Nishimura, Tomohiro

写真a

Affiliation

Faculty of Pharmacy, Department of Pharmacy 薬剤学講座 (Shiba-Kyoritsu)

Position

Associate Professor

Career 【 Display / hide

  • 2007.04
    -
    2008.03

    共立薬科大学, 助手

  • 2008.04
    -
    2013.03

    慶應義塾大学, 薬学部, 助教

  • 2011.09
    -
    2012.08

    Mount Sinai School of Medicine, Visiting Scientist

  • 2014.04
    -
    2017.03

    慶應義塾大学, 薬学部, 専任講師

  • 2017.04
    -
    Present

    慶應義塾大学, 薬学部, 准教授

Academic Background 【 Display / hide

  • 2007.03

    Kanazawa University

    Graduate School, Completed, Doctoral course

Academic Degrees 【 Display / hide

  • 博士(薬学), Kanazawa University, Coursework, 2007.03

Licenses and Qualifications 【 Display / hide

  • 甲種危険物取扱者, 2000.12

  • 薬剤師, 2004.04

 

Books 【 Display / hide

  • 今日のOTC薬 改訂第5版

    伊東明彦, 中村智徳(編集)西村友宏., 南江堂, 2021.02

    Scope: 31 ビタミン剤,  Contact page: 532-549

  • 別冊Newton くすりの科学知識 増補第2版

    中島恵美,西村友宏(監修)., ニュートンプレス, 2019.10

    Contact page: 140-169

  • わかりやすい薬物動態計算問題の解き方

    丸山一雄(監修)中瀬朋夏(編集)西村友宏., ネオメディカル, 2019.03

    Scope: 6.未変化体の尿中排泄量と消失速度定数7.経口投与後の血中濃度推移と吸収速度定数,  Contact page: 29-41

  • 今日のOTC薬 改訂第4版

    中島恵美(監修), 伊東明彦(編集)西村友宏., 南江堂, 2018.04

    Scope: 31 ビタミン剤,  Contact page: 528-547

  • 今日のOTC薬 改訂第3版

    中島恵美, 伊東明彦(編集)西村友宏., 南江堂, 2015.03

    Scope: 31 ビタミン剤,  Contact page: 546-567

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Papers 【 Display / hide

  • Fluorouracil Uptake in Triple-Negative Breast Cancer Cells: Negligible Contribution of Equilibrative Nucleoside Transporters 1 and 2.

    Noguchi S, Takagi A, Tanaka T, Takahashi Y, Pan X, Kibayashi Y, Mizokami R, Nishimura T, Tomi M

    Biopharmaceutics & drug disposition (Biopharmaceutics and Drug Disposition)  42 ( 2-3 ) 85 - 93 2021.01

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  0142-2782

     View Summary

    Equilibrative nucleoside transporters (ENTs) 1 and 2 reportedly accept fluorouracil as a substrate. Here, we evaluated ENT1/2 expression at the messenger RNA (mRNA), protein, and functional levels in a panel of four triple-negative breast cancer (TNBC) cell lines, BT-549, Hs578T, MDA-MB-231, and MDA-MB-435, and we examined the relationship of the observed profiles to fluorouracil sensitivity. Nitrobenzylthioinosine (NBMPR) at 0.1 μM inhibits only ENT1, while dipyridamole at 10 μM or NBMPR at 100 μM inhibits both ENT1 and ENT2. We found that the uptake of [ H]uridine, a typical substrate of ENT1 and ENT2, was decreased to approximately 40% by 0.1 μM NBMPR. At 100 μM, NBMPR almost completely blocked the saturable uptake of [ H]uridine, but this does not imply a functional role of ENT2, because 10 μM dipyridamole showed similar inhibition to 0.1 μM NBMPR. Expression of ENT1 mRNA was almost 1 order of magnitude higher than that of ENT2 in all TNBC cell lines. Liquid chromatography-tandem mass spectrometry(LC-MS/MS) LC-MS/MS-based targeted protein quantification showed that ENT1 protein levels were in the range of 9.3–30 fmol/μg protein in plasma membrane fraction of TNBC cell lines, whereas ENT2 protein was below the detection limit. [ H]Fluorouracil uptake was insensitive to 0.1 μM NBMPR and 10 μM dipyridamole, suggesting a negligible contribution of ENT1 and ENT2 to fluorouracil uptake. The levels of ENT1 mRNA, ENT1 protein, ENT2 mRNA, and ENT1-mediated [ H]uridine uptake in the four TNBC cell lines showed no correlation with fluorouracil sensitivity. These results indicate that neither ENT1 nor ENT2 contributes significantly to the fluorouracil sensitivity of TNBC cell lines. 3 3 3 3

  • Development of a pharmacokinetic model of transplacental transfer of metformin to predict in vivo fetal exposure

    Kurosawa K., Chiba K., Noguchi S., Nishimura T., Tomi M.

    Drug Metabolism and Disposition (Drug Metabolism and Disposition)  48 ( 12 ) 1293 - 1302 2020.12

    Research paper (scientific journal), Accepted,  ISSN  00909556

     View Summary

    Copyright © 2020 The Author(s). Two types of systems are used in ex vivo human placental perfusion studies to predict fetal drug exposures, that is, closed systems with recirculation of the maternal and fetal buffer and open systems using a single-pass mode without recirculation. The in vivo fetal/maternal (F:M) ratio of metformin, a cationic drug that crosses the placenta, is consistent with that reported in an open system ex vivo but not with that in a closed system. In the present study, we aimed to develop a pharmacokinetic (PK) model of transplacental transfer of metformin to predict in vivo fetal exposure to metformin and to resolve the apparent inconsistency between open and closed ex vivo systems. The developed model shows that the difference between open and closed systems is due to the difference in the time required to achieve the steady state. The model-predicted F:M ratio (approx. 0.88) is consistent with reported in vivo values [mean (95% confidence interval): 1.10 (0.69–1.51)]. The model incorporates bidirectional transport via organic cation transporter 3 (OCT3) at the basal plasma membrane, and simulations indicate that the use of trimethoprim (an OCT3 inhibitor) to prevent microbial growth in the placenta ex vivo has a negligible effect on the overall maternal-to-fetal and fetal-to-maternal clearances. The model could successfully predict in vivo fetal exposure using ex vivo human placental perfusion data from both closed and open systems. This transplacental PK modeling approach is expected to be useful for evaluating human fetal exposures to other poorly permeable compounds, besides metformin. SIGNIFICANCE STATEMENT We developed a pharmacokinetic model of transplacental transfer of metformin, used to treat gestational diabetes mellitus, in order to predict in vivo fetal exposure and resolve the discrepancy between reported findings in open and closed ex vivo perfusion systems. The discrepancy is due to a difference in the time required to reach the steady state. The model can predict in vivo fetal exposure using data from both closed and open systems.

  • Contribution of Prostaglandin Transporter OATP2A1/SLCO2A1 to Placenta-to-Maternal Hormone Signaling and Labor Induction

    Inagaki M., Nishimura T., Nakanishi T., Shimada H., Noguchi S., Akanuma S.i., Tachikawa M., Hosoya K.i., Tamai I., Nakashima E., Tomi M.

    iScience (iScience)  23 ( 5 ) 101098 2020.05

    Research paper (scientific journal), Accepted

     View Summary

    © 2020 The Author(s) Molecular Biology; Endocrinology

  • Substrate recognition of renally eliminated angiotensin II receptor blockers by organic anion transporter 4

    Noguchi S., Okochi M., Atsuta H., Kimura R., Fukumoto A., Takahashi K., Nishimura T., Tomi M.

    Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics)  36   100363 2020

    Research paper (scientific journal), Accepted,  ISSN  13474367

     View Summary

    © 2020 The Japanese Society for the Study of Xenobiotics Organic anion transporter (OAT) 4, which is localized at the apical membrane of human renal proximal tubules, transports olmesartan, an angiotensin II receptor blocker (ARB). Many ARBs, including olmesartan, undergo partial tubular secretion as active forms, and inhibit OAT4-mediated uptake activity. Here, we examined the substrate recognition of various ARBs by OAT4 in order to assess whether OAT4 might be involved in the renal handling of ARBs. Concentration-dependent OAT4-mediated uptake of azilsartan, candesartan, carboxylosartan, losartan, and valsartan was observed with Km values of 6.6, 31, 7.2, 13, and 1.7 μM, respectively, in the absence of extracellular Cl−. In the presence of extracellular Cl−, OAT4-mediated uptake of dianionic ARBs (azilsartan, candesartan, carboxylosartan, and valsartan) was lower and reached a steady state faster than in the absence of extracellular Cl−. Thus, OAT4 is proposed to use extracellular Cl− as a counterpart for anion efflux. Our results suggest that OAT4 may play a role in the excretion of azilsartan, candesartan, carboxylosartan, and valsartan, as well as olmesartan. In contrast, OAT4-mediated uptake of losartan, a monoanionic ARB, was little affected by extracellular Cl−, suggesting that only OAT4-mediated dianion transport is Cl−-sensitive.

  • Quantification of ENT1 and ENT2 Proteins at the Placental Barrier and Contribution of These Transporters to Ribavirin Uptake

    Nishimura T., Sano Y., Takahashi Y., Noguchi S., Uchida Y., Takagi A., Tanaka T., Katakura S., Nakashima E., Tachikawa M., Maruyama T., Terasaki T., Tomi M.

    Journal of Pharmaceutical Sciences (Journal of Pharmaceutical Sciences)  108 ( 12 ) 3917 - 3922 2019.12

    Research paper (scientific journal), Accepted,  ISSN  00223549

     View Summary

    © 2019 The Authors The aims of this study are to quantify the protein levels of nucleoside transporters in placental microvillous membranes (MVMs) and to clarify the contributions of these transporters to ribavirin uptake at the placental barrier. Placental MVMs of human and rat expressed equilibrative nucleoside transporter (ENT) 1 protein, whereas the expression of ENT2 protein was obscure. Maternal-to-fetal transfer of [3H]ribavirin in rats was much higher than that of [14C]sucrose. The uptake of [3H]ribavirin by rat placental trophoblast TR-TBT 18 d-1 cells, which functionally express both ENT1 and ENT2 proteins, was saturable, and was significantly inhibited by 0.1 μM nitrobenzylthioinosine, which selectively abolishes ENT1-mediated uptake. Dipyridamole at 10 μM is capable of inhibiting ENT2 as well as ENT1, but a degree of inhibition by 10 μM dipyridamole on [3H]ribavirin uptake was not much different from that by 0.1 μM nitrobenzylthioinosine (ENT1-specific inhibitor). Therefore, ENT2 may contribute little to [3H]ribavirin uptake by these cells. Rat ENT1 cRNA-injected oocytes showed increased [3H]ribavirin uptake compared with water-injected oocytes, while rat ENT2 cRNA-injected oocytes did not. In conclusion, ENT1 protein expressed in placental MVMs appears to play a predominant role in the uptake of ribavirin.

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Papers, etc., Registered in KOARA 【 Display / hide

Reviews, Commentaries, etc. 【 Display / hide

  • PDE5阻害剤は妊娠高血圧症の治療薬となるか

    西村友宏.

    ファルマシア (日本薬学会)  56 ( 8 ) 785 - 785 2020.08

    Introduction and explanation (scientific journal), Single Work,  ISSN  0014-8601

     View Summary

    妊娠高血圧症は妊娠中に発症する高血圧の総称で妊婦の5~8%に発症することが知られる.中でも妊娠高血圧腎症は,タンパク尿,臓器不全,胎盤機能不全を伴うことが知られ(ただし,2018年のガイドライン改定によりタンパク尿は診断要件から外れた),特に重篤である.
    なお,本稿は下記の文献に基づいて,その研究成果を紹介するものである.
    1) Herraiz S. et al., BJOG., 119, 1394-1402(2012).2) Yoshikawa K. et al., Am. J. Hypertens, 31, 89-96(2017).
    3) Maki S. et al., J. Clin. Med., 8, 856(2019).
    4) Hawkes N., BMJ., 362, k3247(2018).
    5) Furuhashi F. et al., J. Matern Fetal Neonatal Med., 17, 1-7(2019).
    6) Walton R. B. et al., Hypertension, 72, 167-176(2018).

  • 【「今さら聞けない」をスッキリ解消する 妊娠・授乳と薬】[妊娠と薬]妊娠による生理学的変化と薬物動態

    西村友宏, 野口幸希.

    薬事 (㈱じほう)  62 ( 4 ) 33 - 44 2020.03

    ISSN  0016-5980

  • Preface

    Takada T., Nishimura T.

    Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics)  35 ( 1 )  2020.02

    ISSN  13474367

  • 胎児成長における胎盤ビタミンCトランスポーターの重要性

    西村友宏.

    ファルマシア (日本薬学会)  47 ( 3 ) 249 - 250 2017.03

    Introduction and explanation (scientific journal), Single Work,  ISSN  0014-8601

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Presentations 【 Display / hide

  • miR-126による LIN28A制御を介した、胎盤栄養膜モデル JEG-3細胞の浸潤抑制

    野口 幸希、潘 暁楽、西村 友宏、登美 斉俊

    日本薬学会第141年会 (WEB) , 2021.03

  • 胎盤におけるOCTN1 の発現とメトホルミン輸送への関与の検討

    中⼝佳美、⻄村友宏、市⽥智久、髙橋優、野⼝幸希、丸⼭哲夫、⽯本尚⼤、加藤将夫、登美⻫俊

    第35 回⽇本薬物動態学会年会 (WEB) , 2020.12

  • Ex vivo ヒト胎盤灌流系からのメトホルミン胎児曝露量予測法の確立

    黒沢 健、千葉 康司、野口 幸希、西村 友宏、登美 斉俊

    第5回トランスポーター研究会関東部会 (WEB) , 2020.11

  • エステル修飾型酸性プロドラッグに対するOATP2B1 の輸送能

    深澤 尚美、野口 幸希、西村 友宏、登美 斉俊

    第5回トランスポーター研究会関東部会 (WEB) , 2020.11, Poster (general)

  • OAT1 及びOAT3 を介したアンジオテンシンⅡ受容体拮抗薬輸送の評価

    三輪 晴香、野口 幸希、加島 里菜、西村 友宏、登美 斉俊

    第5回トランスポーター研究会関東部会 (WEB) , 2020.11, Poster (general)

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • 降圧薬同効薬間の有害事象報告頻度比較分析に基づく妊娠高血圧症治療薬開拓

    2018.04
    -
    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 西村 友宏, Grant-in-Aid for Scientific Research (C), Principal Investigator

  • Adverse fetal effect of thalidomide via semen

    2016.04
    -
    2017.03

    日本医療研究開発機構(AMED), Research on Regulatory Science of Pharmaceuticals and Medical Devices, 西村友宏, Principal Investigator

  • Functional expression of sensing foctors against maternal osmotic stress in the placenta

    2015.04
    -
    2018.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 西村 友宏, Grant-in-Aid for Scientific Research (C), Principal Investigator

  • エズリンを基軸とする胎児発育制御分子ネットワーク

    2014.04
    -
    2015.03

    上原記念生命科学財団

  • Gene network analysis of placental function regulators and a seed gene, ezrin

    2013.04
    -
    2015.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 西村 友宏, Grant-in-Aid for Early-Carrer Scientists (B), Research grant, Principal Investigator

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Awards 【 Display / hide

  • TOP REVIEWER 2020

    2020, J Pharm Sci

    Type of Award: Celebration by Official journal of a scientific society or Academic Journal

  • 学術奨励賞(基礎部門)

    2019, 日本妊娠高血圧学会

    Type of Award: Awards of National Conference, Council and Symposium

  • 奨励賞

    2019, 日本薬剤学会

    Type of Award: Awards of National Conference, Council and Symposium

  • TOP REVIEWER 2019

    2019, J Pharm Sci

    Type of Award: Celebration by Official journal of a scientific society or Academic Journal

 

Courses Taught 【 Display / hide

  • BIOPHARMACEUTICS

    2021, Autumn Semester, Major subject, Lecture, Outside own faculty (within Keio)

  • PHARMACOKINETICS

    2021, Major subject, Lecture, Outside own faculty (within Keio)

  • APPLIED PHARMACOKINETICS

    2019, Spring Semester, Major subject, Lecture, Within own faculty

  • STUDY OF MAJOR FIELD: (PHARMACEUTICS)

    2021

  • SEMINAR: (PHARMACEUTICS)

    2021

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