Tomi, Masatoshi

写真a

Affiliation

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

Position

Professor

Related Websites

External Links

Profile Summary 【 Display / hide

  • 私たちは、胎児への薬物分布を制御する胎盤関門について研究しています。主に安全性の問題から、妊娠中疾患は薬物治療の貢献が不十分です。薬物の胎児影響は実験動物を用いて評価せざるを得ませんが、薬物の胎児移行性を規定する胎盤関門輸送体の中にはヒトだけにあるものや、ヒトとラットの間で発現量が異なるものがあり、ヒト胎児移行性の予測を困難にしています。私たちは、胎盤関門輸送体機能の種差を解明することなどを通じ、ヒト胎児中薬物濃度の予測精度を高め、妊婦で使用可能な薬物の選択肢を増やすことを目指しています。今後の医療は疾患の素因をあらかじめ摘み取る先制医療へとシフトしていきます。生活習慣病や精神・神経疾患の素因が形成される胎児の環境を直接的に制御するのは、胎盤関門です。胎盤関門機能の理解から、将来の疾患発症リスクを軽減する先制医療を実現させることが大きな目標です。

Career 【 Display / hide

  • 2001.04
    -
    2005.09

    Assistant Professor, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University

  • 2005.10
    -
    2006.03

    Assistant Professor, Faculty of Pharmaceutical Sciences, University of Toyama

  • 2006.04
    -
    2008.12

    Postdoctoral Fellow, David Geffen School of Medicine, University of California, Los Angeles (UCLA)

  • 2009.01
    -
    2011.03

    Senior Assistant Professor, Faculty of Pharmacy, Keio University

  • 2011.04
    -
    2016.03

    Associate Professor, Faculty of Pharmacy, Keio University

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Academic Background 【 Display / hide

  • 1998.03

    Tohoku University, Faculty of Pharmaceutical Science, 薬学科

    University, Graduated

  • 2000.03

    Tohoku University, Graduate School, Division of Pharmaceutical Sciences, 分子生命薬学専攻

    Graduate School, Completed, Master's course

  • 2001.03

    Tohoku University, Graduate School, Division of Pharmaceutical Sciences, 生命薬学専攻

    Graduate School, Withdrawal before completion, Doctoral course

Academic Degrees 【 Display / hide

  • Ph.D.(Pharmaceutical Sciences), Tohoku University, Dissertation, 2004.01

Licenses and Qualifications 【 Display / hide

  • 薬剤師, 1999.02

 

Research Areas 【 Display / hide

  • Life Science / Clinical pharmacy

 

Books 【 Display / hide

  • 基礎と臨床の両側面からみた 胎盤学

    日本胎盤学会 (編集) 登美 斉俊, メジカルビュー, 2019.12

    Scope: 物質交換,  Contact page: 80-84

  • 薬の生体内運命 改訂7版

    丸山一雄 (編集) 登美斉俊, ネオメディカル, 2017.03

    Scope: 排泄,  Contact page: 112-134

  • スタンダード薬学シリーズⅡ 6 医療薬学 Ⅵ. 薬の生体内運命

    日本薬学会 (編集) 崔 吉道, 登美斉俊, 東京化学同人, 2016.12

    Scope: 胎盤関門の構造・機能と薬物の胎児への移行,  Contact page: 63-65

  • 薬剤学実験法必携マニュアル - Pharmaceutical Scientistのために Ⅱ 生物薬剤学

    日本薬剤学会出版委員会 (編集) 登美斉俊, 西村友宏, 南江堂, 2014.04

    Scope: 血液胎盤関門,  Contact page: 138-145

  • 薬の生体内運命 改訂5版

    中島恵美 (編集) 登美斉俊, ネオメディカル, 2013.03

    Scope: 薬の運命,  Contact page: 12-18

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Papers 【 Display / hide

  • Involvement of GAT2/Slc6a13 in hypotaurine uptake at fetal-facing plasma membrane of syncytiotrophoblasts at mid-to-late gestation in rats and mice

    Nishimura T., Araki H., Higuchi K., Noguchi S., Saito K., Hara K., Yagishita H., Akashi R., Obata S., Tomi M.

    Placenta (Placenta)  147   59 - 67 2024.03

    ISSN  01434004

     View Summary

    Introduction: Hypotaurine, a precursor to taurine, is known for its antioxidant properties and is prominently present in fetal plasma and the placenta. Our previous research revealed that ezrin-knockout mice experience fetal growth retardation, coinciding with reduced hypotaurine levels in fetal plasma. This study aims to elucidate the expression and role of hypotaurine transporters within the placenta. Methods: We employed quantitative RT-PCR to measure mRNA expression of GAT transporter family members in the placenta during mid-to-late gestation. LC/MS/MS was used to analyze the distribution of hypotaurine in different placental subregions. Immunohistochemistry was utilized to examine the localization of GAT2 in mice. Placental hypotaurine uptake from fetal circulation was studied via umbilical perfusion in rats. Results: Among hypotaurine transporters, GAT2 exhibited increased mRNA and protein expression in murine placenta during mid-to-late gestation. Notably, GAT2/Slc6a13 mRNA and hypotaurine were most concentrated in the labyrinth of murine placenta. In contrast, enzymes responsible for hypotaurine synthesis, such as cysteine dioxygenase, cysteine sulfinic acid decarboxylase, and 2-aminoethanethiol dioxygenase, showed minimal expression in the labyrinth. These findings suggest that GAT2 is a key determinant of hypotaurine levels in the placental labyrinth. Immunohistochemical examination unveiled that GAT2 was predominantly localized on the fetal-facing plasma membrane within syncytiotrophoblasts, which co-localized with ezrin. In rat umbilical perfusion experiments, the GAT2/3 and TauT inhibitor, SNAP-5114, significantly reduced hypotaurine extraction from fetal circulation to the placenta. Discussion: The results suggest that GAT2 plays a pivotal role in the concentrative uptake of hypotaurine from fetal plasma within syncytiotrophoblasts of the placenta.

  • L-Type Amino Acid Transporter 1 (SLC7A5)-Mediated Transport of Pregabalin at the Rat Blood-Spinal Cord Barrier and its Sensitivity to Plasma Branched-Chain Amino Acids.

    Akashi T, Noguchi S, Takahashi Y, Nishimura T, Tomi M

    Journal of pharmaceutical sciences (Journal of Pharmaceutical Sciences)  112 ( 4 ) 1137 - 1144 2023.01

    Accepted,  ISSN  0022-3549

     View Summary

    Pregabalin is an anti-neuropathic pain drug inhibiting the α2δ subunit of the voltage-dependent calcium channel in the spinal cord. The aim of this study is to characterize the transport mechanism of pregabalin at the blood-spinal cord barrier (BSCB) by means of in vivo experiments in rats and in vitro studies using primary-cultured rat spinal cord endothelial cells. We isolated endothelial cells by culturing rat spinal cord tissue in the presence of puromycin, and confirmed the expression of BSCB markers such as Cd31, Mdr1a, and Claudin-5. The uptake of pregabalin by primary-cultured rat spinal cord endothelial cells was sodium-independent and was significantly inhibited by L-leucine, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, and JPH203. These results suggest the involvement of L-type amino acid transporter (LAT) 1. LAT1 mRNA and protein was expressed in primary-cultured rat spinal cord endothelial cells, which is consistent with LAT1 expression at the BSCB. In the in vivo study, the transfer of pregabalin to rat spinal cord and brain was significantly decreased by the pre-administration of branched chain amino acids (BCAAs), which are endogenous substrates of LAT1. Our results indicate that pregabalin transport across the BSCB is mediated at least in part by LAT1 and is inhibited by plasma BCAAs.

  • Breast Cancer Resistance Protein Limits Fetal Transfer of Tadalafil in Mice

    Nishimura T., Ishii M., Tanaka H., Noguchi S., Ikeda T., Tomi M.

    Journal of Pharmaceutical Sciences (Journal of Pharmaceutical Sciences)  113 ( 2 ) 486 - 492 2023

    ISSN  00223549

     View Summary

    Tadalafil, a phosphodiesterase 5 (PDE5) inhibitor, is a candidate therapeutic agent for fetal growth restriction and hypertensive disorders of pregnancy. In this study, we elucidated the fetal transfer of tadalafil in comparison with that of sildenafil, the first PDE5 inhibitor to be approved. We also examined the contributions of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP) to fetal transfer. Tadalafil or sildenafil was administered to wild-type, Mdr1a/b-double-knockout or Bcrp-knockout pregnant mice by continuous infusion from gestational day (GD) 14.5 to 17.5, and the fetal-to-maternal plasma concentration ratio of unbound drug (unbound F/M ratio) was evaluated at GD 17.5. The values of unbound F/M ratio of tadalafil and sildenafil in wild-type mice were 0.80 and 1.6, respectively. The unbound F/M ratio of tadalafil was increased to 1.1 and 1.7 in Mdr1a/b-knockout and Bcrp-knockout mice, respectively, while the corresponding values for sildenafil were equal to or less than that in wild-type mice, respectively. A transcellular transport study revealed that basal-to-apical transport of both tadalafil and sildenafil was significantly higher than transport in the opposite direction in MDCKII-BCRP cells. Our research reveals that tadalafil is a newly identified substrate of human and mouse BCRP, and it appears that the fetal transfer of tadalafil is, at least in part, attributed to the involvement of BCRP within the placental processes in mice. The transfer of sildenafil to the fetus was not significantly constrained by BCRP, even though sildenafil was indeed a substantial substrate for BCRP.

  • Quantitative Comparison of Breast Cancer Resistance Protein (BCRP/ABCG2) Expression and Function Between Maternal Blood-Brain Barrier and Placental Barrier in Mice at Different Gestational Ages

    Arimi Fujita, Saki Noguchi, Rika Hamada, Tsutomu Shimada, Satomi Katakura, Tetsuo Maruyama, Yoshimichi Sai, Tomohiro Nishimura, Masatoshi Tomi

    Frontiers in Drug Delivery (Frontiers)  2   932576 2022.07

    Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted

  • Decellularized Organ-Derived Scaffold Is a Promising Carrier for Human Induced Pluripotent Stem Cells-Derived Hepatocytes

    Kojima H., Yagi H., Kushige H., Toda Y., Takayama K., Masuda S., Morisaku T., Tsuchida T., Kuroda K., Hirukawa K., Inui J., Nishi K., Nakano Y., Tanaka M., Hori S., Hasegawa Y., Abe Y., Kitago M., Adachi S., Tomi M., Matsuura K., Mizuguchi H., Kitagawa Y.

    Cells (Cells)  11 ( 8 )  2022.04

     View Summary

    Human induced pluripotent stem cells (hiPSCs) are a promising cell source for elucidating disease pathology and therapy. The mass supply of hiPSC-derived cells is technically feasible. Carriers that can contain a large number of hiPSC-derived cells and evaluate their functions in vivo-like environments will become increasingly important for understanding disease pathogenesis or treating end-stage organ failure. hiPSC-derived hepatocyte-like cells (hiPSC-HLCs; 5 × 108) were seeded into decellularized organ-derived scaffolds under circumfusion culture. The scaffolds were implanted into immunodeficient microminiature pigs to examine their applicability in vivo. The seeded hiPSC-HLCs demonstrated increased albumin secretion and up-regulated cytochrome P450 activities compared with those in standard two-dimensional culture conditions. Moreover, they showed long-term survival accompanied by neovascularization in vivo. The decellularized organ-derived scaffold is a promising carrier for hiPSC-derived cells for ex vivo and in vivo use and is an essential platform for regenerative medicine and research.

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

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Reviews, Commentaries, etc. 【 Display / hide

  • 【妊娠・授乳中の薬剤の安全性について科学する】薬物の胎児移行性評価と薬物療法

    登美 斉俊

    Precision Medicine ((株)北隆館)  4 ( 10 ) 918 - 921 2021.09

    ISSN  2434-3625

     View Summary

    薬物の胎児移行性を評価し、その機構を理解するには、定常状態における胎児血/母体血濃度比を基準とすることが重要である。定常状態における濃度比に影響するのは薬物の脂溶性やタンパク結合率に限らず、むしろトランスポーターを介した透過クリアランスによる影響が大きい。本稿では、妊婦に用いられる薬物として血糖降下薬や甲状腺機能亢進症治療薬、ジゴキシンに焦点を当て、定常状態における濃度比に基づく胎児移行性評価と、胎児移行に果たす胎盤トランスポーターの役割、胎児への影響について概説する。(著者抄録)

  • Faculty challenges during the SARS-CoV-2 pandemic and the results of student questionnaires for the implementation of online and face-to-face classes

    Ishikawa Satoko, Inoue Kae, Tomi Masatoshi

    Japanese Journal of Pharmaceutical Education (Japan Society for Pharmaceutical Education)  5 ( 0 ) n/a 2021

    ISSN  2432-4124

     View Summary

    <p>Review of the challenges posed by the SARS-CoV-2 pandemic at Keio University Faculty of Pharmacy. We shared the latest information needed to conduct online classes with faculty and staff, held seminars on using learning management systems, creating video content, and for copyright adherence of educational materials. For freshmen of the Faculty of Pharmacy, an online communication session was held in April of 2020 and a subsequent environment for conducting face-to-face classes once a week was implemented from June of 2020. At our campus, students were able to participate more actively as college students, have interactions with their peers, ask questions, and consult with the faculty. From questionnaires about online classes, problems facing the students were identified and presented to our faculty for purposes of improving learning content. The number of students who chose the option "I don't have an opportunity to talk with my friends" tends to decrease as the academic year of education rises. Hence, more consideration should be given particularly to the first-year students. All students tended to have relatively good impressions about online classes due to the efficiency and ability for repeated viewing of lecture content. We would like to utilize the knowledge acquired from the past 10 months to provide more effective classes and further enhance the educational impact at the Faculty of Pharmacy.</p>

  • 【周産期の薬】産科編 総論 薬物の経胎盤透過

    登美 斉俊

    周産期医学 ((株)東京医学社)  50 ( 増刊 ) 46 - 48 2020.12

    ISSN  0386-9881

  • 【「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]薬物の胎児移行性を規定するメカニズム

    登美 斉俊, 野村 岳広

    薬事 ((株)じほう)  62 ( 4 ) 729 - 734 2020.03

    ISSN  0016-5980

     View Summary

    <Points>▼薬物が胎盤関門を介して胎児に移行する速度は、受動拡散による透過の場合、脂溶性に依存するが、定常状態における胎児血中濃度が移行速度に比例して高くなるわけではない。▼血漿タンパク結合した薬物は胎盤関門を透過できないが、血漿タンパク結合率は100%ではない。遊離形薬物は胎盤関門を透過できるため、血漿タンパク結合率が高い薬物であっても、定常状態においては胎児血中の遊離形薬物濃度が母体血並みに高くなっている可能性は十分にある。▼胎盤関門において、母体側細胞膜の頂端膜と胎児側細胞膜の基底細胞膜には、それぞれトランスポーターが極性をもって局在し、基質薬物の胎児血への移行速度と、定常状態における胎児血中濃度の両方を規定する。(著者抄録)

  • 【「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]胎盤透過と薬物選択

    登美 斉俊, 植田 有美

    薬事 ((株)じほう)  62 ( 4 ) 735 - 739 2020.03

    ISSN  0016-5980

     View Summary

    <Points>▼母体の治療には胎盤透過性の低い薬物がより望ましく、インスリンやヘパリンなどの高分子医薬品や、プレドニゾロンのように胎盤での代謝を強く受ける薬物が代表例である。▼胎児の経胎盤治療にはチアマゾールやベタメタゾン、ジゴキシンなど、一定の胎盤透過性を有した薬物が用いられている。▼胎盤透過する薬物の胎児への影響や胎盤透過性は妊娠進行に伴い変動することがあり、チアマゾールのように妊娠初期は禁忌でも、妊娠中後期には用いられる場合がある。(著者抄録)

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Presentations 【 Display / hide

  • Transport mechanism of propionic acid in human choriocarcinoma JEG-3 cells

    Kasuya A, Noguchi S, Nishimura T, Tomi M.

    Asian Federation for Pharmaceutical Sciences 2023 (Hanoi, Vietnam) , 

    2023.11

    Oral presentation (general)

  • Prediction of Fetal Drug Exposure by integrating in vitro, in vivo, ex vivo, and in silico approaches

    Tomi M.

    Asian Federation for Pharmaceutical Sciences 2023 (Hanoi, Vietnam) , 

    2023.11

    Oral presentation (invited, special)

  • Enhanced invasion of extravascular trophoblast cells by human vascular endothelial cells and its effect on gene expression

    Harada Y, Nishimura T, Tajima Y, Noguchi S, Tomi M.

    Asian Federation for Pharmaceutical Sciences 2023 (Hanoi, Vietnam) , 

    2023.11

    Oral presentation (general)

  • Fetal transfer of tadalafil, a PDE5 inhibitor, is limited by BCRP at murine placental barrier

    Nishimura T, Ishii M, Tanaka H, Noguchi S, Ikeda T, Tomi M.

    Asian Federation for Pharmaceutical Sciences 2023 (Hanoi, Vietnam) , 

    2023.11

    Oral presentation (general)

  • マウス胎盤におけるMFSD2Aの発現とlysophosphatidylcholine結合型docosahexaenoic acid透過に与える影響

    登美斉俊, 野口幸希, 関瑞生, 関誠悟, 山本元輝, 定村龍太, 赤沼伸乙, 河野早弥賀, 盛武浩, 細谷健一, 西村友宏

    第44回生体膜と薬物の相互作用シンポジウム (福岡) , 

    2023.10

    Oral presentation (general)

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

  • 輸送分子種差と遊離形濃度に基づくヒト胎児への経胎盤薬物曝露量予測モデルの構築

    2021.04
    -
    2024.03

    Keio University, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), No Setting

     View Summary

    胎児血中薬物濃度は妊婦への薬物治療において重要な指標であるが、ヒトで実測可能な薬物は限られる。本研究では、ヒト胎盤灌流およびラットでの薬物の胎児移行性評価から、ヒト胎児移行性を定量的に予測することを目指している。具体的には、定常状態での遊離形薬物濃度比を基準とし、実験手法の差や輸送体の種差を克服可能な胎盤透過の薬物動態モデルを構築することを目指す。

  • Regulation of pharmacokinetics during pregnancy by placental exosomes

    2020.07
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    2022.03

    Keio University, Grants-in-Aid for Scientific Research, Tomi Masatoshi, Challenging Research (Exploratory), No Setting

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    Syncytin-2, a molecule specifically expressed in the placenta, has membrane fusion capacities and contributes to the barrier formation through syncytialization. In this study, it is indicated that the uptake of JEG-3 cell-derived exosome to human hepatic HepG2 cells was significantly enhanced when the expression of syncytin-2 in JEG-3 cells was induced. The placenta-specific miRNA is detected from HepG2 cells exposed to JEG-3 cell-derived exosomes, implying that exosomal syncytin-2 is capable to mediate cell-to-cell communication through the exosome. However, the expression of MFSD2A, a receptor of syncytin-2, is found not to be constitutively expressed in the mouse liver. Therefore, it is necessary to further confirm whether syncytin-2-expressing exosome is preferably binds to hepatic cells. We also found that MFSD2A involves in the supply of docosahexaenoic acid to the fetus.

  • Significance of a balanced tryptophan diet for supporting fetal growth

    2018.04
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    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Tomi Masatoshi, Grant-in-Aid for Scientific Research (B), Principal investigator

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    The purpose of the present study was to clarify the transporters mediating the fetal transfer of tryptophan and examine the importance of an adequate supply of tryptophan into the fetus. This study described the amount and localization of LAT1 protein, a transporter for large neutral amino acids including tryptophan, at the placental barrier. It is also observed that the tissue distribution of LAT1 substrate is suppressed by an increase of LAT1-substrate amino acids in the plasma. For serotonin, we have clarified OCTN1 protein accepts it as a substrate and is expressed at the placental barrier at term. However, the effect of tryptophan imbalance in the diet was negligible in the plasma concentration of amino acids.

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

    2015.04
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    2018.03

    Keio University, NISHIMURA Tomohiro, Grant-in-Aid for Scientific Research (C), No Setting

     View Summary

    Placenta is an interface between mother and fetus and it has a role of nutrients transfer. The placenta has the function mitigating the osmotic stress exposed from maternal blood. Part of amino acid is transferred via amino acid transport system A from mother to fetus in the placenta. In this study, we clarified that expression of the system A molecule can be more quickly increased in response to the osmotic stress than other molecules and we investigated how the system A molecules is induced by hypertonic stress.

  • Medication for pregnant women based on 'barrier transition' behavior in feto-placental circulation

    2015.04
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    2017.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Tomi Masatoshi, Grant-in-Aid for Challenging Exploratory Research, Principal investigator

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    We have clarified the developmental change in the placental transporters such as glucose transporter 1 (GLUT1) and monocarboxylate transporter 1 (MCT1), while the expressions of ABC transporters such as MDR1 and BCRP were unchanged during pregnancy. We also found a placenta-derived miRNA which may work for maturation of both placental and blood-brain barrier. These observations are helpful for examining the interorgan network in the fetoplacental circulation for establishing and managing barriers in the placenta and the brain.

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Awards 【 Display / hide

  • 2019 Top Reviewer

    2019, Journal of Pharmaceutical Sciences

    Type of Award: Honored in official journal of a scientific society, scientific journal

  • 2018 Top Reviewer

    2018, Journal of Pharmaceutical Sciences

    Type of Award: Honored in official journal of a scientific society, scientific journal

  • 2017 Top Reviewer

    2017, Journal of Pharmaceutical Sciences

    Type of Award: Honored in official journal of a scientific society, scientific journal

  • 日本薬剤学会奨励賞

    2015, The Academy of Pharmaceutical Science and Technology, Japan, 関門トランスポーターによる薬物組織分布制御機構の研究

    Type of Award: Award from Japanese society, conference, symposium, etc.

  • 学部長賞

    2015, 慶應義塾大学薬学部

    Type of Award: Keio commendation etc.

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Courses Taught 【 Display / hide

  • STUDY OF MAJOR FIELD: (PHARMACEUTICS)

    2024

  • SEMINAR: (PHARMACEUTICS)

    2024

  • RESEARCH FRONTIERS IN BIOMEDICAL SCIENCE

    2024

  • RESEARCH FOR BACHELOR'S THESIS 1

    2024

  • PHYSICAL PHARMACY

    2024

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