KEIO RESEARCHERS INFORMATION SYSTEM

Career 【 Display / hide 】

Career 【 Display / hide 】

• 2022.07

  -

  2024.08

  ShanghaiTech University, iHuman Institute, Postdoctoral researcher

• 2022.10

  -

  2025.03

  Josai International University, 客員特定研究員

• 2024.08

  -

  Present

  Keio University, Faculty of Pharmacy, Division of Pharmaceutics, Assistant Professor

Academic Background 【 Display / hide 】

Academic Background 【 Display / hide 】

• 2012.04

  -

  2018.03

  Keio University, Faculty of Pharmacy, Department of Pharmacy

• 2018.04

  -

  2022.03

  Keio University, Graduate School of Pharmaceutical Sciences (Doctoral)

Research Areas 【 Display / hide 】

Research Areas 【 Display / hide 】

• Life Science / Clinical pharmacy (薬剤学/薬物動態)

Research Keywords 【 Display / hide 】

Research Keywords 【 Display / hide 】

• PBPKモデル

• in vitro-to-in vivo extrapolation

• Transporter

• modeling&simulation

• Pharmacokinetics

Papers 【 Display / hide 】

Papers 【 Display / hide 】

• Net Renal Drug Secretion Critically Requires Significant Contribution of Basal Uptake Transporters: Perspective From Mechanistic Kidney Model Simulation and Integration of Clinical and In Vitro Data.

  Toshiaki Tsuchitani, Masatoshi Tomi, Yuichi Sugiyama

  CPT: pharmacometrics & systems pharmacology 15 ( 9 ) e70336 2026.09

  Lead author, Last author, Corresponding author, Accepted,  ISSN  2163-8306

  　View Summary

  Renal clearance (CLr) is the net outcome of glomerular filtration, secretion, and reabsorption, which makes the quantitative requirements for net renal secretion difficult to infer from simple clearance models. Using a mechanistic kidney model (MechKiM), we simulated blood-referenced CLr (CLr,b) for 30,000 virtual drugs (neutral, monoanionic, and monocationic) under continuous infusion and across all eight combinations of three proximal-tubule transporters (basal uptake, basal efflux, apical efflux). Net renal secretion (clearance ratio CR = CLr,b/(fu,b × GFR) > 1.5, where fu,b and GFR are the unbound fraction in blood and the glomerular filtration rate) occurred only when basal uptake transport was present; apical efflux alone produced proximal secretion that was offset by downstream reabsorption, yielding no net secretion. In the scenario where all three transporters were present within the MechKiM framework, five quantitative criteria distinguished secretion-type drugs, including basal transporter-mediated uptake (> 4.2 L/h) and its fractional contribution to total basal uptake (> 94% for non-cationic compounds). Clinical CLr,p (plasma-referenced CLr) versus in vitro uptake-transporter data (n = 217) and published MechKiM-PBPK models (n = 19, typically assigning > 99% of basal uptake to transporters) were consistent with these findings. A sufficient contribution of basal uptake transporters in the proximal tubule is essential for observing net renal secretion. This study provides quantitative, in vitro-translatable criteria to anticipate renal secretion and transporter-mediated drug-drug interaction liability.

  • Access to Document (DOI)

• Mechanistic insights into edoxaban's nonlinear pharmacokinetics and quinidine interaction via P-glycoprotein using physiologically based pharmacokinetic modeling.

  Wen Kou, Toshiaki Tsuchitani, Kazuya Maeda, Ryuto Tomabechi, Yuichi Sugiyama

  Drug metabolism and disposition: the biological fate of chemicals 54 ( 7 ) 100333 - 100333 2026.05

  Lead author, Last author, Corresponding author, Accepted,  ISSN  00909556

  　View Summary

  Edoxaban, a direct factor Xa inhibitor and known P-glycoprotein (P-gp) substrate, exhibits nonlinear increases in systemic exposure after oral administration and significant interaction with quinidine, a P-gp inhibitor. However, it remains unclear how P-gp in each organ contributes to these phenomena. We developed a physiologically based pharmacokinetic (PK) model to describe PK of edoxaban after oral (0.05-60 mg) and intravenous administration (30 mg), as well as its interaction with quinidine following edoxaban intravenously. Parameters were estimated using the Cluster Gauss-Newton method through top-down and middle-out approaches. Accurate description of renal clearance, which required incorporation of a hypothetical basolateral uptake process, underscoring the importance of unidentified renal transporters involved in edoxaban urinary secretion. Nonlinearity of dose-normalized area under blood concentration-time curve was highly sensitive to KmP-gp, with intestinal unbound concentrations exceeding KmP-gp at clinically relevant doses, consistent with intestinal P-gp saturation as the major driver of nonlinearity. In intravenous edoxaban-oral quinidine drug-drug interaction analysis, quinidine markedly reduced renal clearance and modestly increased hepatic availability, reflecting inhibition of renal and, to a lesser extent, hepatic P-gp. In conclusion, an edoxaban physiologically based PK model incorporating renal uptake transport enabled physiologically consistent description of renal clearance. Saturation of intestinal P-gp was identified as the primary contributor to nonlinear PK, while inhibition of renal P-gp was the main mechanism underlying the edoxaban intravenously administered with quinidine. These findings provide mechanistic insight into transporter contributions to edoxaban disposition and drug-drug interactions and highlight the importance of tissue-specific transporter processes in nonlinear pharmacokinetics. SIGNIFICANCE STATEMENT: Incorporating renal uptake transport is essential for mechanistically describing edoxaban renal clearance in physiologically based pharmacokinetic (PK) modeling. The model identifies intestinal P-glycoprotein saturation as the primary driver of nonlinear PK and renal P-glycoprotein inhibition as the major mechanism of the intraveous edoxaban-quinidine drug-drug interaction. These findings offer mechanistic insight into transporter contributions to edoxaban disposition and drug-drug interactions and emphasize the role of tissue-specific transport processes in nonlinear PK.

  • Access to Document (DOI)

• MCT1-mediated bidirectional propionate transport across human placental syncytiotrophoblast layer: insights from a trophoblast stem cell-derived barrier model.

  Toshiaki Tsuchitani, Rin Midorikawa, Akari Kasuya, Saki Noguchi, Kohei Yamamoto, Tomohiro Nishimura, Hirokazu Kaji, Takeshi Hori, Masatoshi Tomi

  The Journal of physiology  2026.04

  Lead author, Last author, Corresponding author, Accepted,  ISSN  00223751

  　View Summary

  Propionate, a gut microbiota-derived short-chain fatty acid, influences fetal development and postnatal metabolic programming. Although the fetus lacks microbiota and endogenous propionate production, human pregnancies show a fetal-to-maternal propionate concentration ratio greater than unity, suggesting concentrative transport across the placenta. However, its underlying mechanism remains undefined. The present study aimed to identify the transporter responsible for transplacental transport of propionate across the syncytiotrophoblast (SynT) layer. Transporter knockdown in human choriocarcinoma JEG-3 cells revealed that MCT1 (SLC16A1) silencing reduced [3H]propionate uptake, whereas knockdown of other anion transporters had no effect. Functional assays using Xenopus oocytes demonstrated that the expression of human MCT1, but not MCT4 (SLC16A3), increased [3H]propionate transport. In human trophoblast stem cell (hTSC)-derived SynT, [3H]propionate uptake was pH-dependent and significantly inhibited by MCT1-selective inhibitors. Subsequently, to evaluate transcellular transport, we performed quantitative permeability assays using a hTSC-derived placental barrier model. [3H]Propionate permeability was significantly higher than that of [14C]d-mannitol, a paracellular marker. MCT1 inhibition reduced [3H]propionate permeability in both apical-to-basal and opposite directions, whereas MCT4 inhibition had minimal effects. Notably, the hTSC-derived model exhibited a directional bias in [3H]propionate transfer, reflecting the fetal-directed enrichment observed in vivo. Mathematical model analysis further indicated that MCT1 functions at both the apical and basal membranes to facilitate bidirectional transport of propionate. Together, these findings identify MCT1 as the predominant mediator of propionate transfer across the human SynT layer, providing mechanistic insights into how the placenta governs fetal exposure to maternal microbiota-derived metabolites. KEY POINTS: The fetus relies on maternal-derived propionate for development, but the molecular mechanism responsible for its concentrative transport across the human placenta remains undefined. Using multiple human trophoblast models and functional expression assays, we identified MCT1, but not MCT4, as the primary mediator of propionate transport. A human trophoblast stem cell-derived placental barrier model successfully exhibited a directional bias in propionate transfer, reflecting the fetal-directed enrichment observed in vivo. Mathematical modelling of the permeability data from the human trophoblast stem cell-derived barrier model indicates that MCT1 functions at both the apical and basal membranes of the syncytiotrophoblast to facilitate bidirectional transport. These findings establish MCT1 as a key gateway for transplacental propionate transfer, providing mechanistic insights into how the placenta regulates fetal exposure to maternal microbiota-derived metabolites.

  • Access to Document (DOI)

• Analysis of the Correlation Between Membrane Permeability in RPMI 2650 Cells and Human Nasal Absorption

  Tokio Morita, Toshiaki Tsuchitani, Hiroyuki Yoshida, Naomi Tomita, Yoji Sato

  AAPS PharmSciTech 27 ( 2 ) 96 - 96 2025.12

  Research paper (scientific journal), Joint Work, Accepted,  ISSN  1530-9932

  　View Summary

  Nasal drug delivery offers several advantages, such as rapid onset and avoidance of hepatic first-pass metabolism, making it a promising option for delivering drugs both locally and systemically. In the early phases of pharmaceutical development, predictive tools for nasal absorption are critical for selecting suitable candidates. This study evaluates the utility of RPMI 2650 cells as an in vitro model for predicting nasal drug absorption. First, we confirmed the reproducibility of membrane permeability across two air-liquid interface culture conditions (shifted on days 1 and 3), demonstrating consistent permeability profiles and agreement with previously reported Papp values. We investigated the correlation between the permeability of RPMI 2650 cells and both clinical nasal bioavailability (nasal BA) and the estimated human nasal fraction absorbed (nasal Fa), revealing good correlations in both cases. To our knowledge, this is the first study to demonstrate a significant correlation between in vitro permeability and estimated human nasal Fa levels. Although some compounds deviated from the correlation curve, these findings indicate that RPMI 2650 cells are useful in vitro tools for predicting nasal drug absorption during the early phases of pharmaceutical development.

  • Access to Document (DOI)

• Characterizing Apixaban Pharmacokinetics Through Physiologically-Based Pharmacokinetic Modeling: Critical Role of Biliary Secretion and Enterohepatic Circulation in Humans.

  Toshiaki Tsuchitani, Wen Kou, Masatoshi Tomi, Yuichi Sugiyama

  CPT: pharmacometrics & systems pharmacology 15 ( 1 ) e70163 2025.12

  Research paper (scientific journal), Joint Work, Lead author, Accepted,  ISSN  2163-8306

  　View Summary

  Apixaban, a factor Xa inhibitor, is a direct oral anticoagulant with a well-balanced elimination; it is eliminated evenly via feces, urine (with no active secretion), and as metabolites after oral administration. The common understanding is that biliary secretion and enterohepatic circulation (EHC) of apixaban are limited in humans, and that fecal excretion may be attributable to intestinal secretion. However, a decrease in apixaban blood concentration with activated charcoal coadministration in humans suggests possible involvement of EHC. This study aimed to evaluate the contribution of biliary excretion, EHC, and intestinal secretion to apixaban pharmacokinetics (PK) using a physiologically-based pharmacokinetic (PBPK) model. A top-down analysis was performed using blood concentration and mass balance data from healthy volunteers. Model parameters were optimized using the Cluster-Gauss Newton method (CGNM), followed by the bootstrap method. The model accurately described observed data and indicated moderate to high biliary secretion relative to metabolic clearance. Simulated biliary secretion into the duodenum well predicted the biliary secretion data in humans (< 1% of dose at 8 h post-dose). Virtual knockout of EHC resulted in a shortened half-life from 8.7 to 2.9 h, and 17% and 55% decrease in area under the concentration curve (AUC) and fecal excretion after intravenous dosing, respectively, confirming the significant contribution of biliary excretion and EHC. The model also accurately described apixaban PK with activated charcoal coadministration at 2 or 6 h post-dose. Although further experimental validation (e.g., sandwich-cultured hepatocytes) would strengthen these findings, our study demonstrates that biliary secretion and EHC play a substantial role in apixaban elimination and disposition in humans.

  • Access to Document (DOI)

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

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

• Bottom-up法による薬物の消化管吸収および消化管P-gpを介した薬物間相互作用の定量的予測 (要約)

  Tsuchitani, Toshiaki

  (慶應義塾大学大学院薬学研究科)  2021

• Bottom-up法による薬物の消化管吸収および消化管P-gpを介した薬物間相互作用の定量的予測 (要旨)

  Tsuchitani, Toshiaki

  (慶應義塾大学大学院薬学研究科)  2021

• Bottom-up法による薬物の消化管吸収および消化管P-gpを介した薬物間相互作用の定量的予測 (審査報告)

  Tsuchitani, Toshiaki

  (慶應義塾大学大学院薬学研究科)  2021

• The effect of gastrointestinal damage on drug absorption

  Tsuchitani, Toshiaki

  科学研究費補助金研究成果報告書 2017

Reviews, Commentaries, etc. 【 Display / hide 】

Reviews, Commentaries, etc. 【 Display / hide 】

• 動態研究に取り組むNEW POWER 世界一の薬物動態研究者を追いかけた先で見た，創薬民主化の最前線

  土谷 聡耀

  JSSX ニュースレター  2025.02

• 第16回 留学とは「自分」を知ること:自らの文化と特性を理解し薬学の未来に生かす

  土谷 聡耀

  ファルマシア (公益社団法人 日本薬学会)  55 ( 12 ) 1160 - 1161 2019

  ISSN  0014-8601

  　View Summary

  薬剤師あるいは薬剤師を目指すものにとっても留学は必要だ。私が経験した米国の病院での実習では実習生が主体的に業務に従事し、見学中心の日本とは大きく異なる。また、文化や制度が異なる場所で業務に従事することで、日本にいるだけでは認識できないことを多く学べる。私たちは留学を通して自らの文化や特性に対する理解を深め、これらを糧に実務実習や薬剤師業務の未来を考えるべきだ。

  • Access to Document (DOI)
  • CiNii Research

Presentations 【 Display / hide 】

Presentations 【 Display / hide 】

• MCT1はヒト胎盤バリアモデルにおいてプロピオン酸の双方向輸送を促進するが、MCT4は促進しない。

  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, 

  2026.03

  , 

  Oral presentation (general)

• In vivo・ex vivoにおけるIgG経胎盤透過を説明可能な生理学的薬物速度論モデルの構築

  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, 

  2026.03

  , 

  Poster presentation

• Characterizing Apixaban Pharmacokinetics via PBPK Modeling: The Critical Roles of Biliary Secretion and Enterohepatic Circulation in Humans.

  Toshiaki Tsuchitani

  [International presentation]  Focus on Pharmacology Virtual Series: Current Advances in Drug Metabolism: PBPK Modeling for Human Drug Disposition: From Mechanistic Insights to Clinical Dosing, 

  2026.02

  , 

  Oral presentation (invited, special)

• 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, 

  2025.12

  , 

  Poster presentation

• Single-Cell Transcriptomic Analysis of Wnt/β-Catenin-mediated Differentiation Pathways in Mouse Trophoblast Stem Cells

  Takuro Ishinabe, Saki Noguchi , Natsuki Suganuma , Tomohiro Nishimura ,Toshiaki Tsuchitani , Masatoshi Tomi .

  [International presentation]  Asian Federation for Pharmaceutical Sciences Conference 2025, 

  2025.12

  , 

  Poster presentation

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

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

• Integrated modeling of drugs and endogenous ligands based on physiologically based pharmacokinetic models

  2025.04

  -

  2027.03

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Early-Career Scientists, Principal investigator

• Establishment of a novel methodology for estimating pharmacological target occupancy and therapeutic dosage in Phase I clinical trials for drug development.

  2022.06

  -

  2024.03

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Challenging Research (Exploratory), No Setting

  　View Summary

  生理学的薬物速度論(PBPK)モデルに薬理標的への結合過程を追加することで、低分子医薬品の薬物動態と薬効を正確に予測する新たな手法の確立を目指す。以下のように研究を進めている。 Target Mediated Drug Disposition（TMDD）を示す低分子薬としてボセンタン(BOS)、テルミサルタン（TLM）、ワルファリン(WAR)、複数のアンジオテンシンII酵素阻害剤（ACEIs）について解析している。BOS, TLM, ACEIsはほぼ全臓器の血管内皮細胞に、WARは肝臓実質細胞内のみに薬理標的蛋白が存在する。これら化合物のPBPKモデルは、文献から入手可能な in silico、in vitro、および臨床PKデータに基づいて構築した。青木康憲博士（現、アストラゼネカ社（スエーデン））と共同で開発したCluster Gauss Newton Method (CGNM)は、in vivo 臨床データを基にtop-downあるいはmiddle-out 解析を行い薬物動態パラメータや薬理標的結合パラメータを算出可能な方法である。CGNMを使用して、広い投与量範囲にわたって非線形PKプロファイルを示す論文データにあてはめ計算を行うことによりパラメータを最適化した。BOS, WARについては、血中薬物動態プロファイルのみに基づいて最適化されたパラメータセットのみで、in vivo 薬理標的占有率の時間推移を記述できた。低用量からの薬物動態データを含めると、薬理標的結合関連パラメータの推測性が上昇することもわかった。TLMについても、同様に解析を進め、薬物動態の非線形性が、肝臓取り込みトランスポータ OATP1B3 の飽和のみならず、受容体であるアンジオテンシンII受容体結合の飽和も少なくとも一部、非線形薬物動態に関わることが示された。

• The effect of gastrointestinal damage on drug absorption

  2015.04

  -

  2018.03

  Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, AKIYOSHI Takeshi, OHTANI Hisakazu, IMAOKA Ayuko, TSUJII Kazunari, WADA Naoki, YOTSUMOTO Keiichi, HATTORI Tomoki, TSUCHITANI Toshiaki, Grant-in-Aid for Young Scientists (B), No Setting

  　View Summary

  5‐Fluorouracil (5‐FU) and Irinotecan, an anticancer drug, causes severe gastrointestinal damage, which may affect the absorption of orally administered drugs including the ubstrates of intestinal uptake and efflux transporters. This study aimed to investigate quantitatively the effect of 5‐FU or Irinotecan‐induced intestinal damage on the PK/PD of Dabigatran using rat model. The 5‐FU and Irinotecan‐induced intestinal damage may affect transporter‐mediated drug absorption of orally administered drugs in the clinical setting.

Courses Taught 【 Display / hide 】

Courses Taught 【 Display / hide 】

• PHARMACEUTICAL-ENGLISH SEMINAR

  2026

• BACHELOR'S THESIS

  2026

• ENGLISH EXERCISES FOR PHARMACEUTICAL SCIENCES

  2026

• DRUG DELIVERY AND PHARMACOKINETICS

  2026

• RESEARCH FOR BACHELOR'S THESIS 1

  2026

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