Pharmacokinetics prediction of drugs in humans associated with flavin-containing monooxygenase dependent-oxygenations in livers and kidneys of animal models

• Project/Area Number: 16K08380
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Showa Pharmaceutical University
• Principal Investigator: SHIMIZU Makiko 昭和薬科大学, 薬学部, 准教授 (90307075)
• Co-Investigator(Kenkyū-buntansha): 山崎 浩史 昭和薬科大学, 薬学部, 教授 (30191274) ; 村山 典惠 昭和薬科大学, 薬学部, 講師 (90219949)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: フラビン含有酸素添加酵素 / FMO / サル / 薬物代謝

Outline of Final Research Achievements

The flavin-containing monooxygenase (FMO) is an NADPH-dependent enzyme that catalyzes the oxygenation of a wide variety of nitrogen- and sulfur-containing medicines and xenobiotic substances. Human FMO3 and FMO1 are considered prominent functional forms expressed in adult livers and kidney, respectively. FMO dependent oxygenation activities in humanized-liver mice, marmoset, and monkey were determined. The oxidation rates of FMO substrate in mouse kidney may need to be taken into consideration when directly scaling up without consideration of an interspecies factor between in vitro hepatic clearances and in vivo clearances of FMO probe drugs in humanized-liver mice. Expression of FMO1 and FMO3 mRNA were determined in the marmoset liver and kidney. Monkey FMO1 was expressed and functional in kidneys, similar to human FMO1. These results suggest that investigation of drug-drug or drug-food interactions associated with FMO enzymes could be evaluated in non human primate models.

Academic Significance and Societal Importance of the Research Achievements

本研究は、肝のみならず腎の酸素添加酵素活性を考慮する点に学術的意義がある。医薬品開発で用いられている実験動物の肝および腎のFMO各分子種の触媒活性および薬物相互作用の情報は少なく、FMOの関与する薬物の体内動態の詳細を明らかにすることは、FMO が代謝を触媒する医薬品の開発を進める上で意義深いと考える。さらに、FMO3によって食品由来成分トリメチルアミンから生成するN酸化体は動脈硬化悪化が提唱されており、疾患の影響因子として基盤となることが期待できる。

Research Products

• [Journal Article] Expression and metabolic activity of flavin-containing monooxygenase 1 (FMO1) in cynomolgus macaque kidney. (2019)
  • Author(s): Uno Y, Shimizu M, Yoda H, Yamazaki H.
  • Journal Title: J.Med.Primatol. Volume: 48 Issue: 1 Pages: 51-53
  • DOI: 10.1111/jmp.12385
  • Peer Reviewed
• [Journal Article] Non-synonymous genetic variants of flavin-containing monooxygenase 3 (FMO3) in cynomolgus macaques. (2019)
  • Author(s): Uno, Y., Shimizu, M., Yoda, H., Origuchi, Y., and Yamazaki, H.
  • Journal Title: Drug Metab. Pharmacokinet., Volume: 34 Issue: 1 Pages: 104-109
  • DOI: 10.1016/j.dmpk.2018.09.001
  • NAID: 50014558505
  • Peer Reviewed
• [Journal Article] Novel variants and haplotypes of human flavin-containing monooxygenase 3 (FMO3) gene associated with Japanese subjects suffering from trimethylaminuria. (2019)
  • Author(s): Shimizu, M., Yoda, H., Igarashi, N., Makino, M., Tokuyama, E., and Yamazaki, H.
  • Journal Title: Xenobiotica Volume: - Issue: 10 Pages: 1244-1250
  • DOI: 10.1080/00498254.2018.1539279
  • Peer Reviewed
• [Journal Article] Human plasma concentrations of trimethylamine <i>N</i>-oxide extrapolated using pharmacokinetic modeling based on metabolic profiles of deuterium-labeled trimethylamine in humanized-liver mice (2018)
  • Author(s): Shimizu, M., Suemizu, H., Mizuno, S., Kusama, T., Miura, T., Uehara, S., and Yamazaki, H.
  • Journal Title: The Journal of Toxicological Sciences Volume: 43 Issue: 6 Pages: 387-393
  • DOI: 10.2131/jts.43.387
  • NAID: 130007384444
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed / Open Access
• [Journal Article] Human plasma metabolic profiles of benzydamine, a flavin-containing monooxygenase probe substrate, simulated with pharmacokinetic data from control and humanized-liver mice. (2017)
  • Author(s): Yamazaki-Nishioka M, Shimizu M, Suemizu H, Nishiwaki M, Mitsui M, Yamazaki H.
  • Journal Title: Xenobiotica Volume: 印刷中 Issue: 2 Pages: 117-123
  • DOI: 10.1080/00498254.2017.1288280
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Human plasma and urinary metabolic profiles of trimethylamine and trimethylamine <i>N</i>-oxide extrapolated using a simple physiologically based pharmacokinetic model (2017)
  • Author(s): Shimizu M, Yamazaki H.
  • Journal Title: The Journal of Toxicological Sciences Volume: 42 Issue: 4 Pages: 485-490
  • DOI: 10.2131/jts.42.485
  • NAID: 130005765918
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed / Open Access
• [Journal Article] Marmoset Flavin-Containing Monooxygenase 3 in the Liver Is a Major Benzydamine and Sulindac Sulfide Oxygenase. (2017)
  • Author(s): Uehara, S., Shimizu, M., Uno, Y., Inoue, T., Sasaki, E., and Yamazaki, H.
  • Journal Title: Drug Metab Dispos. Volume: 45 Issue: 5 Pages: 497-500
  • DOI: 10.1124/dmd.117.075184
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Metabolic profiles of pomalidomide in human plasma simulated with pharmacokinetic data in control and humanized-liver mice. (2017)
  • Author(s): Shimizu M, Suemizu H, Mitsui M, Shibata N, Guengerich FP, Yamazaki H.
  • Journal Title: Xenobiotica Volume: 印刷中 Issue: 10 Pages: 844-848
  • DOI: 10.1080/00498254.2016.1247218
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Mutations of flavin-containing monooxygenase 3 (FMO3) gene in Japanese cohorts (2018)
  • Author(s): Makiko Shimizu, Komei Nakakuki, Hiromi Yoda, Masahiro Hiratsuka, and Hiroshi Yamazaki
  • Organizer: 22nd North American ISSX Meeting
  • Int'l Joint Research
• [Presentation] Genetic Polymorphisms of Flavin-containing Monooxygenase 3 Gene in Japanese Cohorts (2018)
  • Author(s): Makiko Shimizu, Komei Nakakuki, Hiromi Yoda, Masahiro Hiratsuka, and Hiroshi Yamazaki
  • Organizer: 2018 International Meeting on 22nd MDO and 33rd JSSX
  • Int'l Joint Research
• [Presentation] Human plasma and urinary metabolic profiles of trimethylamine and its N-oxide extrapolated using humanized-liver mice and simple physiologically based pharmacokinetic models (2018)
  • Author(s): Hiroshi Yamazaki, Hiroshi Suemizu, and Makiko Shimizu
  • Organizer: SOT 57th Annual Meeting and ToxExpo
  • Int'l Joint Research
• [Presentation] 東北メディカル・メガバンク統合データベースより見出された新規フラビン含有モノオキシゲナーゼ3 遺伝子変異の組換え酵素を用いた機能解析 (2018)
  • Author(s): 中莖昂明、清水万紀子、菱沼英史、平塚真弘、山崎浩史
  • Organizer: 日本薬学会第138年会
• [Presentation] ヒト肝細胞移植マウスの薬物血中濃度および生理学的薬物動態モデルを組み合わせたヒト薬物血中濃度推移予測 (2017)
  • Author(s): 三井満里奈、清水万紀子、山崎美穂、末水洋志、山崎浩史
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台国際センター（宮城県、仙台市)
  • Year and Date: 2017-03-25
• [Presentation] 日本人トリメチルアミン尿症の一因となる新規フラビン含有モノオキシゲナーゼ3変異型酵素の触媒機能 (2017)
  • Author(s): 清水万紀子、依田紘美、五十嵐成美、武井まどか、中莖昂明、山崎浩史
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台国際センター（宮城県、仙台市)
  • Year and Date: 2017-03-25
• [Presentation] Metabolic Profiles of Benzydamine in Humanized-liver Mice (2017)
  • Author(s): Makiko Shimizu, Hiroshi Suemizu, and Hiroshi Yamazaki
  • Organizer: 21st North American ISSX Meeting
  • Int'l Joint Research
• [Presentation] フラビン含有酸素添加酵素およびチトクロム P450 の共通基質ベンジダミンのヒト肝移植マウスを用いた in vivo 血中動態予測 (2016)
  • Author(s): 清水万紀子、末水洋志 、三井満里奈、山崎美穂、山崎浩史
  • Organizer: 第37回日本臨床薬理学会学術総会
  • Place of Presentation: 米子コンベンションセンター (鳥取県 米子市）
  • Year and Date: 2016-12-01
• [Presentation] Drug Oxidations Mediated by Polymorphic Flavin-Containing Monooxygenase (2016)
  • Author(s): Shimizu, M., and Yamazaki, H.
  • Organizer: The 21st International Symposium on Microsomes and Drug Oxidations
  • Place of Presentation: USA, California, UC Davis Conference Centre
  • Year and Date: 2016-10-02
  • Int'l Joint Research