西村 友宏 (ニシムラ トモヒロ)

Nishimura, Tomohiro

写真a

所属(所属キャンパス)

薬学部 薬学科 薬剤学講座 (芝共立)

職名

准教授

外部リンク

経歴 【 表示 / 非表示

  • 2007年04月
    -
    2008年03月

    共立薬科大学, 助手

  • 2008年04月
    -
    2013年03月

    慶應義塾大学, 薬学部, 助教

  • 2011年09月
    -
    2012年08月

    マウントサイナイ医科大学, 訪問科学者

  • 2014年04月
    -
    2017年03月

    慶應義塾大学, 薬学部, 専任講師

  • 2017年04月
    -
    継続中

    慶應義塾大学, 薬学部, 准教授

学歴 【 表示 / 非表示

  • 2007年03月

    金沢大学

    大学院, 修了, 博士後期

学位 【 表示 / 非表示

  • 博士(薬学), 金沢大学, 課程, 2007年03月

免許・資格 【 表示 / 非表示

  • 甲種危険物取扱者, 2000年12月

  • 薬剤師, 2004年04月

 

著書 【 表示 / 非表示

  • 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年02月

    担当範囲: 31 ビタミン剤,  担当ページ: 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年10月

    担当ページ: 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年03月

    担当範囲: 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,  担当ページ: 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年04月

    担当範囲: 31 ビタミン剤,  担当ページ: 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年03月

    担当範囲: 31 ビタミン剤,  担当ページ: 546-567

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論文 【 表示 / 非表示

  • Limited Impact of Murine Placental MDR1 on Fetal Exposure of Certain Drugs Explained by Bypass Transfer Between Adjacent Syncytiotrophoblast Layers.

    Fujita A, Noguchi S, Hamada R, Inoue S, Shimada T, Katakura S, Maruyama T, Sai Y, Nishimura T, Tomi M

    Pharmaceutical research (Pharmaceutical Research)  39 ( 7 ) 1645 - 1658 2022年01月

    研究論文(学術雑誌), 査読有り,  ISSN  0724-8741

     概要を見る

    Purpose: Multidrug resistance protein 1 (MDR1) is located at the interface between two syncytiotrophoblast layers in rodent placenta, and may influence fetal drug distribution. Here, we quantitatively compare the functional impact per single MDR1 molecule of MDR1 at the placental barrier and blood-brain barrier in mice. Methods: MDR1A and MDR1B proteins were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Paclitaxel or digoxin was continuously administered to pregnant Mdr1a−/−/Mdr1b−/− or wild-type mice, and the drug concentrations in the maternal and fetal plasma and maternal brain were quantified by LC-MS/MS. Results: MDR1A and MDR1B proteins are expressed in the membrane of mouse placental labyrinth, and total MDR1 at the placental barrier amounts to about 30% of that at the blood-brain barrier. The fetal-to-maternal plasma concentration ratio of digoxin was only marginally affected in Mdr1a−/−/Mdr1b−/− mice, while that of paclitaxel showed a several-fold increase. No such difference between the two drugs was found in the maternal brain distribution. The impact per single MDR1 molecule on the fetal distribution of digoxin was calculated to be much lower than that on the brain distribution, but this was not the case for paclitaxel. Our pharmacokinetic model indicates that the impact of placental MDR1 is inversely correlated to the ratio of permeability through gap junctions connecting the two syncytiotrophoblast layers to passive diffusion permeability. Conclusion: Our findings indicate that murine placental MDR1 has a minimal influence on the fetal concentration of certain substrates, such as digoxin, due to bypass transfer, probably via connexin26 gap junctions.

  • Transplacental pharmacokinetic model of digoxin based on <i>ex vivo</i> human placental perfusion study.

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

    Drug metabolism and disposition: the biological fate of chemicals (Drug Metabolism and Disposition)  50 ( 3 ) 287 - 298 2021年12月

    査読有り,  ISSN  0090-9556

     概要を見る

    Digoxin is used as first-line therapy to treat fetal supraventricular tachycardia; however, because of the narrow therapeutic window, it is essential to estimate digoxin exposure in the fetus. The data from ex vivo human placental perfusion study are used to predict in vivo fetal exposure noninvasively, but the ex vivo fetal-to-maternal concentration (F:M) ratios observed in digoxin perfusion studies were much lower than those in vivo. In the present study, we developed a human transplacental pharmacokinetic model of digoxin using previously reported ex vivo human placental perfusion data. The model consists of maternal intervillous, fetal capillary, non-perfused tissue, and syncytiotrophoblast compartments, with multidrug resistance protein (MDR) 1 and influx transporter at the microvillous membrane (MVM) and influx and efflux transporters at the basal plasma membrane (BM). The model-predicted F:M ratio was 0.66, which is consistent with the mean in vivo value of 0.77 (95% confidence interval: 0.64-0.91). The time to achieve the steady state from the ex vivo perfusion study was estimated as 1,500 minutes, which is considerably longer than the reported ex vivo experimental durations, and this difference is considered to account for the inconsistency between ex vivo and in vivo F:M ratios. Reported digoxin concentrations in a drug-drug interaction study with MDR1 inhibitors quinidine and verapamil were consistent with the profiles simulated by our model incorporating inhibition of efflux transporter at the BM in addition to MVM. Our modeling and simulation approach should be a powerful tool to predict fetal exposure and DDIs in human placenta. SIGNIFICANCE STATEMENT We developed a human transplacental pharmacokinetic model of digoxin based on ex vivo human placental perfusion studies in order to resolve inconsistencies between reported ex vivo and in vivo fetal-to-maternal concentration ratios. The model successfully predicted the in vivo fetal exposure to digoxin and the drug-drug interactions of digoxin and P-glycoprotein/multidrug resistance protein 1 inhibitors in human placenta.

  • MicroRNA-126 suppresses the invasion of trophoblast-model JEG-3 cells by targeting LIN28A.

    Pan X, Noguchi S, Ando M, Nishimura T, Tomi M

    Biochemical and biophysical research communications (Biochemical and Biophysical Research Communications)  545   132 - 137 2021年03月

    査読有り,  ISSN  0006-291X

     概要を見る

    Inadequate trophoblast invasion and impaired trophoblast-induced vascular remodeling are features of preeclampsia. In this context, an angiogenesis-related microRNA, miR-126, is abnormally expressed in preeclampsia placentas, but its role in trophoblast development remains unclear. The purpose of this study was to investigate the roles of miR-126 in the proliferation, migration, and invasion processes of trophoblast cells using the human choriocarcinoma-derived JEG-3 cell line as a model. The mRNA expression profiling of JEG-3 cells with and without miR-126 overexpression, in combination with bioinformatics analysis, identified LIN28A as a putative target of miR-126. The results of real-time RT-PCR and luciferase assay were consistent with this idea. Overexpression of miR-126 in JEG-3 cells decreased the invasive ability of the cells without affecting proliferation or migration. The invasiveness of JEG-3 cells was significantly reduced to a similar extent by knockdown of LIN28A with siRNA and by miR-126-overexpression-induced downregulation of LIN28A, although the level of LIN28A protein was much lower in the siLIN28A-transfected cells. These results indicate that miR-126 suppresses JEG-3 cell invasion by targeting LIN28A, and suggest that miR-126-mediated downregulation of LIN28A might contribute to the onset/deterioration of preeclampsia.

  • 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年01月

    研究論文(学術雑誌), 共著, 査読有り,  ISSN  0142-2782

     概要を見る

    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年12月

    研究論文(学術雑誌), 査読有り,  ISSN  00909556

     概要を見る

    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.

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KOARA(リポジトリ)収録論文等 【 表示 / 非表示

総説・解説等 【 表示 / 非表示

  • 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年08月

    記事・総説・解説・論説等(学術雑誌), 単著,  ISSN  0014-8601

     概要を見る

    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).

  • 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年03月

    ISSN  0016-5980

  • Committee for Academic Affairs JSSHP Research Award 2019 Basic Research Screening of an Angiotensin II Receptor Blocker with Low Adverse Fetal Effect using Adverse Event Reporting System and Mechanism of the Low Placental Transfer

    Nishimura Tomohiro, Ishikawa Yu, Noguchi Saki, Tomi Masatoshi

    Hypertension Research in Pregnancy (日本妊娠高血圧学会)  8 ( 1 ) 3 - 3 2020年

    ISSN  2187-5987

  • 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年03月

    記事・総説・解説・論説等(学術雑誌), 単著,  ISSN  0014-8601

  • 脳が決める効果:プラセボ効果の要因解析からわかること

    井澤 美苗, 信野 明美, 西村 友宏, 中島 恵美.

    日本香粧品学会誌 (日本香粧品学会)  37 ( 3 ) 197 - 200 2013年09月

    研究発表ペーパー・要旨(全国大会,その他学術会議), 共著,  ISSN  1880-2532

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研究発表 【 表示 / 非表示

  • 副作用報告頻度に基づく低胎児毒性アンジオテンシンII受容体拮抗薬の探索と低胎盤透過性の要因

    西村 友宏, 石川 優, 野口 幸希, 登美 斉俊

    第41回日本妊娠高血圧学会学術集会 (奈良) , 

    2021年12月

    口頭発表(招待・特別)

  • タダラフィルおよびシルデナフィルのマウス胎仔移行性比較と胎盤透過制御機構

    石井 まり, 西村 友宏, 野口 幸希, 田中 博明, 池田 智明, 登美 斉俊

    第41回日本妊娠高血圧学会学術集会 (奈良) , 

    2021年12月

    口頭発表(一般)

  • マウス胎盤におけるPGE2受容体の発現解析

    高橋 駿太, 稲垣 舞, 野口 幸希, 西村 友宏, 登美 斉俊

    第29回日本胎盤学会学術集会 (Web) , 

    2021年11月

    口頭発表(一般)

  • LIN28A発現抑制を介したmiR-126によるJEG-3細胞の浸潤抑制

    野口 幸希, 潘 暁楽, 安藤 美鈴, 西村 友宏, 登美 斉俊

    第29回日本胎盤学会学術集会 (WEB) , 

    2021年11月

    口頭発表(一般)

  • Ex vivoヒト胎盤灌流試験を用いたジゴキシンのヒト胎盤薬物動態モデル

    黒沢 健, 千葉 康司, 野口 幸希, 西村 友宏, 登美 斉俊

    日本薬物動態学会第36回年会 (Web) , 

    2021年11月

    ポスター発表

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競争的研究費の研究課題 【 表示 / 非表示

  • 子宮内膜螺旋動脈の成熟過程依存的な妊娠高血圧症候群に対する薬物療法の開発

    2022年04月
    -
    2025年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 西村 友宏, 基盤研究(C), 補助金,  研究代表者

  • 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年04月
    -
    2021年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 西村 友宏, 基盤研究(C), 補助金,  研究代表者

  • サリドマイド類の精液移行と胎児への影響

    2016年04月
    -
    2017年03月

    日本医療研究開発機構(AMED), 医薬品等規制調和・評価研究事業, 西村友宏, 研究代表者

  • 胎盤における母体環境ストレス緩和初動因子の機能発現制御

    2015年04月
    -
    2018年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 西村 友宏, 基盤研究(C), 補助金,  研究代表者

  • 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年04月
    -
    2015年03月

    上原記念生命科学財団, 未設定

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受賞 【 表示 / 非表示

  • TOP REVIEWER 2020

    2020年, J Pharm Sci

    受賞区分: 学会誌・学術雑誌による顕彰

  • 学術奨励賞(基礎部門)

    2019年, 日本妊娠高血圧学会

    受賞区分: 国内学会・会議・シンポジウム等の賞

  • 奨励賞

    2019年, 日本薬剤学会

    受賞区分: 国内学会・会議・シンポジウム等の賞

  • TOP REVIEWER 2019

    2019年, J Pharm Sci

    受賞区分: 学会誌・学術雑誌による顕彰

 

担当授業科目 【 表示 / 非表示

  • 薬物動態学1

    2021年度, 秋学期, 講義, 兼任

  • 薬物動態学2

    2021年度, 講義, 兼任

  • アプライド薬物動態学

    2019年度, 春学期, 講義, 専任

  • 課題研究(薬剤学)

    2022年度

  • 演習(薬剤学)

    2022年度

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