Noguchi, Saki

写真a

Affiliation

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

Position

Research Associate/Assistant Professor/Instructor

External Links

Academic Background 【 Display / hide 】

  • 2006.04
    -
    2012.03

    Keio University, Faculty of Pharmacy, 薬学科

  • 2013.04
    -
    2017.03

    Keio University, Graduate School of Pharmacy, 薬学専攻

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Academic Degrees 【 Display / hide 】

  • Ph.D.(Pharmacy), Keio University, Coursework, 2017.03

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Licenses and Qualifications 【 Display / hide 】

  • Pharmacist, 2012.04

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Research Areas 【 Display / hide 】

  • Life Science / Clinical pharmacy (Pharmaceutics, Pharmacokinetics, Transporter)

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Papers 【 Display / hide 】

  • Rat-Specific Expression of Placental MATE1 Contributes to Species Difference in Fetal Transfer of Metformin and 1-Methyl-4-Phenylpyridinium

    Suzuki A., Noguchi S., Tsuchitani T., Sakamoto R., Yamauchi A., Ishinabe T., Hashimoto R., Nakaguchi Y., Sakai M., Imayoshi N., Ishimoto T., Kato Y., Shirasaka Y., Katakura S., Maruyama T., Nishimura T., Tomi M.

    Molecular Pharmaceutics 22 ( 12 ) 7412 - 7422 2025.12

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  15438384

    　View Summary

    Metformin readily crosses the human placenta. However, the fetal-to-maternal plasma concentration ratio (F/M ratio) of metformin has been reported to be as low as 0.057 in rats. This study investigated the underlying mechanisms of these interspecies differences by examining the expression and function of candidate transporters, organic cation transporter 3 (OCT3/SLC22A3) and multidrug and toxin extrusion protein 1 (MATE1/SLC47A1), in the placenta across species. Expression analysis at gene and protein levels using RNA-sequencing and absolute quantification by LC-MS/MS revealed minimal species differences in placental OCT3 expression (less than 4-fold). In contrast, MATE1 showed almost exclusive expression in the rat placental labyrinth, but minimal or undetectable levels were observed in samples prepared from human placental villi and mouse placental labyrinth. To evaluate the function of the placental MATE1, we compared the placental transfer of two dual substrates of MATE1 and OCT3, metformin and 1-methyl-4-phenylpyridinium (MPP<sup>+</sup>), in pregnant rats and mice in the presence and absence of pyrimethamine, a MATE1 inhibitor. The pyrimethamine was dosed to reach the plasma concentration, which specifically inhibits MATE1 based on the measured IC<inf>50</inf> of pyrimethamine to rat MATE1 and OCT3, which were 0.015 and 100 μM, respectively. The F/M ratios of metformin and MPP<sup>+</sup> in the absence of pyrimethamine were half or less in rats compared to mice. Notably, preadministration of pyrimethamine increased the F/M ratios of metformin and MPP<sup>+</sup> by approximately 50% in rats but not mice. These findings demonstrate that functional placental MATE1 expression is specific to rats, which, in part, contributes to the low fetal transfer of cationic compounds compared with other species. This is of significant concern, as it suggests that nonclinical developmental and reproductive toxicity studies of MATE1 substrate drugs in rats may underestimate fetal exposure and toxicity when extrapolated to humans.

  • Fetal ezrin expression affects macrophages and regulatory T cells in mouse placental decidua

    Tomohiro Nishimura, Ryo Mizokami, Mayuko Yamanaka, Masaya Takahashi, Yuko Yoshida, Yuya Ogawa, Saki Noguchi, Masatoshi Tomi

    Biochemical and Biophysical Research Communications 735 2024.11

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  0006291X

    　View Summary

    Ezrin is a cross-linker protein between membrane proteins and cytosolic actin, abundantly expressed in the placenta among the ERM protein family. Ezrin gene knockout mice exhibit fetal growth restriction after gestational day (GD) 15.5. This study aimed to clarify the effect of ezrin on immune cells that influence fetal growth and immune tolerance. Ezrin heterozygous knockout (Ez+/−) mice were interbred, and the gene expressions and immune cell distributions in the placentas of wild-type (Ez+/+) and ezrin knockout (Ez−/−) fetuses were analyzed. IL-6 expression in the placenta of Ez−/− fetuses was significantly higher than in Ez+/+ fetuses at GD 15.5. The mRNA expression of IL-6 in the uterine decidua attached to Ez−/− fetuses was higher compared to that attached to Ez+/+ fetuses but not in the junctional zone and labyrinth. Classical M1 and M2 macrophages in the decidua were analyzed by flow cytometry using CD86 and CD206 as markers. M1 macrophages increased in the decidua attached to Ez−/− mice compared to Ez+/+ mice, while M2 macrophages did not increase. CD4-positive T cells showed a reduction in the decidua attached to Ez−/− fetuses. Further analysis involved the subcutaneous administration of tacrolimus in pregnant Ez+/− mice from GD 8.5 to GD 15.5, which prevented the decrease in fetal body weight and decidual CD4-positive T cells in Ez−/− mice at GD 15.5. These results suggest that impaired expression of fetoplacental-derived ezrin induces inflammatory conditions in the uterine decidua through M1 polarization of macrophages, increased IL-6, and decreased CD4-positive T cells, including Treg cells.

  • Conversion of Olmesartan to Olmesartan Medoxomil, A Prodrug that Improves Intestinal Absorption, Confers Substrate Recognition by OATP2B1.

    Naomi Fukazawa, Tomohiro Nishimura, Keisuke Orii, Saki Noguchi, Masatoshi Tomi

    Pharmaceutical research 41 ( 5 ) 849 - 861 2024.05

    Research paper (scientific journal), Accepted,  ISSN  07248741

    　View Summary

    PURPOSE: Olmesartan medoxomil (olmesartan-MX), an ester-type prodrug of the angiotensin II receptor blocker (ARB) olmesartan, is predominantly anionic at intestinal pH. Human organic anion transporting polypeptide 2B1 (OATP2B1) is expressed in the small intestine and is involved in the absorption of various acidic drugs. This study was designed to test the hypothesis that OATP2B1-mediated uptake contributes to the enhanced intestinal absorption of olmesartan-MX, even though olmesartan itself is not a substrate of OATP2B1. METHODS: Tetracycline-inducible human OATP2B1- and rat Oatp2b1-overexpressing HEK 293 cell lines (hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293, respectively) were established to characterize OATP2B1-mediated uptake. Rat jejunal permeability was measured using Ussing chambers. ARBs were quantified by liquid chromatography-tandem mass spectrometry. RESULTS: Significant olmesartan-MX uptake was observed in hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293 cells, whereas olmesartan uptake was undetectable or much lower than olmesartan-MX uptake, respectively. Furthermore, olmesartan-MX exhibited several-fold higher uptake in Caco-2 cells and greater permeability in rat jejunum compared to olmesartan. Olmesartan-MX uptake in hOATP2B1/T-REx-293 cells and in Caco-2 cells was significantly decreased by OATP2B1 substrates/inhibitors such as 1 mM estrone-3-sulfate, 100 µM rifamycin SV, and 100 µM fluvastatin. Rat Oatp2b1-mediated uptake and rat jejunal permeability of olmesartan-MX were significantly decreased by 50 µM naringin, an OATP2B1 inhibitor. Oral administration of olmesartan-MX with 50 µM naringin to rats significantly reduced the area under the plasma concentration-time curve of olmesartan to 76.9%. CONCLUSION: Olmesartan-MX is a substrate for OATP2B1, and the naringin-sensitive transport system contributes to the improved intestinal absorption of olmesartan-MX compared with its parent drug, olmesartan.

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

    Tomohiro Nishimura, Hikari Araki, Kei Higuchi, Saki Noguchi, Kei Saito, Kanako Hara, Haruya Yagishita, Risa Akashi, Sakiko Obata, Masatoshi Tomi

    Placenta 147   59 - 67 2024.03

    Research paper (scientific journal), Accepted,  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.

  • 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 2023.11

    Research paper (scientific journal), Accepted,  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.

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

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Reviews, Commentaries, etc. 【 Display / hide 】

  • タダラフィルのマウス胎仔移行におけるBCRPの関与

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

    日本薬学会年会要旨集 ((公社)日本薬学会)  142年会   26C - pm04 2022.03

    ISSN  0918-9823

  • 【「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 ((株)じほう)  62 ( 4 ) 717 - 727 2020.03

    Other, Joint Work,  ISSN  0016-5980

    　View Summary

    ＜Points＞▼妊娠による生理学的変動は薬物血中濃度に影響を与えるため、投与量や投与頻度の調節が必要な場合がある。▼血漿容積の増加により血漿タンパク濃度が減少するため、血漿タンパク結合率が減少し、薬物の分布容積や消失速度の増大につながる。▼肝薬物代謝酵素の発現変動が起こるが、その変動は代謝酵素の分子種により異なる。▼糸球体濾過量の上昇により、腎排泄型薬物の消失が促進される。▼治療薬物モニタリング(TDM)対象薬物にはTDMを行うことが推奨され、また血中濃度の解釈は血漿タンパク結合率が変動していることを考慮する必要がある。(著者抄録)

  • 血液脳関門における中性アミノ酸トランスポーターLAT1を介したpregabalin輸送

    高橋優, 西村友宏, 樋口慧, 野口幸希, 手賀悠真, 黒澤俊樹, 出口芳春, 登美斉俊

    生体膜と薬物の相互作用シンポジウム講演要旨集 40th 2018

    ISSN  0919-2131

  • ROLE OF ORGANIC ANION TRANSPORTER 4 ON THE TRANSPORT OF OLMESARTAN ACROSS THE BASAL PLASMA MEMBRANE OF HUMAN PLACENTAL SYNCYTIOTROPHOBLAST

    Masatoshi Tomi, Saki Noguchi, Ayasa Fujibayashi, Tetsuo Maruyama, Emi Nakashima, Tomohiro Nishimura

    PLACENTA 45   133 - 133 2016.09

    ISSN  0143-4004

  • OAT4-MEDIATED TRANSPORT OF OLMESARTAN AT THE BASAL PLASMA MEMBRANE OF THE HUMAN PLACENTAL BARRIER

    Saki Noguchi, Tomohiro Nishimura, Tetsuo Maruyama, Masatoshi Tomi, Emi Nakashima

    DRUG METABOLISM REVIEWS 47   296 - 296 2015.11

    ISSN  0360-2532

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Presentations 【 Display / hide 】

  • MFSD2A-mediated transplacental transfer of LPC-DHA involving molecular species conversion

    野口幸希.

    [Domestic presentation]  日本薬学会第146年会 (大阪) , 

    2026.03
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    Symposium, workshop panel (public)

  • MCT1, but not MCT4, facilitates bidirectional propionic acid transport across a human placental barrier model

    山本耕平, 緑川凜, 土谷聡耀, 野口幸希, 堀武志, 梶弘和, 登美斉俊.

    [Domestic presentation]  日本薬学会第146年会 (大阪) , 

    2026.03
    , 

    Oral presentation (general)

  • Development of Physiologically Based Pharmacokinetic Model explaining in vivo and ex vivo transplacental IgG transfer

    藤﨑舞友子, 土谷聡耀, 野口幸希, 登美斉俊.

    [Domestic presentation]  日本薬学会第146年会 (大阪) , 

    2026.03
    , 

    Poster presentation

  • Placental MATE2 Expression in Rats Explains Species Differences in Fetal Transfer of Organic Cations

    Masatoshi Tomi, Ashukan Suzuki, Ryo Sakamoto, Ririka Hashimoto, Aoi Yamauchi, Maiko Sakai, Tomohiro Nishimura, Toshiaki Tsuchitani, Saki Noguchi.

    [International presentation]  Asian Federation for Pharmaceutical Sciences Conference 2025 (Sydney, Australia) , 

    2025.12
    , 

    Oral presentation (general)

  • Identification of syncytiotrophoblast-specific transporter genes and their protein expression in mouse placenta

    Kurumi Inagaki, Saki Noguchi, Ryusei Takei, Takuro Ishinabe, Tomohiro Nishimura, Toshiaki Tsuchitani, Masatoshi Tomi

    [International presentation]  Asian Federation for Pharmaceutical Sciences Conference 2025 (Sydney, Australia) , 

    2025.12
    , 

    Poster presentation

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

  • Ex vivo-in silicoハイブリッドによるヒト胎児薬物移行の新解析プラットフォーム構築

    2024.04
    -
    2027.03

    日本学術振興会, 科学研究費助成事業, 基盤研究(B), No Setting

  • Analysis of the regulation of placental barrier factors for prediction of placental endocrine disruption

    2023.04
    -
    2026.03

    野口 幸希, 基盤研究(C), Principal investigator

  • 有機酸取り込みトランスポーターを標的とした腎不全予防法の提案

    2022.08
    -
    2024.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 野口 幸希, 研究活動スタート支援, Principal investigator

  • Regulation of pharmacokinetics during pregnancy by placental exosomes

    2020.07
    -
    2022.03

    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Tomi Masatoshi, Grant-in-Aid for 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.

  • 尿細管の両面動態にアプローチする先天性代謝疾患治療法の開拓

    2020.04
    -
    2022.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 野口 幸希, Grant-in-Aid for Early-Career Scientists , Principal investigator

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Courses Taught 【 Display / hide 】

  • STUDY OF MAJOR FIELD: (PHARMACEUTICS)

    2025

  • SPECIAL PRACTICE IN TISSUE CULTURE AND GENE TECHNOLOGY

    2025

  • SEMINAR: (PHARMACEUTICS)

    2025

  • RESEARCH FOR BACHELOR'S THESIS 1

    2025

  • PHARMACEUTICS LABORATORY COURSE

    2025

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Courses Previously Taught 【 Display / hide 】

  • ENGLISH EXERCISES FOR PHARMACEUTICAL SCIENCES

    Keio University

    2023.04
    -
    2024.03

  • PHARMACEUTICS LABORATORY COURSE

    Keio University

    2023.04
    -
    2024.03

  • BIOPHARMACEUTICS

    Keio University

    2023.04
    -
    2024.03

  • STUDY OF MAJOR FIELD: (PHARMACEUTICS)

    Keio University

    2023.04
    -
    2024.03

  • PHARMACEUTICAL-ENGLISH SEMINAR

    Keio University

    2023.04
    -
    2024.03

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