Evaluation of hepatotoxicity of industrial chemicals based on intestinal absorption and physiologically based pharmacokinetic modelling

• Project/Area Number: 19K16422
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Showa Pharmaceutical University
• Principal Investigator: Kamiya Yusuke 昭和薬科大学, 薬学部, 特任助教 (20802945)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2019: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: 消化管吸収性 / 薬物動態予測 / 化学物質 / 肝毒性評価 / 生理学的薬物動態モデル / 一般化学物質

Outline of Research at the Start

本研究では、医薬領域において小腸吸収性評価に汎用されている培養ヒト腸由来細胞を活用し、多様な化合物の消化管吸収性を評価することで、吸収性に及ぼす化合物側の変動要因について解析し、得られた情報を生理学的薬物動態モデルに還元することで、吸収過程を精緻化した生理学的薬物動態モデルを開発すること、さらに、それを用いた化学物質経口投与後の肝毒性発現リスクの新規評価法の確立を目指す。

Outline of Final Research Achievements

Apparent permeability coefficient values of industrial chemicals via Caco-2 cell monolayer, human intestinal epithelial cell line, showed a significant association with reported their hepatic no-observed effect level values in rats. The areas under the hepatic concentration-time curves after virtual oral administration of chemicals estimated using simplified physiologically based pharmacokinetic modelling were inversely associated with hepatic lowest-observed effect levels. These results suggest that intestinal permeability coefficients and simulating the hepatic levels of industrial chemicals are important to determine the onset of hepatotoxicity and risk assessment.

Academic Significance and Societal Importance of the Research Achievements

工業用に生産される化学物質のヒトに対するリスクは、化審法に従い実験動物を用いた反復経口投与による毒性試験の結果から種差や個人差を補正した値にて評価されている。しかし、化学物質の投与後、毒性発現に至るまでの体内動態はほとんど考慮されていない。一方、動物愛護やコストの削減の観点から、化学物質の毒性を評価し得る代替法に関する研究が広く行われている。本課題では、化学物質が生体に吸収される過程や、生体内でどのような運命を辿るかに着目した、新しい毒性評価方法に関する研究を行った。本研究で得られた知見は、従来の動物実験に取って代わる毒性評価手法開発の基盤情報となりうる極めて有意義なものである。

Research Products

• [Journal Article] In Silico Prediction of Input Parameters for Simplified Physiologically Based Pharmacokinetic Models for Estimating Plasma, Liver, and Kidney Exposures in Rats after Oral Doses of 246 Disparate Chemicals (2021)
  • Author(s): Kamiya Yusuke、Handa Kentaro、Miura Tomonori、Yanagi Mayu、Shigeta Kazuki、Hina Shiori、Shimizu Makiko、Kitajima Masato、Shono Fumiaki、Funatsu Kimito、Yamazaki Hiroshi
  • Journal Title: Chemical Research in Toxicology Volume: 34 Issue: 2 Pages: 507-513
  • DOI: 10.1021/acs.chemrestox.0c00336
  • Peer Reviewed / Open Access
• [Journal Article] Hepatotoxicological potential of P-toluic acid in humanised-liver mice investigated using simplified physiologically based pharmacokinetic models (2021)
  • Author(s): Miura Tomonori、Kamiya Yusuke、Uehara Shotaro、Murayama Norie、Shimizu Makiko、Suemizu Hiroshi、Yamazaki Hiroshi
  • Journal Title: Xenobiotica Volume: － Pages: 1-7
  • DOI: 10.1080/00498254.2021.1908643
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Determination and prediction of permeability across intestinal epithelial cell monolayer of a diverse range of industrial chemicals/drugs for estimation of oral absorption as a putative marker of hepatotoxicity. (2020)
  • Author(s): .Kamiya, Y., Takaku, H., Yamada, R., Akase, C., Abe, Y., Sekiguchi, Y., Murayama, N., Shimizu, M., Kitajima, M., Shono, F., Funatsu, K., and Yamazaki, H.
  • Journal Title: Toxicol. Rep. Volume: 149 Pages: 149-154
  • DOI: 10.1016/j.toxrep.2020.01.004
  • Peer Reviewed / Open Access
• [Journal Article] Increased plasma concentrations of an antidyslipidemic drug pemafibrate co-administered with rifampicin or cyclosporine A in cynomolgus monkeys genotyped for the organic anion transporting polypeptide 1B1 (2020)
  • Author(s): Ogawa Shin-ichiro、Shimizu Makiko、Kamiya Yusuke、Uehara Shotaro、Suemizu Hiroshi、Yamazaki Hiroshi
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 35 Issue: 4 Pages: 354-360
  • DOI: 10.1016/j.dmpk.2020.03.005
  • NAID: 50014558608
  • Peer Reviewed / Open Access
• [Journal Article] Physiologically Based Pharmacokinetic Models Predicting Renal and Hepatic Concentrations of Industrial Chemicals after Virtual Oral Doses in Rats (2020)
  • Author(s): Kamiya Yusuke、Otsuka Shohei、Miura Tomonori、Yoshizawa Manae、Nakano Ayane、Iwasaki Miyu、Kobayashi Yui、Shimizu Makiko、Kitajima Masato、Shono Fumiaki、Funatsu Kimito、Yamazaki Hiroshi
  • Journal Title: Chemical Research in Toxicology Volume: 33 Issue: 7 Pages: 1736-1751
  • DOI: 10.1021/acs.chemrestox.0c00009
  • Peer Reviewed / Open Access
• [Journal Article] Metabolic profiles of coumarin in human plasma extrapolated from a rat data set with a simplified physiologically based pharmacokinetic model (2020)
  • Author(s): 47.Miura T, Kamiya Y, Hina S, Kobayashi Y, Murayama N, Shimizu M, Yamazaki H.
  • Journal Title: The Journal of Toxicological Sciences Volume: 45 Issue: 11 Pages: 695-700
  • DOI: 10.2131/jts.45.695
  • NAID: 130007935150
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed / Open Access
• [Journal Article] Plasma, liver, and kidney exposures in rats after oral doses of industrial chemicals predicted using physiologically based pharmacokinetic models: A case study of perfluorooctane sulfonic acid (2020)
  • Author(s): Kamiya Yusuke、Yanagi Mayu、Hina Shiori、Shigeta Kazuki、Miura Tomonori、Yamazaki Hiroshi
  • Journal Title: The Journal of Toxicological Sciences Volume: 45 Issue: 12 Pages: 763-767
  • DOI: 10.2131/jts.45.763
  • NAID: 130007948827
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed / Open Access
• [Journal Article] Different Hepatic Concentrations of Bromobenzene, 1,2-Dibromobenzene, and 1,4-Dibromobenzene in Humanized-Liver Mice Predicted Using Simplified Physiologically Based Pharmacokinetic Models as Putative Markers of Toxicological Potential (2020)
  • Author(s): Miura Tomonori、Shimizu Makiko、Uehara Shotaro、Yoshizawa Manae、Nakano Ayane、Yanagi Mayu、Kamiya Yusuke、Murayama Norie、Suemizu Hiroshi、Yamazaki Hiroshi
  • Journal Title: Chemical Research in Toxicology Volume: 33 Issue: 12 Pages: 3048-3053
  • DOI: 10.1021/acs.chemrestox.0c00387
  • Peer Reviewed / Open Access
• [Journal Article] Metabolic Profiles of Tetrabromobisphenol A in Humans Extrapolated from Humanized-Liver Mouse Data Using a Simplified Physiologically Based Pharmacokinetic Model (2020)
  • Author(s): Miura Tomonori、Uehara Shotaro、Shigeta Kazuki、Yoshizawa Manae、Kamiya Yusuke、Murayama Norie、Shimizu Makiko、Suemizu Hiroshi、Yamazaki Hiroshi
  • Journal Title: Chemical Research in Toxicology Volume: 34 Issue: 2 Pages: 522-528
  • DOI: 10.1021/acs.chemrestox.0c00358
  • Peer Reviewed / Open Access
• [Presentation] 培養ヒトおよびラット腸細胞を用いた一般化学物質の膜透過性および動物肝無毒性指標の関連 (2020)
  • Author(s): 神矢佑輔、大村明日香、關口佑子、赤瀨千聡、阿部雄人、庄野文章、山崎浩史
  • Organizer: 日本薬学会第140年会
• [Presentation] 多様な一般化学物質および医薬品の培養ヒト小腸上皮膜透過係数の予測 (2020)
  • Author(s): 關口佑子、神矢佑輔、大村明日香、赤瀨千聡、阿部雄人、庄野文章、船津公人、山崎浩史
  • Organizer: 日本薬学会第140年会
• [Presentation] 一般化学物質のラット血中濃度推移情報と生理学的薬物動態モデルを活用した予測肝中濃度と臓器毒性 (2020)
  • Author(s): 村山典恵、柳麻由、岩崎美友、小林由惟、中野彩音、三浦智徳、神矢佑輔、庄野文章、山崎浩史
  • Organizer: 日本薬学会第140年会
• [Presentation] 腎を独立させた生理学的薬物動態モデルで予測した一般化学物質のラット組織中濃度と臓器毒性 (2020)
  • Author(s): 重田和樹、村山典恵、吉沢愛映、大西潮、大塚昌平、神矢佑輔、庄野文章、山崎浩史
  • Organizer: 日本薬学会第140年会
• [Presentation] Determination of permeability across Caco-2 cell monolayer and development of predictable equations for oral absorbability of general chemical substances (2019)
  • Author(s): Kamiya Yusuke、Takaku Hiroka、Yamada Rio、Yamazaki Hiroshi
  • Organizer: 12th International ISSX Meeting
  • Int'l Joint Research