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

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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 】

  • 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)   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.

  • 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

    Tomoya Akashi, Saki Noguchi, Yu Takahashi, Tomohiro Nishimura, Masatoshi Tomi

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

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  00223549

    　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.

  • Quantitative comparison of breast cancer resistance protein (BCRP/ABCG2) expression and function between blood-brain barrier and placental barrier in mice at different gestational ages.

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

    Frontiers in Drug Delivery  2022.07

    Research paper (scientific journal), Joint Work, Accepted

  • 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 2022.07

    Accepted,  ISSN  07248741

    　View Summary

    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 Ex Vivo 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: the biological fate of chemicals)  50 （ 3 ） 287 - 298 2022.03

    ISSN  00909556

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    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.

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

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Reviews, Commentaries, etc. 【 Display / hide 】

  • 【「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)

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Presentations 【 Display / hide 】

  • Ezrin遺伝子欠損に伴う胎仔発育不全と胎盤免疫寛容の機能低下の関連解析

    山中真悠子, 西村友宏, 溝上遼, 野口幸希, 登美⻫俊

    日本薬学会第144年会 (横浜) , 

    2024.03
    , 

    Poster presentation

  • OAT4介在輸送がアンジオテンシンII受容体拮抗薬(ARB)の経細胞透過に果たす役割

    野口幸希, 榊原早織, 平原優有, 舟橋和毅, 増田豪, 大槻純男, 西村友宏, 登美斉俊

    日本薬学会第144年会 (横浜) , 

    2024.03
    , 

    Poster presentation

  • 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)

  • 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)

  • 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)

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

  • 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

  • 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

  • トリプトファンバランスに着目した食事による胎児成長支援戦略の構築

    2018.04
    -
    2021.03

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

    　View Summary

    胎盤関門においてトリプトファン(Trp)輸送を担う可能性が高いLAT輸送体のタンパク発現分子数を定量した結果、ヒトおよびラット胎盤関門において、LAT1およびLAT2タンパクの発現分子数定量に成功した。ヒトではLAT1およびLAT2の発現分子数が共に高かったのに対し、ラットにおいてはLAT1の発現量がLAT2に比べて数倍高いことが示された。げっ歯類胎盤における免疫染色においても、LAT1は胎盤関門の母体側細胞膜において高く発現していたのに対し、LAT2の発現は明確には示されなかった。さらに、LAT1が同様に高く発現している血液脳関門においては、血中アミノ酸濃度の変動がLAT1を介した脳への輸送速度を制御していることを、実験的に明らかにした。これらの結果は、LAT基質アミノ酸の総量に対するTrp存在比率(%)で定義されるTrpインデックスが、胎児など組織関門で制御されている領域へのTrp供給量、そしてキヌレインおよびセロトニン濃度を規定するとの仮説をサポートする成果として、重要である。
    日本食品標準成分表に基づきTrpインデックスを算出したところ、食品の種類によってTrpインデックスは5倍以上異なっていた。得られたTrpインデックスに基づくと、Trp欠乏を補う食品としては通常、タンパク質に富み、Trpのアミノ酸スコアが100%を満たす魚・肉・大豆などが同列に推奨されるが、Trpインデックスがより低い魚類や肉類と比較して、高い大豆が望ましいといったより適切な指導が可能となる。

  • 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

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

    　View Summary

    妊婦においては治療方法が限定的であり、有効な薬物治療法が確立されていない妊娠高血圧症候群に対して、現在は使用が禁忌とされている降圧薬の有効性、安全性を検証し、妊婦においても安全な降圧薬を見出すことを目的としている。これまでに臨床における副作用データベース検索によって、禁忌とされている降圧薬としてアンジオテンシンII受容体拮抗薬（ARB）のうちIrbesartanが比較的胎児に対して毒性を示す頻度が低い可能性を見出している。今年度は、ARB同効薬間で胎児移行性や副作用が異なる可能性を非臨床において検討した。ARBの胎児移行性は、ARB同効薬間で差が生じることを示すため、妊娠高血圧症を呈するモデルラットにおいてOlmesartanとIrbesartanを投与して血圧、母体血中濃度、胎児血中濃度等を評価した。OlmesartanおよびIrbesartanはいずれも母体の高血圧を改善した。胎児移行性はOlmesartanが高く、Irbesartanが低いことを見出し、胎児における血清アルブミンへの結合を考慮した非結合型血漿中濃度においてもIrbesartanは胎児移行性が低いことを見出した。また、Olmesartan投与時には当該妊娠高血圧症モデルラットが呈する胎児発育不全が改善されなかったのに対し、Irbesartan投与においては改善されたため、IrbesartanはARB同効薬の中でも比較的選択的に妊娠高血圧症の改善効果と低胎児毒性を表すことが示された。

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Courses Taught 【 Display / hide 】

  • STUDY OF MAJOR FIELD: (PHARMACEUTICS)

    2024

  • SPECIAL PRACTICE IN TISSUE CULTURE AND GENE TECHNOLOGY

    2024

  • SEMINAR: (PHARMACEUTICS)

    2024

  • RESEARCH FOR BACHELOR'S THESIS 1

    2024

  • PHARMACEUTICS LABORATORY COURSE

    2024

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Courses Previously Taught 【 Display / hide 】

  • STUDY OF MAJOR FIELD: (PHARMACEUTICS)

    Keio University

    2023.04
    -
    2024.03

  • 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

  • PHARMACEUTICAL-ENGLISH SEMINAR

    Keio University

    2023.04
    -
    2024.03

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