/-)) mice was much lower than that in wild-type mice. Lower intestinal absorption of [³H]E3S in pdzk1(-/-) mice was confirmed in Ussing-type chamber experiments, which showed smaller uptake of [³H]E3S from the apical side in intestinal tissues of pdzk1(-/-) mice compared with wild-type mice. The kinetics and inhibition profile of [³H]E3S uptake in the Ussing-type chamber were similar to those in HEK293 cells stably expressing Oatp1a5, suggesting involvement of Oatp1a5 in [³H]E3S uptake. Immunoreactivity to anti-Oatp1a antibody was colocalized with PDZK1 in the small intestine of wild-type mice, whereas apical localization of Oatp1a protein was reduced in pdzk1(-/-) mice. An immunoprecipitation study revealed physical interaction of PDZK1 with Oatp1a. Thus, PDZK1 appears to act as an adaptor for Oatp1a. This is the first demonstration of a regulatory protein directly interacting with small-intestinal OATP.
    Drug Metabolism and Pharmacokinetics 11/2010; 25(6):588-98. DOI:10.2133/dmpk.DMPK-10-RG-074 · 2.07 Impact Factor
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    ABSTRACT: The aim of the present study was to characterize the mechanism of erythromycin transport at the blood-placenta barrier, using TR-TBT 18d-1 cells as a model of rat syncytiotrophoblasts. [(14)C]Erythromycin was taken up by TR-TBT 18d-1 cells with a Michaelis constant of 466 microM. Although the uptake was not dependent on extracellular Na(+) or Cl(-), it was increased at weakly alkaline pH. Significant overshoot of [(14)C]erythromycin uptake by placental brush-border membrane vesicles was observed in the presence of an outwardly directed proton gradient. These results indicate that erythromycin is transferred by the H(+)-coupled transport system in syncytiotrophoblasts. To address the physiological transport of erythromycin in rat placenta, fetal-to-maternal transport clearance was estimated by means of the single placental perfusion technique. Clearance of [(14)C]erythromycin was higher than that of [(14)C]inulin, a paracellular pathway marker, and was decreased by the addition of 5 mM erythromycin, indicating that saturable efflux system from fetus to mother is involved. The effect of various transporter inhibitors on [(14)C]erythromycin efflux from TR-TBT 18d-1 cells was evaluated. cyclosporin A, fumitremorgin C, and probenecid had no effect, whereas ethylisopropylamiloride, a specific inhibitor of Na(+)/H(+) exchangers (NHEs), was significantly inhibitory. These results suggest that erythromycin efflux transport at the rat blood-placenta barrier is mediated by an erythromycin/H(+) antiport system, driven by H(+) supplied by NHEs.
    Drug metabolism and disposition: the biological fate of chemicals 09/2010; 38(9):1576-81. DOI:10.1124/dmd.110.033266 · 3.74 Impact Factor
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    ABSTRACT: The syncytiotrophoblast, which regulates maternal-fetal transfer of drugs, consists of a single layer in humans, but two layers, i.e., SynI and SynII, in rodents. Polar distribution of transporters in the apical and basal plasma membranes of syncytiotrophoblast is important for placental function in terms of vectorial transport of substrates, but the mechanisms that control protein distribution in the syncytiotrophoblast remain unclear. We have previously established rat syncytiotrophoblast cell lines, TR-TBT 18d-1 and TR-TBT 18d-2, which retain characteristics of SynI and SynII, respectively. In this study, we aimed to characterize the gene expression profiles in the two layers by using these cell lines. DNA microarray analysis indicated that more than 25 mRNAs, including cytoskeleton binding proteins, ezrin and CLP36, are differentially expressed between TR-TBT 18d-1 and TR-TBT 18d-2. Quantitative real time-polymerase chain reaction (PCR) analysis indicated that mRNA expression of ezrin, CLP36, CCN1, and CCN2 is higher in TR-TBT 18d-1 and mRNA expression of elf-1a, hsc70 and flot2 is higher in TR-TBT 18d-2, compared with their counterparts. Immunohistochemical analysis indicated that ezrin is expressed in rat placental villi in vivo, and is located on the apical membranes of TR-TBT 18d-1, while CLP36 is located in the apical and basal sides of TR-TBT 18d-1. The expression of ezrin was highest at gestational days 14 and 18 and was highest among the ezrin/radixin/moesin (ERM) family members. These results may help to clarify the mechanisms controlling polarization of the syncytiotrophoblast and the significance of the double epithelial layers in rat and mouse.
    Biological & Pharmaceutical Bulletin 01/2010; 33(8):1400-6. DOI:10.1248/bpb.33.1400 · 1.85 Impact Factor
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    ABSTRACT: The purpose of this research was to clarify the effect of repeated administration of 2 kinds of energy drink,1 containing vitamins,taurine and caffeine (simple-type),and the other containing vitamins,taurine,caffeine and several botanical herb extracts (herb-type),on work performance using cognitively subjective and objective indicators.The simple-type and herb-type drinks were given to 14 healthy young adults in a consecutive double-blind,randomized,2-period cross-over clinical trial.Participants took each energy drink once a day for five days during separate periods.Motivation,feeling of drowsiness,and general fatigue were evaluated on a subjective scale using a self-reported questionnaire both before and after administration.Other subjective evaluations were those based on the fatigue-visual analog scale (Fatigue-VAS) and multi-dimensional fatigue inventory-20 (MFI-20).As an objective measure,work performance was examined using the Kreapelin mental work test.Compared to the simple-type drink,the herb-type drink achieved a significant reduction in drowsiness and significantly increased motivation based on the self-reported questionnaire results for the post-administration assessment.In the Kreapelin mental work test,the mean amount of work was significantly increased by both drinks.MFI-20 revealed significant decreases in 2 categories of physical fatigue and general fatigue due to the 2 drinks.The fatigue-VAS also indicated decreases but they were not statistically significant.Both types of energy drink appeared to be effective in terms of subjective and objective indicators.Though the herb-type drink was found to be superior to the simple-type drink regarding subjective measures,there was no significant difference between the 2 regarding the objective measure.
    01/2010; 36(12):847-854. DOI:10.5649/jjphcs.36.847
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    ABSTRACT: AZT (3'-azido-3'-deoxythymidine; zidovudine), which is used for the prevention of mother-to-child transmission of HIV-1, is transplacentally transferred to the fetus across the blood-placenta barrier, which is composed of syncytiotrophoblasts. We recently showed that apical uptake of AZT by syncytiotrophoblasts is mediated by saturable transport system(s) in the TR-TBT 18d-1 cell line, and the cellular accumulation of AZT was increased in the presence of dehydroepiandrosterone sulfate (DHEAS). Here, we aimed to clarify the mechanism of this effect of DHEAS. Inhibitors of efflux transporters, including breast cancer resistance protein, P-glycoprotein, and multidrug resistance proteins, had little effect on the cellular accumulation of AZT in TR-TBT 18d-1. Kinetic study revealed that the rate constant for AZT uptake was greatly increased in the presence of 1 mM DHEAS. These results suggested that the effect of DHEAS was because of enhancement of the uptake process(es), rather than inhibition of efflux. When AZT uptake was analyzed according to the Michaelis-Menten equation, the estimated Michaelis constant, Km, for AZT uptake in the presence of 1 mM DHEAS was lower than that in its absence, whereas maximum uptake velocity, Vmax, and nonsaturable uptake clearance, kns, were similar in the presence and absence of DHEAS, indicating that DHEAS may change the recognition characteristics of the transporter for AZT in TR-TBT 18d-1. Thus, the increase of AZT uptake in TR-TBT 18d-1 cells in the presence of DHEAS was concluded to be because of a DHEAS-induced change in the affinity of AZT uptake system, although the transporter responsible for AZT uptake has not been identified.
    Drug metabolism and disposition: the biological fate of chemicals 10/2008; 36(10):2080-5. DOI:10.1124/dmd.108.021345 · 3.74 Impact Factor
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    ABSTRACT: Oral bioavailability of some drugs is substantially lower in cynomolgus monkeys than in various other species, including humans. In the present study, midazolam was used as a model drug to investigate the reason for the lower bioavailability in these monkeys. The bioavailability of midazolam after oral administration was minimal in monkeys and rats, being only 2.1 and 1.1%, respectively. In monkeys, this low bioavailability could not be explained simply in terms of a hepatic first-pass effect. To examine the roles of intestinal metabolism and transport, we evaluated apical-to-basal and basal-to-apical transport of midazolam, and the formation of metabolites in small intestinal tissues using an Ussing-type chamber. The values of mucosal extraction ratio were estimated to be 0.97, 0.93, and 0.89 during apical-to-basal transport in the upper, middle, and lower small intestine of monkeys, respectively, whereas the corresponding values for rats were close to zero, indicating that extensive metabolism of midazolam occurs, particularly in the upper region of the small intestine in monkeys, but not rats. Interestingly, formation of the metabolites was much greater during transport in the apical-to-basal direction than in the basal-to-apical direction, and this could be well explained by a mathematical model based on the assumption that extensive metabolism is associated with the uptake process of midazolam from the apical cell surface. Thus, we conclude that an asymmetric distribution of metabolic activity in the small intestine, leading to extensive metabolism during uptake from the apical cell surface, accounts for the minimal oral bioavailability of midazolam in cynomolgus monkeys.
    Drug Metabolism and Disposition 09/2007; 35(8):1275-84. DOI:10.1124/dmd.106.013037 · 3.33 Impact Factor
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    ABSTRACT: M17055 is under development as a novel loop diuretic for oral administration. To investigate the molecular mechanism of its gastrointestinal absorption, we initially aimed to clarify the mechanism of uptake of M17055 by Caco-2 cells, focusing on possible involvement of OATP-B (SLCO2B1), which is localized in the apical membranes of human intestinal epithelial cells. The uptake of [14C]M17055 by Caco-2 cells cultured on multi-well dishes was measured after cultivation for 14 days. Uptake of [14C]M17055 by HEK293 cells stably expressing OATP-B (HEK293/OATP-B cells) was also examined. M17055 uptake by Caco-2 cells was saturable, and was inhibited by various organic anions, including other loop diuretics, and several bile acids. Uptake of M17055 by HEK293/OATP-B cells was much higher than that by mock cells. The inhibitory profiles of various organic anions and the estimated Km values for M17055 uptake were similar in Caco-2 and HEK293/OATP-B cells. Moreover, the values of inhibition constants of several inhibitors for M17055 uptake were comparable in the two cell lines. Our data suggest that OATP-B plays a major role in the uptake of the novel loop diuretic M17055 from apical membranes in Caco-2 cells.
    Pharmaceutical Research 02/2007; 24(1):90-8. DOI:10.1007/s11095-006-9127-x · 3.95 Impact Factor
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    ABSTRACT: Y-700, a novel xanthine oxidase inhibitor, was recently developed for the treatment of hyperuricemia and gout. Since the major elimination route of this compound is hepatic metabolism and excretion, the aim of the present study was to characterize the uptake mechanism of Y-700 in the liver, which is also the pharmacological target of Y-700. Efficient uptake of Y-700 was observed both in the liver in vivo and in isolated rat hepatocytes. The uptake was Na(+)-dependent, saturable and inhibited both by ATP-depressants and various organic anions. Indomethacin competitively inhibited Y-700 uptake, whereas the inhibitory effect of organic cations and nucleosides was not so remarkable. Saturable and Na(+)-dependent uptake of Y-700 was also observed in freshly isolated human hepatocytes. Uptake of Y-700 by sinusoidal membrane transporters, such as organic anion transporter (Oat) 2 and organic anion transporting polypeptide (OATP)-B, OATP-C, OATP-8, and Oatp1, could not be detected although uptake of Y-700 in the oocytes expressing sodium/taurocholate cotransporting polypeptide (NTCP) was slightly observed. In conclusion, active transport system(s), which specifically recognize certain types of anionic compounds, are involved in the hepatic uptake of Y-700 and, at least partially, relevant to its elimination from the circulation as well as delivery to pharmacological target.
    Journal of Pharmaceutical Sciences 02/2006; 95(2):336-47. DOI:10.1002/jps.20540 · 3.01 Impact Factor

Publication Stats

87 Citations
59.20 Total Impact Points

Institutions

  • 2014
    • Teikyo Heisei University
      Edo, Tōkyō, Japan
  • 2008–2014
    • Keio University
      • Faculty of Pharmacy
      Edo, Tōkyō, Japan
  • 2004–2007
    • Kanazawa University
      • Graduate School of Natural Science and Technology
      Kanazawa-shi, Ishikawa-ken, Japan