Reverse translational research based on a novel pharmacokinetic control theory for immunosuppressive drugs

• Project/Area Number: 20K16080
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: University of Miyazaki
• Principal Investigator: Yoshikawa Naoki 宮崎大学, 医学部, 薬剤部長補佐 (60866383)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 免疫抑制薬 / タクロリムス / 赤血球 / FKBP / 薬物動態

Outline of Research at the Start

タクロリムスは薬物体内動態の個人差が極めて大きい薬物である。本研究では、これまで不明であった生体内でのタクロリムスの赤血球移行におけるFKBPの役割を明らかにし、新たなタクロリムスの体内動態制御理論を構築することを目的とする。タクロリムスの赤血球移行機序に着眼し、赤血球移行においてFKBPが果たす役割とその寄与率を明らかにすることで、FKBPによるタクロリムスの体内動態制御機構を初めて証明する。本研究は、臨床で生じた課題に対しリバーストランスレーショナルなアプローチを行う。

Outline of Final Research Achievements

In this study, we attempted to clarify the role of FK506 binding protein (FKBP) in the red blood cells (RBCs) distribution of tacrolimus in vivo by elucidating the intracellular distribution mechanism of tacrolimus based on its interaction with FKBP.
It was suggested that the capture of tacrolimus by FKBP12 prior to its contact with RBCs decreases the RBCs distribution of tacrolimus. In addition, the contribution of intracellular FKBP12 molecules was found to be extremely significant in the intracellular distribution of tacrolimus.

Academic Significance and Societal Importance of the Research Achievements

本研究において、生体内でのタクロリムスの赤血球移行におけるFKBPの役割を一部明らかにした。本成果は、これまで不明であったタクロリムスの赤血球移行機序において、FKBPが果たす役割とその寄与率の解明に迫るものと考える。本研究成果はタクロリムスの新たな体内動態制御理論の構築につながる極めて有益な知見である。

Research Products

• [Journal Article] Diffusion coefficient of cationic liposomes during lipoplex formation determines transfection efficiency in HepG2 cells (2023)
  • Author(s): Hu Die、Fumoto Shintaro、Yoshikawa Naoki、Peng Jianqing、Miyamoto Hirotaka、Tanaka Masakazu、Nishida Koyo
  • Journal Title: International Journal of Pharmaceutics Volume: 637 Pages: 122881-122881
  • DOI: 10.1016/j.ijpharm.2023.122881
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Evaluation of a Webinar for Pharmacists Learning Basic Clinical-Oncology during COVID-19 Pandemic in Japan (2022)
  • Author(s): Terazono Hideyuki、Tsuchiya Masami、Maki Yosuke、Yoshikawa Naoki、Kawahara Yosuke、Nishimura Keiko、Shinohara Keisuke、Ogawa Daisuke、Mori Riho、Iwamoto Yoshihiro、Itagaki Fumio、Masuko Hiroyuki、Yonemura Masahito、Uchida Mayako
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 45 Issue: 7 Pages: 856-862
  • DOI: 10.1248/bpb.b21-00844
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2022-07-01
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant Expression of Cardiac Troponin-T in Lung Cancer Tissues in Association With Pathological Severity (2022)
  • Author(s): Tsuruda Toshihiro、Sato Yuichiro、Tomita Masaki、Tanaka Hiroyuki、Hatakeyama Kinta、Otsu Misa、Kawano Aya、Nagatomo Keiko、Yoshikawa Naoki、Ikeda Ryuji、Asada Yujiro、Kaikita Koichi
  • Journal Title: Frontiers in Cardiovascular Medicine Volume: 9 Pages: 833649-833649
  • DOI: 10.3389/fcvm.2022.833649
  • Peer Reviewed / Open Access
• [Journal Article] Hepatocyte Growth Factor Enhances Antineoplastic Effect of 5-Fluorouracil by Increasing UPP1 Expression in HepG2 Cells (2022)
  • Author(s): Okumura Manabu、Iwakiri Tomomi、Yoshikawa Naoki、Nagatomo Takao、Ayabe Takanori、Tsuneyoshi Isao、Ikeda Ryuji
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 16 Pages: 9108-9108
  • DOI: 10.3390/ijms23169108
  • Peer Reviewed / Open Access
• [Journal Article] Fine-tuned cholesterol solubilizer, mono-6-O-α-D-maltosyl-γ-cyclodextrin, ameliorates experimental Niemann?Pick disease type C without hearing loss (2022)
  • Author(s): Yamada Y, Miwa T, Nakashima M, Shirakawa A, Ishii A, Namba N, Kondo Y, Takeo T, Nakagata N, Motoyama K, Higashi T, Arima H, Kurauchi Y, Seki T, Katsuki H, Okada Y, Ichikawa A, Higaki K, Hayashi K, Minami K, Yoshikawa N, Ikeda R, Ishikawa Y, Kajii T, Tachii K, Takeda H, Orita Y, Matsuo M, Irie T, Ishitsuka Y
  • Journal Title: Biomedicine & Pharmacotherapy Volume: 155 Pages: 113698-113698
  • DOI: 10.1016/j.biopha.2022.113698
  • Peer Reviewed / Open Access
• [Journal Article] Association between CYP3A5*3 polymorphism and graft-versus-host disease in allogeneic hematopoietic stem cell transplant patients receiving tacrolimus (2022)
  • Author(s): Yoshikawa Naoki, Takeshima Hidemi, Matsusaka Kotaro, Yokota Tsubasa, Shimoda Kazuya, Ikeda Ryuji
  • Journal Title: Die Pharmazie Volume: 77 Pages: 335-337
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between prognosis and timing of antimicrobial use in the treatment of severe flame burns: a single-centre retrospective study (2022)
  • Author(s): Koreeda Hidehiko, Yoshikawa Naoki, Minami Kentaro, Yokota Tsubasa, Ochiai Hidenobu, Ikeda Ryuji
  • Journal Title: Die Pharmazie Volume: 77 Pages: 348-351
  • Peer Reviewed / Open Access
• [Journal Article] Ursodeoxycholic acid markedly promotes the absorption of microemulsion-formulated cyclosporine A: A case report (2022)
  • Author(s): Takeshima, H., Yoshikawa, N., Akizuki, K., Hidaka, T., Shimoda, K., Ikeda, R.
  • Journal Title: Journal of Clinical Pharmacy and Therapeutics Volume: 47 Issue: 2 Pages: 260-262
  • DOI: 10.1111/jcpt.13496
  • Peer Reviewed
• [Journal Article] The Cytokine Expression in Patients with Cardiac Complication after Immune Checkpoint Inhibitor Therapy (2021)
  • Author(s): Tsuruda T, Yoshikawa N, Kai M, Yamaguchi M, Toida R, Kodama T, Kajihara K, Kawabata T, Nakamura T, Sakata K, Hatakeyama K, Gi T, Asada Y, Tono T, Kitamura K, Ikeda R.
  • Journal Title: Internal Medicine Volume: 60 Issue: 3 Pages: 423-429
  • DOI: 10.2169/internalmedicine.5317-20
  • NAID: 130007979736
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-02-01
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between CYP3A5 Polymorphism and Tacrolimus Blood Concentration Changes in Allogeneic Hematopoietic Stem Cell Transplant Recipients during Continuous Infusion (2021)
  • Author(s): Yoshikawa, N., Takeshima, H., Sekine, M., Akizuki, K., Hidaka, T., Shimoda, K., Ikeda, R.
  • Journal Title: Pharmaceuticals Volume: 14 Issue: 4 Pages: 353-353
  • DOI: 10.3390/ph14040353
  • Peer Reviewed / Open Access
• [Journal Article] Delayed methotrexate elimination in a patient with primary central nervous system lymphoma: A case report (2021)
  • Author(s): Urata, S., Yoshikawa, N, Saito, K., Tazaki, T., Ohno, R., Takeshima, H., Ikeda, R.
  • Journal Title: Journal of Clinical Pharmacy and Therapeutics Volume: 46 Issue: 6 Pages: 1796-1799
  • DOI: 10.1111/jcpt.13425
  • Peer Reviewed
• [Journal Article] Potentially harmful excipients in neonatal medications: a multicenter nationwide observational study in Japan (2021)
  • Author(s): Saito Jumpei、Nadatani Naomi、Setoguchi Makoto、Nakao Masahiko、Kimura Hitomi、Sameshima Mayuri、Kobayashi Keiko、Matsumoto Hiroaki、Yoshikawa Naoki、他
  • Journal Title: Journal of Pharmaceutical Health Care and Sciences Volume: 7 Issue: 1 Pages: 23-23
  • DOI: 10.1186/s40780-021-00208-9
  • Peer Reviewed / Open Access
• [Journal Article] 心臓移植予定患者のヘリ搬送時に携行する医薬品リストの整備と運用体制の構築 (2021)
  • Author(s): 高橋 沙季、吉川 直樹、鶴田 敏博、鬼塚 久充、横田 翼、関屋 裕史、平原 康寿、北村和雄、池田 龍二
  • Journal Title: 日本病院薬剤師会雑誌 Volume: 57 Pages: 771-775
  • NAID: 40022639465
  • Peer Reviewed
• [Journal Article] Evaluation of a web‐based educational programme for pharmacists during the COVID‐19 pandemic in Japan (2021)
  • Author(s): Tsuchiya Masami、Terazono Hideyuki、Maki Yosuke、Yoshikawa Naoki、Kawahara Yosuke、Nishimura Keiko、Shinohara Keisuke、Ogawa Daisuke、Mori Riho、Iwamoto Yoshihiro、Itagaki Fumio、Masuko Hiroyuki、Yonemura Masahito、Uchida Mayako
  • Journal Title: Journal of Clinical Pharmacy and Therapeutics Volume: 46 Issue: 6 Pages: 1743-1749
  • DOI: 10.1111/jcpt.13526
  • Peer Reviewed
• [Journal Article] Development and Validation of an HPLC Method for Analysis of Topotecan in Human Cerebrospinal Fluid and Its Application in Elimination Evaluation of Topotecan after Intraventricular Injection (2021)
  • Author(s): Yoshikawa,N., Yamada, A., Yokota, T., Yamada,Y., Kinoshita, M., Moritake, H., Ikeda, R.
  • Journal Title: Cancers Volume: 13 Issue: 18 Pages: 4643-4643
  • DOI: 10.3390/cancers13184643
  • Peer Reviewed / Open Access
• [Journal Article] Impact of green tea intake on the pharmacokinetics of celiprolol in healthy?subjects (2021)
  • Author(s): Sonoda Junichiro、Ogata Kenji、Yoshikawa Naoki、Sato Keizo、Ikeda Ryuji、Shimodozono Yoshihiro
  • Journal Title: Int. Journal of Clinical Pharmacology and Therapeutics Volume: 59 Issue: 03 Pages: 198-201
  • DOI: 10.5414/cp203795
  • Peer Reviewed
• [Journal Article] Measurement of methotrexate in human cerebrospinal fluid using a chemiluminescence immunoassay intended for serum and plasma matrices (2021)
  • Author(s): Yoshikawa N, Yamada A, Yokota T, Moritake H, Hirabara Y, Ikeda R
  • Journal Title: J Clin Lab Anal Volume: 35 Issue: 3
  • DOI: 10.1002/jcla.23661
  • Peer Reviewed / Open Access
• [Journal Article] Role of FK506 Binding Protein on Tacrolimus Distribution in Red Blood Cells (2020)
  • Author(s): Yoshikawa N, Yokota T, Matsuo A, Matsumoto N, Iwakiri T, Ikeda R.
  • Journal Title: Pharm Res Volume: 37 Issue: 7 Pages: 143-143
  • DOI: 10.1007/s11095-020-02875-z
  • Peer Reviewed / Open Access
• [Journal Article] Interaction of Lipoplex with Albumin Enhances Gene Expression in Hepatitis Mice (2020)
  • Author(s): Yoshikawa Naoki、Fumoto Shintaro、Yoshikawa Keiko、Hu Die、Okami Kazuya、Kato Riku、Nakashima Mikiro、Miyamoto Hirotaka、Nishida Koyo
  • Journal Title: Pharmaceutics Volume: 12 Issue: 4 Pages: 341-341
  • DOI: 10.3390/pharmaceutics12040341
  • NAID: 120006988209
  • Peer Reviewed / Open Access
• [Journal Article] Retrospective analysis of risk factors for liposomal amphotericin B-associated nephrotoxicity (2020)
  • Author(s): Yoshikawa Naoki、Yokota Tsubasa、Arimori Kazuhiko、Ikeda Ryuji
  • Journal Title: Die Pharmazie Volume: 75 Pages: 599-601
  • Peer Reviewed / Open Access
• [Journal Article] Development and Evaluation of Orders to Measure Drug Concentrations in Blood by using an Electronic Medical Record System (2020)
  • Author(s): Yoshikawa Naoki、Okumura Manabu、Ogura Yuki、Urata Shuhei、Hagihara Sakurako、Ikeda Ryuji
  • Journal Title: Journal of Advances in Pharmacy Practices Volume: 3 Issue: 1 Pages: 1-6
  • DOI: 10.46610/japp.2021.v03i01.001
  • Peer Reviewed
• [Presentation] 脳脊髄液中topotecan濃度のHPLC分析法構築と髄腔内薬物投与後の排泄評価への応用 (2023)
  • Author(s): 吉川直樹、山田愛、山田侑世、新地瑠海、木下真理子、盛武浩、池田龍二
  • Organizer: 日本薬学会第143年会
• [Presentation] 化学量論に基づいたシクロデキストリンの shuttle - sink機能制御によるニーマン・ピック病C型治療の最適化 (2023)
  • Author(s): 山田侑世、西澤まど香、西山麻美、石井亮良、河田達哉、白川愛奈、中島将貴、近藤悠希、竹尾透、中潟直己、三輪徹、竹田大樹、折田頼尚、東大志、本山敬一、有馬英俊、関貴弘、倉内祐樹、香月博志、檜垣克美、南謙太朗、吉川直樹、池田龍二、松尾宗明、入江徹美、石塚洋一
  • Organizer: 日本薬学会第143年会
• [Presentation] 潰瘍性大腸炎患者における食事開始後のタクロリムス血中濃度変動に関連する因子の解析 (2022)
  • Author(s): 谷口裕紀、吉川直樹、長友隆雄、横田翼、池田龍二
  • Organizer: 第38回日本TDM学会・学術大会
• [Presentation] 潰瘍性大腸炎患者における食事再開時のタクロリムス血中濃度変動に関連する因子の検討 (2022)
  • Author(s): 長友隆雄、吉川直樹、谷口裕紀、横田翼、池田龍二
  • Organizer: 第32回日本医療薬学会年会
• [Presentation] Mono-6-O-α-maltosyl-γ-cyclodextrinのNiemann-Pick病C型治療薬として有用性評価 (2022)
  • Author(s): 中島将貴、山田侑世、三輪徹、白川愛奈、難波七海、近藤悠希、竹尾透、中潟直己、本山敬一、東大志、有馬英俊、倉内祐樹、関貴弘、香月博志、岡田安代、檜垣克美、南謙太朗、吉川直樹、池田龍二、折田頼尚、松尾宗明、入江徹美、石塚洋一
  • Organizer: 第39回 日本薬学会九州山口支部大会
• [Presentation] ヒト脳脊髄液中topotecan濃度のHPLC分析法構築と髄腔内薬物投与後の排泄評価 (2022)
  • Author(s): 吉川直樹、山田愛、横田翼、山田侑世、木下真理子、盛武浩、池田龍二
  • Organizer: 第43回日本臨床薬理学会学術総会
• [Presentation] 造血幹細胞移植後免疫抑制薬TDMの進歩 (2022)
  • Author(s): 吉川直樹、池田龍二
  • Organizer: 第38回日本TDM学会・学術大会
  • Invited
• [Presentation] Affinity chrome-mediated immunoassay（ACMIA）法による全血中エベロリムス濃度測定環境の評価検証 (2022)
  • Author(s): 吉川直樹
  • Organizer: 第38回日本TDM学会・学術大会
  • Invited
• [Presentation] 免疫抑制薬の新規薬物動態制御理論に立脚したリバーストランスレーショナルリサーチ (2022)
  • Author(s): 吉川直樹、池田龍二
  • Organizer: 日本薬学会第142年会
  • Invited
• [Presentation] 同種造血幹細胞移植患者におけるタクロリムス持続点滴静注時の血中濃度変化とCYP3A5遺伝子多型の関係の解析 (2021)
  • Author(s): 吉川直樹、竹島秀美、関根雅明、秋月渓一、日髙智徳、下田和哉、池田龍二
  • Organizer: 第37回日本TDM学会・学術大会
• [Presentation] 重症熱傷治療の予後に抗菌薬使用が与える影響に関する単施設後方視的調査 (2021)
  • Author(s): 是枝秀彦、吉川直樹、落合秀信、池田龍二
  • Organizer: 第24回日本臨床救急医学会総会・学術集会
• [Presentation] 重症熱傷治療の予後と抗菌薬使用時期の関係についての単施設後方視的調査 (2021)
  • Author(s): 是枝秀彦、吉川直樹、落合秀信、池田龍二
  • Organizer: 医療薬学フォーラム2021/第29回クリニカルファーマシーシンポジウム
• [Presentation] メトトレキサート排泄遅延を生じた中枢神経原発悪性リンパ腫患者の一症例 (2021)
  • Author(s): 浦田修平、吉川直樹、齋藤清貴、田崎智也、大野梨絵、竹島秀雄、池田龍二
  • Organizer: 第31回日本医療薬学会年会
• [Presentation] タクロリムスの赤血球への分布におけるFK506結合タンパク質の役割 (2021)
  • Author(s): 吉川直樹、横田翼、松尾彩子、山田侑世、岩切智美、池田龍二
  • Organizer: 第38回日本薬学会九州山口支部大会
• [Presentation] Relationship between CYP3A5 polymorphism and tacrolimus blood concentration changes in allogeneic hematopoietic stem cell transplant recipients during continuous infusion (2021)
  • Author(s): Naoki Yoshikawa、Ryuji Ikeda
  • Organizer: 第31回日本医療薬学会年会
  • Invited
• [Presentation] 臨床薬理学的基盤に立脚した同種造血幹細胞移植患者におけるタクロリムス体内動態の個人差の検討 (2021)
  • Author(s): 吉川直樹、池田龍二
  • Organizer: 第42回日本臨床薬理学会学術総会
  • Invited
• [Presentation] FK506-binding protein contributes to tacrolimus distribution in red blood cells (2021)
  • Author(s): Naoki Yoshikawa, Ayako Matsuo, Tsubasa Yokota, Tomomi Iwakiri, Ryuji Ikeda
  • Organizer: 第94回日本薬理学会年会
• [Presentation] がん医療におけるTDMを介した人材育成とチーム医療への参画 (2021)
  • Author(s): 吉川直樹、池田龍二
  • Organizer: 日本臨床腫瘍薬学会学術大会2021
  • Invited
• [Presentation] A HPLC method for analysis of methotrexate in human cerebrospinal fluid and comparison with the chemiluminescence immunoassay (2020)
  • Author(s): Naoki Yoshikawa，Ai Yamada，Tsubasa Yokota，Hiroshi Moritake，Yasutoshi Hidabara，Ryuji Ikeda
  • Organizer: 第30回日本医療薬学会年会
• [Presentation] Liposomal-amphotericin Bによる腎機能障害発現の危険因子の後方視的調査 (2020)
  • Author(s): 横田翼、吉川直樹、有森和彦、池田龍二
  • Organizer: 第30回日本医療薬学会年会
• [Presentation] 胆汁酸製剤の併用でシクロスポリンマイクロエマルジョン製剤の吸収が顕著に促進された1症例 (2020)
  • Author(s): 竹島秀美、吉川直樹、秋月渓一、日高智徳、下田和哉、池田龍二
  • Organizer: 第30回日本医療薬学会年会
• [Presentation] 血清・血漿マトリックスを分析対象とした化学発光免疫測定法によるヒト脳脊髄液中Methotrexate濃度の測定 (2020)
  • Author(s): 吉川直樹、山田愛、横田翼、盛武浩、平原康寿、池田龍二
  • Organizer: 第41回日本臨床薬理学会学術総会