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

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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

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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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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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Comparison of the transport kinetics of fexofenadine and its pH dependency among OATP1A2 genetic variants

Han H., Akiyoshi T., Morita T., Kataoka H., Katayama K., Yajima K., Imaoka A., Ohtani H.

Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics) 47 2022.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

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Little is known about the influence of non-synonymous genetic variations in the organic anion-transporting polypeptide (OATP) 1A2 on the transport kinetics of its substrate fexofenadine. Moreover, the pH-dependency of fexofenadine uptake also remains unclear. This study aimed to evaluate the effects of genetic variants (Ile13Thr, Asn128Tyr, Glu172Asp, Ala187Thr, and Thr668Ser) on the OATP1A2-mediated uptake of fexofenadine at pH 6.3 and 7.4 and compare the pH dependency of OATP1A2-mediated uptake of fexofenadine and estrone 3-sulfate. The uptake clearances of 0.3 μM and 300 μM fexofenadine were compared with those of 0.3 μM and 300 μM estrone 3-sulfate at pH 6.3 and 7.4. Among the six variants examined, the Thr668Ser variant showed the highest fexofenadine uptake clearance (Vmax/Km); i.e., 4.53- and 6.28-fold higher uptake clearance than the wild type at pH 6.3 and 7.4, respectively. All variants exhibited significantly higher fexofenadine uptake at pH 6.3 than at pH 7.4. Compared with estrone 3-sulfate uptake, the uptake of 0.3 μM fexofenadine was less sensitive to pH. Our findings suggest that genetic variations in OATP1A2 may lead to altered intestinal absorption of fexofenadine, such as increased absorption in subjects bearing the Thr668Ser variant, which showed higher uptake activity.
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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
- Access to Document (DOI)
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 】

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)
炎症性腸疾患患者におけるウステキヌマブ体内動態変動因子の探索

島千尋, 増井翔, 矢島広大, 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
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Oral presentation (general)
質量分析法を用いたバイオ医薬におけるバイオトランスフォーメーションの発見

4. 増井翔, 湧谷華織, 中島碧斗, 嶋田崇史, 矢島広大, 大西輝, 山本修司, 橋井則貴, 石井明子, 米澤淳

[Domestic presentation] 第19回次世代を担う若手のための医療薬科学シンポジウム,

2025.09
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Oral presentation (general)
Exploration of epitope on Infliximab recognized by anti-drug antibody

矢島広大, 八木亮爾, 増井翔, 大西輝, 山本修司, 津田真弘, 寺田智祐, 米澤淳

[Domestic presentation] 日本薬学会第145年会 (福岡国際会議場・マリンメッセ福岡B館・福岡サンパレス) ,

2025.03
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Oral presentation (general), 日本薬学会