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 】

• 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  2025.12

  Research paper (scientific journal), Joint Work, Accepted

• 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)

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

  Ashukan Suzuki, Saki Noguchi, Toshiaki Tsuchitani, Ryo Sakamoto, Aoi Yamauchi, Takuro Ishinabe, Ririka Hashimoto, Yoshimi Nakaguchi, Maiko Sakai, Natsuki Imayoshi, Takahiro Ishimoto, Yukio Kato, Yoshiyuki Shirasaka, Satomi Katakura, Tetsuo Maruyama, Tomohiro Nishimura, Masatoshi Tomi

  Molecular pharmaceutics 22 ( 12 ) 7412 - 7422 2025.11

  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+), 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 IC50 of pyrimethamine to rat MATE1 and OCT3, which were 0.015 and 100 μM, respectively. The F/M ratios of metformin and MPP+ 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+ 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.

  • Access to Document (DOI)

• Bridging in vitro and clinical data: Experimental insights into the IC50 variability of dolutegravir as an organic cation transporter 2 inhibitor

  Tomoki Koishikawa, Yukana Tomoda, Toshiaki Tsuchitani, Kunal Taskar, Kenta Yoshida, Jialin Mao, Tadayuki Takashima, Yurong Lai, Yuichi Sugiyama, Hiroyuki Kusuhara

  Drug Metabolism and Disposition 53 ( 6 ) 100087 2025.06

  Research paper (scientific journal), Joint Work, Accepted,  ISSN  00909556

  　View Summary

  Dolutegravir is a clinically confirmed inhibitor of organic cation transporter 2 (OCT2)/SLC22A2; however, its in vitro IC<inf>50</inf> varies widely across studies. Using OCT2-expressing human embryonic kidney 293 cells, we investigated experimental conditions affecting IC<inf>50</inf> determination. Based on clinical drug-drug interaction (DDI) data, an inhibition constant (K<inf>i</inf>) of 0.0890 μM was estimated through pharmacokinetic (PK) modeling using both plasma concentration and urinary excretion profiles of metformin. In vitro, dolutegravir was found to be a noncompetitive inhibitor of OCT2. IC<inf>50</inf> values increased with longer uptake times. A 2.9-fold difference was already observed between 1-minute and 5-minute uptake, and further extension to 30 minutes resulted in a 27-fold increase, attributable to the inhibition of both uptake and efflux processes. Preincubation of the cells with dolutegravir for 30 minutes additionally enhanced its inhibitory effect, resulting in a 5.8-fold decrease in IC<inf>50</inf>. Similar uptake time dependency was observed with other inhibitors (cimetidine and pyrimethamine). However, the extent of variability differed among metformin, N¹-methylnicotinamide, atenolol, frovatriptan, and sumatriptan, likely reflecting differences in cellular kinetics. The lowest in vitro IC<inf>50</inf> of dolutegravir for metformin uptake (0.126 μM), obtained under a 1-minute uptake and 30-minute preincubation condition, closely matched the estimated in vivo K<inf>i</inf>. DDI predictions using in vitro IC<inf>50</inf> values suggested repeated dolutegravir administration could raise the area under the curve of OCT substrates, such as atenolol, nadolol, and sulpiride beyond regulatory thresholds. In conclusion, we identified optimized in vitro conditions that yield IC<inf>50</inf> values consistent with in vivo K<inf>i</inf> estimates, offering valuable guidance for predicting OCT2-mediated DDIs. Significance Statement: This study identified experimental conditions affecting the IC<inf>50</inf> variability of dolutegravir as an organic cation transporter 2 inhibitor. These findings offer valuable insights for improving in vitro to in vivo drug-drug interaction predictions and optimizing inhibition experiments for transporter-mediated drug-drug interactions.

  • Access to Document (DOI)

• Trends of in vitro pharmacological potency and in vivo pharmacokinetics parameters of modern drugs: Can the therapeutic/subtherapeutic dose be estimated from in vitro Ki and pharmacokinetic parameters?

  Toshiaki Tsuchitani, Motohiro Kato, Atsuko Tomaru, Yasunori Aoki, Yuichi Sugiyama

  Clinical and translational science 17 ( 12 ) e70034 2024.12

  Research paper (scientific journal), Joint Work, Lead author, Accepted,  ISSN  17528054

  　View Summary

  In drug discovery and development, estimating therapeutic and subtherapeutic doses is crucial for designing early-phase clinical trials, particularly first-in-human (FIH) studies. While increasing the in vitro pharmacological potency (lowering Ki) of a compound to its target is expected to decrease the therapeutic dose, its benefit is not necessarily clarified. We analyzed in vitro Ki, human in vivo pharmacokinetics (PK) parameters, and therapeutics doses of 144 oral small-molecule drugs approved in Japan (2010-2021). The data on classic drugs were obtained from Goodman and Gilman's textbook, 9th ed. (published in 1996). Modern drugs had lower Ki (2.5 nM) and daily doses (88 μmol/day) than classic drugs (33 nM and 313 μmol/day), but 3.6-fold higher intrinsic clearance (CLint; 171 vs. 47 L/h), suggest that increasing potency over the years has not resulted in a reduction in dosage as expected. Estimating therapeutic doses using target receptor occupancy (tRO)-optimized approach improved estimation accuracy (63% within 10-fold of observed values) compared with tRO-fixed approaches. Subtherapeutic dose estimations revealed a risk of overdosing in FIH trials, indicating that these estimates are not necessarily as conservative as is generally understood. Notably, the unbound average concentration-to-Ki ratio (Cave,u/Ki) varied among drugs and correlated negatively with Ki, suggesting the possible necessity of incorporating it into dose estimation methods. This study provides insights into the relationship between in vitro Ki, in vivo PK parameters, and therapeutic dose of modern drugs, proposing strategies and revealing the risk for dose estimation and drug development in the era of highly potent small molecules.

  • Access to Document (DOI)

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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 】

• 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

• 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)

• 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)

• Placental MATE1 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, 

  2025.12

  , 

  Poster presentation

• 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

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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 】

• STUDY OF MAJOR FIELD: (PHARMACEUTICS)

  2025

• SEMINAR: (PHARMACEUTICS)

  2025

• RESEARCH FOR BACHELOR'S THESIS 1

  2025

• PHARMACOKINETICS

  2025

• PHARMACEUTICS LABORATORY COURSE

  2025

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