Physiological factors involved in variability of OATP1B activity

• Project/Area Number: 19K16455
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Meiji Pharmaceutical University
• Principal Investigator: Suzuki Yosuke 明治薬科大学, 薬学部, 講師 (10737191)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: トランスポーター / バイオマーカー / OATP1B / フェノタイピング / 薬物動態 / coproporphyrin-I / CMPF / 慢性腎臓病 / 関節リウマチ / 慢性腎不全

Outline of Research at the Start

Organic anion transporting polypeptides（OATP）1B活性は遺伝的、環境的、および生理的要因によって変動すると考えられるが、生理的要因がOATP1B活性に及ぼす影響はほとんど明らかにされていない。本研究計画では、生理的要因として腎機能障害と慢性炎症性疾患に焦点を当て、これらがin vivoでのOATP1B活性に及ぼす影響を評価する。

Outline of Final Research Achievements

The aim of this study was to identify significant factors associated with the inter-individual variation in OATP1B activity. First, we performed clinical study in general population and confirmed the utility of plasma CP-I concentrations as an endogenous biomarker for phenotyping of OATP1B activity. Next, we performed clinical study in patients with rheumatoid arthritis and chronic kidney disease and confirmed significant positive correlation between plasma CP-I and CMPF concentrations, suggested that dose adjustment for OATP1B substrates may be needed in patients with accumulation of CMPF.

Academic Significance and Societal Importance of the Research Achievements

今回の研究で、生体内で薬などの物質を運搬するトランスポーターの1種であるOATP1Bの働きの程度に大きな個人差があることが分かり、その個人差にCMPFと呼ばれる尿毒症物質の蓄積の程度が関わっていることが分かりました。このことから、CMPFが体に蓄積しやすい腎臓病などを患う患者さんが、OATP1Bで輸送される薬を使用する際には、投与量を減らすなどの対策が必要である可能性があることが分かりました。

Research Products

• [Journal Article] Factors Influencing Plasma Coproporphyrin-I Concentration as Biomarker of OATP1B Activity in Patients With Rheumatoid Arthritis (2021)
  • Author(s): Ono H, Tanaka R, Suzuki Y, Oda A, Ozaki T, Tatsuta R, Maeshima K, Ishii K, Ohno K, Shibata H, Itoh H.
  • Journal Title: Clin Pharmacol Ther Volume: 110 Issue: 4 Pages: 1096-1105
  • DOI: 10.1002/cpt.2375
  • Peer Reviewed
• [Journal Article] Substantially Increased Plasma Coproporphyrin-I Concentrations Associated With OATP1B1*15 Allele in Japanese General Population (2021)
  • Author(s): Suzuki Y, Sasamoto Y, Koyama T, Yoshijima C, Nakatochi M, Kubo M, Momozawa Y, Uehara R, Ohno K
  • Journal Title: Clin Transl Sci Volume: 14 Issue: 1 Pages: 382-388
  • DOI: 10.1111/cts.12889
  • Peer Reviewed / Open Access
• [Journal Article] Relationship of Hemoglobin Level and Plasma Coproporphyrin-I Concentrations as an Endogenous Probe for Phenotyping OATP1B (2021)
  • Author(s): Suzuki Y, Sasamoto Y, Koyama T, Yoshijima C, Oda A, Nakatochi M, Kubo M, Momozawa Y, Uehara R, Ohno K
  • Journal Title: Clin Transl Sci Volume: - Issue: 4 Pages: 1403-1411
  • DOI: 10.1111/cts.12996
  • Peer Reviewed / Open Access
• [Journal Article] Simultaneous quantification of coproporphyrin-I and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid in human plasma using ultra-high performance liquid chromatography coupled to tandem mass spectrometry (2020)
  • Author(s): Suzuki Y, Sasamoto Y, Yoshijima C, Tanaka R, Ono H, Ando T, Shin T, Mimata H, Itoh H, Ohno K
  • Journal Title: Journal of Pharmaceutical and Biomedical Analysis Volume: 184 Pages: 113202-113202
  • DOI: 10.1016/j.jpba.2020.113202
  • Peer Reviewed
• [Presentation] 関節リウマチ患者における血漿Coproporphyrin-I濃度を指標としたOATP1B活性個人差の要因解析 (2021)
  • Author(s): 小野寛之, 田中遼大, 鈴木陽介, 小田絢子, 尾崎貴士, 龍田涼佑, 大野恵子, 柴田洋孝, 伊東弘樹
  • Organizer: 第31回日本医療薬学会年会
• [Presentation] 血漿中コプロポルフィリンI濃度を用いた関節リウマチ患者のOATP1B活性に影響を与える因子の探索 (2021)
  • Author(s): 小野寛之, 田中遼大, 鈴木陽介, 小田絢子, 尾崎貴士, 龍田涼佑, 大野恵子, 柴田洋孝, 伊東弘樹
  • Organizer: 第15回次世代を担う若手のための医療薬科学シンポジウム
• [Presentation] Substantially increased plasma coproporphyrin-I concentrations associated with OATP1B1*15 allele in Japanese general population (2020)
  • Author(s): Suzuki Y, Sasamoto Y, Koyama T, Yoshijima C, Ohno K
  • Organizer: 18th International Congress of Therapeutic Drug Monitoring & Clinical Toxicology
  • Int'l Joint Research
• [Presentation] UHPLC-MS/MS法による血漿中coproporphyrin-Iの定量法の確立 (2020)
  • Author(s): 笹本 雄理、鈴木 陽介、吉島 千智、田中 遼大、小野 寛之、秦 聡孝、三股 浩光、伊東 弘樹、大野 恵子
  • Organizer: 日本薬学会第140年会