KEIO RESEARCHERS INFORMATION SYSTEM

Career 【 Display / hide 】

Career 【 Display / hide 】

• 2022.07

  -

  2024.08

  ShanghaiTech University, iHuman Institute, Postdoctoral researcher

• 2022.10

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  Present

  Josai International University, 客員特定研究員

• 2024.08

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  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 】

• 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)

• Elucidating nonlinear pharmacokinetics of telmisartan: Integration of target‐mediated drug disposition and OATP1B3‐mediated hepatic uptake in a physiologically based model

  Toshiaki Tsuchitani, Atsuko Tomaru, Yasunori Aoki, Naoki Ishiguro, Yasuhiro Tsuda, Yuichi Sugiyama

  CPT: Pharmacometrics & Systems Pharmacology 13 ( 7 ) 1224 - 1237 2024.07

  Research paper (scientific journal), Lead author, Accepted

  　View Summary

  Telmisartan, a selective inhibitor of angiotensin II receptor type 1 (AT1), demonstrates nonlinear pharmacokinetics (PK) when orally administered in ascending doses to healthy volunteers, but the underlying mechanisms remain unclear. This study presents a physiologically based pharmacokinetic model integrated with target-mediated drug disposition (TMDD-PBPK model) to explore the mechanism of its nonlinear PK. We employed the Cluster-Gauss Newton method for top-down analysis, estimating the in vivo Km,OATP1B3 (Michaelis–Menten constant for telmisartan hepatic uptake via Organic Anion Transporting Polypeptide 1B3) to be 2.0–5.7 nM. This range is significantly lower than the reported in vitro value of 810 nM, obtained in 0.3% human serum albumin (HSA) conditions. Further validation was achieved through in vitro assessment in plated human hepatocytes with 4.5% HSA, showing a Km of 4.5 nM. These results underscore the importance of albumin-mediated uptake effect for the hepatic uptake of telmisartan. Our TMDD-PBPK model, developed through a “middle-out” approach, underwent sensitivity analysis to identify key factors in the nonlinear PK of telmisartan. We found that the nonlinearity in the area under the concentration–time curve (AUC) and/or maximum concentration (Cmax) of telmisartan is sensitive to Km,OATP1B3 across all dosages. Additionally, the dissociation constant (Kd) for telmisartan binding to the AT1 receptor, along with its receptor abundance, notably influences PK at lower doses (below 20 mg). In conclusion, the nonlinear PK of telmisartan appears primarily driven by hepatic uptake saturation across all dose ranges and by AT1-receptor binding saturation, notably at lower doses.

  • Access to Document (DOI)

• The Effects of Jabara Juice on the Intestinal Permeation of Fexofenadine.

  Hongye Han, Takeshi Akiyoshi, Tokio Morita, Toshiaki Tsuchitani, Momoko Nabeta, Kodai Yajima, Ayuko Imaoka, Hisakazu Ohtani

  Biological & pharmaceutical bulletin 46 ( 12 ) 1745 - 1752 2023

  Research paper (scientific journal), Accepted,  ISSN  09186158

  　View Summary

  Jabara juice and its component narirutin inhibit the activity of organic anion-transporting polypeptides (OATPs) 1A2 and OATP2B1, which are considered to play significant roles in the intestinal absorption of fexofenadine. In this study, we investigated the effects of jabara juice on the intestinal absorption of fexofenadine in mice and the inhibitory effects of jabara juice and narirutin on the permeation of fexofenadine using Caco-2 cell monolayers and LLC-GA5-COL300 cell monolayers. In the in vivo study, the area under the plasma concentration-time curve (AUC) of fexofenadine in mice was increased 1.8-fold by jabara juice. In the permeation study, 5% jabara juice significantly decreased the efflux ratio (ER) of fexofenadine for Caco-2 monolayers. Furthermore, the ERs of fexofenadine and digoxin, which is a typical substrate of P-glycoprotein (P-gp), for LLC-GA5-COL300 cell monolayers were decreased in a concentration-dependent manner by jabara juice extract, suggesting that jabara juice may increase the intestinal absorption of fexofenadine by inhibiting P-gp, rather than by narirutin inhibiting OATPs. The present study showed that jabara juice increases the intestinal absorption of fexofenadine both in vivo and in vitro. The intestinal absorption of fexofenadine may be altered by the co-administration of jabara juice in the clinical setting.

  • Access to Document (DOI)

• Mechanistic bottom-up estimation of passive drug absorption from the gastrointestinal tract: Comparison among primary cultured human intestinal cells, Caco-2 cells, artificial membrane, and animal scale-up.

  Toshiaki Tsuchitani, Takeshi Akiyoshi, Ayuko Imaoka, Hisakazu Ohtani

  International journal of clinical pharmacology and therapeutics 60 ( 5 ) 217 - 224 2022.05

  Joint Work, Lead author, Accepted,  ISSN  09461965

  　View Summary

  OBJECTIVE: The fraction of drug absorbed (Fa) from the intestine is an important parameter to characterize the pharmacokinetics of a drug. We aimed to search for an experimental system that provides the best parameters for estimating the effective permeability (Peff) used for the bottom-up prediction of Fa. MATERIALS AND METHODS: The absorption kinetics of 12 passively absorbed drugs were simulated by a compartment absorption transit (CAT) model using absorption parameters from four different experimental systems: human intestinal epithelial cell (HIEC) monolayer, Caco-2 monolayer, parallel artificial membrane permeability assay (PAMPA), and in situ rat intestinal perfusion. All absorption parameters were obtained from the literature. The in vitro apparent permeability coefficient (Papp) and rat in situ Peff were converted to human Peff using a bottom-up approach for each region, based on the morphological features of the human intestine. The simulated Fa values were compared to the respective observed values. Furthermore, plasma concentration profiles of the drugs were simulated by convolution using the time-course of the absorption rate simulated using the Peff values calculated from the HIEC Papp. RESULTS: The Fa values were best predicted by using the Peff values calculated from HEIC, within a 1.3-fold range of observed Fa in 11 out of 12 drugs. The simulated Cmax values of pharmacokinetic simulation using HIEC Papp fell within a 1.5-fold range of observed values for all the drugs examined. CONCLUSION: The HIEC monolayer was identified as the most suitable permeation parameter for estimating Fa and Cmax using a morphological feature-based bottom-up approach.

  • Access to Document (DOI)

• Inhibitory Effects of Cranberry Juice and Its Components on Intestinal OATP1A2 and OATP2B1: Identification of Avicularin as a Novel Inhibitor.

  Tokio Morita, Takeshi Akiyoshi, Toshiaki Tsuchitani, Hiroki Kataoka, Naoya Araki, Kodai Yajima, Kazuhiro Katayama, Ayuko Imaoka, Hisakazu Ohtani

  Journal of agricultural and food chemistry 70 ( 10 ) 3310 - 3320 2022.03

  Research paper (scientific journal), Joint Work, Accepted,  ISSN  00218561

  　View Summary

  Organic anion-transporting polypeptide (OATP) 1A2 and OATP2B1 mediate the intestinal absorption of drugs. This study aimed to identify fruit juices or fruit juice components that inhibit OATPs and assess the risk of associated food-drug interactions. Inhibitory potency was assessed by examining the uptake of [3H]estrone 3-sulfate and [3H]fexofenadine into HEK293 cells expressing OATP1A2 or OATP2B1. In vivo experiments were conducted using mice to evaluate the effects of cranberry juice on the pharmacokinetics of orally administered fexofenadine. Of eight examined fruit juices, cranberry juice inhibited the functions of both OATPs most potently. Avicularin, a component of cranberry juice, was identified as a novel OATP inhibitor. It exhibited IC50 values of 9.0 and 37 μM for the inhibition of estrone 3-sulfate uptake mediated by OATP1A2 and OATP2B1, respectively. A pharmacokinetic experiment revealed that fexofenadine exposure was significantly reduced (by 50%) by cranberry juice. Cranberry juice may cause drug interactions with OATP substrates.

  • 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)

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

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

• 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

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  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.