Details of a Researcher - Yajima, Kodai

Yajima, Kodai

写真a

Affiliation: Faculty of Pharmacy, Department of Pharmacy 統合臨床薬理学講座 ( Shiba-Kyoritsu )

Position: Research Associate/Assistant Professor/Instructor

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Academic Background 【 Display / hide 】

2012.04

-

2018.03

Keio University, 薬学部, 薬学科

University, Graduated
2019.04

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2024.03

慶應義塾大学大学院, 薬学研究科, 薬学専攻

Graduate School, Completed, Doctoral course

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Academic Degrees 【 Display / hide 】

博士（薬学）, Keio University, Coursework, 2024.03

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Licenses and Qualifications 【 Display / hide 】

薬剤師, 2018.04

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Research Areas 【 Display / hide 】

Life Science / Clinical pharmacy (薬物動態学)

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Research Keywords 【 Display / hide 】

トランスポーター、抗体医薬品

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Papers 【 Display / hide 】

Population pharmacokinetic analysis of bevacizumab in Japanese cancer patients with proteinuria: a prospective cohort study

Masuda T., Funakoshi T., Horimatsu T., Masui S., Hira D., Inoue M., Yajima K., Nakagawa S., Ikemi Y., Hamanishi J., Takai A., Yamamoto S., Matsubara T., Mandai M., Seno H., Yanagita M., Muto M., Terada T., Yonezawa A.

Cancer Chemotherapy and Pharmacology 95 ( 1 ) 2025.12

ISSN 03445704

　View Summary

Purpose: Bevacizumab (BV) is an effective therapeutic antibody utilized in various cancers. Serum BV concentration can be a factor that potentially affects its therapeutic efficacy. Although proteinuria could affect BV pharmacokinetics, its influence was not evaluated in the previous population pharmacokinetic (PopPK) studies. Because BV can cause proteinuria as an adverse event, the present study aimed to develop a PopPK model in patients with proteinuria and to evaluate the influence of proteinuria on BV pharmacokinetics. Methods: This prospective cohort study enrolled 70 Japanese cancer patients newly starting BV, and 368 concentration samples from these patients were analyzed. Serum BV concentrations were measured at several time points including at the onset of proteinuria. PopPK analysis was conducted using a non-linear mixed-effects modeling program. A two-compartment model was used to estimate total body clearance (CL). Results: Serum BV concentrations divided by the dose per body weight and dosing interval tended to be lower in patients with higher urinary protein to creatinine ratio (UPCR). The covariate analysis showed that increasing BV CL was associated with decreasing serum albumin concentration and increasing body weight and UPCR. The simulated median trough concentrations of BV in patients with Common Terminology Criteria for Adverse Events grades 1, 2, and 3 proteinuria were decreased by 12.0%, 20.6%, and 31.5%, respectively, compared to those in patients with grade 0. Conclusion: We successfully established a PopPK model incorporating UPCR to predict serum BV concentrations in patients with proteinuria. Our study provides additional insights to better understand BV pharmacokinetics.
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Stoichiometric transport of estrone 3-sulfate among genetic variants of OATP1A2 and OATP2B1 and structural analysis by molecular dynamics simulation: Impairment of gating mechanism in the unstable inward-open conformation of OATP2B1 (Asp215Val) significantly suppress the transport activity

Akiyoshi T., Tonduru A.K., Kataoka H., Morita T., Yajima K., Imaoka A., Katayama K., Medarametla P., Uchida Y., Poso A., Ohtani H., Terasaki T.

Drug Metabolism and Disposition 53 ( 12 ) 2025.12

ISSN 00909556

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This study investigated the impact of genetic variations in organic anion transporting polypeptides (OATPs) 1A2 and 2B1 on their transport activity at pH 6.3 and 7.4 by using HEK293 cells expressing OATP variants, focusing on stoichiometric transport kinetic parameters corrected for the number of transporters on the plasma membrane. In the OATP2B1 Asp215Val, the maximal velocity per OATP molecule and intrinsic clearance at pH 6.3 were drastically reduced to 0.0648- and 0.0178-fold, respectively, compared with the wild type. All tested OATP1A2 variants exhibited increased transport activity at pH 6.3, suggesting that OATP1A2 is more sensitive to extracellular pH. Furthermore, we used the AlphaFold model to explain the observed differences in transport activity among genetic variants. In OATP1A2, the Glu172Asp mutation replaces a longer glutamate side chain with a shorter aspartate, which may enhance substrate interactions while weakening the salt-bridge interactions with neighboring residues, potentially compromising structural integrity. In OATP2B1, the Asp215Val variant was found to disrupt a key salt-bridge interaction with Lys595, which destabilizes the outward-open conformation. Moreover, the Val201Met mutation appears to lock the transporter in a single conformational state. Our findings underscore the importance of transmembrane helix 4 in maintaining functional conformational dynamics and suggest that mutations in this region can significantly alter substrate binding and transport efficiency in OATP1A2 and 2B1. Significance Statement: This study combined uptake assays using transporter-expressing cell lines, liquid chromatography–tandem mass spectrometry transporter quantification, and computer modeling to clarify the changes in transport activity per molecule, and these mechanisms caused by amino acid substitutions in organic anion transporting polypeptides 1A2 and 2B1.
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Comparative analysis of the single-molecule transport kinetics of OATP1B1 genetic variants

Tsujii K., Yajima K., Akiyoshi T., Sakamoto K., Suzuki Y., Oka T., Imaoka A., Yamamura H., Kurokawa J., Ohtani H.

Journal of Pharmacological Sciences 158 ( 3 ) 166 - 171 2025.07

ISSN 13478613

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Several genetic variants of OATP1B1, a hepatic uptake transporter, increase the blood concentrations of substrate drugs, e.g., ∗15 carriers exhibit higher blood substrate concentrations than ∗1b carriers. It remains unclear whether these differences are due to changes in expression or intrinsic activity (transport activity per OATP1B1 molecule). This study compared the intrinsic activity of four OATP1B1 variants, ∗1a, ∗1b, ∗5, and ∗15, using HEK293 cell lines that co-expressed large-conductance Ca2+-activated K+ (BK) channels and one of the OATP1B1 variants. To estimate the kinetic parameters K<inf>m</inf> and V<inf>max</inf>, 2′, 7′-dichlorofluorescein uptake was evaluated. The number of OATP molecules per cell (Q<inf>T</inf>) was calculated from BK channel-mediated whole-cell conductance and the OATP1B1/BK channel expression ratio (ρ) (determined by LC-MS/MS). V<inf>max,int</inf> (maximum intrinsic transport velocity) was obtained by dividing V<inf>max</inf> by Q<inf>T</inf>, and intrinsic clearance (CL<inf>int</inf>) was calculated as V<inf>max,int</inf>/K<inf>m</inf>. The K<inf>m</inf> values of ∗1a, ∗1b, ∗5, and ∗15 were 12.5, 9.19, 7.53, and 10.4 μM, and their V<inf>max,int</inf> values were 3.0, 7.0, 1.5, and 1.2 × 10−21 mol/OATP molecule/min, respectively. Accordingly, the CL<inf>int</inf> value for OATP1B1∗15 was 15 % lower than that for OATP1B1∗1b, suggesting that the increased blood substrate concentrations observed in OATP1B1∗15 carriers may be due to the decreased intrinsic activity of OATP1B1∗15.
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Determination of single-molecule transport activity of OATP2B1 by measuring the number of transporter molecules using electrophysiological approach

Yajima K., Akiyoshi T., Sakamoto K., Suzuki Y., Oka T., Imaoka A., Yamamura H., Kurokawa J., Ohtani H.

Journal of Pharmacological Sciences (Journal of Pharmacological Sciences) 153 ( 3 ) 153 - 160 2023.11

Research paper (scientific journal), Lead author, Accepted, ISSN 13478613

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Transporter-mediated clearance is determined by two factors, its single-molecule clearance, and expression level. However, no reliable method has been developed to evaluate them separately. This study aimed to develop a reliable method for evaluating the single-molecule activity of membrane transporters, such as organic anion transporting polypeptide (OATP) 2B1. HEK293 cells that co-expressed large conductance calcium-activated potassium (BK) channel and OATP2B1 were established and used for the following experiments. i) BK channel-mediated whole-cell conductance was measured using patch-clamp technique and divided by its unitary conductance to estimate the number of channels on plasma membrane (QI). ii) Using plasma membrane fraction, quantitative targeted absolute proteomics determined the stoichiometric ratio (ρ) of OATP2B1 to BK channel. iii) The uptake of estrone 3-sulfate was evaluated to calculate the Michaelis constant and uptake clearance (CL) per cell. Single-molecule clearance (CLint) was calculated by dividing CL by QI·ρ. QI and ρ values were estimated to be 916 and 2.16, respectively, yielding CLint of 5.23 fL/min/molecule. We successfully developed a novel method to reliably measure the single-molecule activity of a transporter, which could be used to evaluate the influences of factors such as genetic variations and post-translational modifications on the intrinsic activity of transporters.
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The Effects of Jabara Juice on the Intestinal Permeation of Fexofenadine

Han H., Akiyoshi T., Morita T., Tsuchitani T., Nabeta M., Yajima K., Imaoka A., Ohtani H.

Biological and Pharmaceutical Bulletin (Biological and Pharmaceutical Bulletin) 46 ( 12 ) 1745 - 1752 2023

Research paper (scientific journal), Joint Work, Accepted, ISSN 09186158

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

トランスポーター単分子輸送活性の新規評価法の開発 (要旨)

Yajima, Kodai

(慶應義塾大学大学院薬学研究科) 2023

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Reviews, Commentaries, etc. 【 Display / hide 】

Citrus Fruit-Derived Flavanone Glycoside Narirutin is a Novel Potent Inhibitor of Organic Anion-Transporting Polypeptides

Journal of Agricultural and Food Chemistry 2020.12

Article, review, commentary, editorial, etc. (scientific journal), Joint Work, ISSN 0021-8561
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pH-dependent transport kinetics of the human organic anion-transporting polypeptide 1A2

Tokio Morita and Takeshi Akiyoshi and Ryo Sato and Kazuhiro Katayama and Kodai Yajima and Hiroki Kataoka and Ayuko Imaoka and Yoshikazu Sugimoto and Hisakazu Ohtani

Drug Metabolism and Pharmacokinetics (Elsevier {BV}) 35 ( 2 ) 220 - 227 2020.04

Article, review, commentary, editorial, etc. (scientific journal), Joint Work, ISSN 1347-4367
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Presentations 【 Display / hide 】

先行品特異的抗エタネルセプト抗体の特性解析

岩井華那, 岡本恵理子, 矢島広大, 中山葵, 増井翔, 大西輝, 津田真弘, 寺田智祐, 米澤淳

[Domestic presentation] 第35回日本医療薬学会年会,

2025.11
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Oral presentation (general)
Evaluation of infliximab biotransformation through comparison of quantification by ligand-binding assay and mass spectrometry

Sho Masui, Aoto Nakajima, Kodai Yajima, Takashi Shimada, Akira Onishi, Shuji Yamamoto, Masahiro Tsuda, Tomohiro Terada, Atsushi Yonezawa

[Domestic presentation] 第35回日本医療薬学会年会,

2025.11
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Oral presentation (general)
患者血中抗インフリキシマブ抗体における認識エピトープの探索

大岩由佳, 矢島広大, 八木亮爾, 増井翔, 嶋田崇史, 山本修司, 津田真弘, 寺田智祐, 米澤淳

[Domestic presentation] 第35回日本医療薬学会年会,

2025.11
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Poster presentation
実臨床における抗インフリキシマブ抗体発生の実態調査

岩船杏南, 矢島広大, 増井翔, 岡部誠, 津田真弘, 寺田智祐, 嶋田崇史, 米澤淳

[Domestic presentation] 第69回日本薬学会関東支部大会,

2025.09
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Oral presentation (general)
関節リウマチ患者におけるトシリズマブの血中濃度予測モデルの作成

鈴木晴之, 増井翔, 中山葵, 矢島広大, 大西輝, 嶋田崇史, 米澤淳

[Domestic presentation] 第69回日本薬学会関東支部大会,

2025.09
,
Oral presentation (general)