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Mechanisms underlying clinical drug-drug interactions of antiepileptic drugs

Research Project

Project/Area Number 16K08407
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Medical pharmacy
Research InstitutionUniversity of Shizuoka

Principal Investigator

Kagawa Yoshiyuki  静岡県立大学, 薬学部, 教授 (90397505)

Co-Investigator(Kenkyū-buntansha) 山本 吉章  独立行政法人国立病院機構(静岡・てんかん神経医療センター臨床研究部), その他部局等, その他 (60596245)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords4β-hydroxycholesterol / antiepileptic drug / enzyme induction / CYP3A4 / 抗てんかん薬 / CYP3A / CYP3A4/5 / antiepileptics / drug interaction / 薬物代謝酵素 / 遺伝子多型
Outline of Final Research Achievements

The purpose of this study was to investigate mechanisms underlying drug-drug interactions of antiepileptic drugs in epilepsy patients. We used plasma 4β-hydroxycholesterol(4βOHC)concentration as a probe for the CYP3A activity, Administration of CYP3A inducers, such as carbamazepine or phenytoin, markedly increased plasma 4βOHC concentration up to 3.2-fold of those of non-inducer. Polymorphisms of CYP3A5*3 and POR*28 did not affect plasma 4βOHC concentration. These results indicated that a decrease in plasma concentrations of antiepileptic drugs was caused by the increased activity of CYP3A, but polymorphisms of CYP3A5*3 or POR*28 hardly influenced the CYP3A activity.

Academic Significance and Societal Importance of the Research Achievements

難治性てんかんでは抗てんかん薬の併用が必要となることが多い。これまで臨床的に抗てんかん薬併用時には薬物相互作用があり、併用薬の血中濃度が変動することが知られていた。酵素誘導剤では併用により併用薬の血中濃度低下することが報告されていたが、臨床的にその発現機序については不明であった。本研究では、4β-hydroxycholesterolをプローブとして用いることで、酵素誘導剤とされるカルバマゼピンやフェニトンなどの抗てんかん薬がCYP3A系の酵素活性を増大させることを初めて明らかにした。本研究成果は、難治性てんかんなど抗てんかん薬の併用時における治療効果を高める上で重要と考える。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (27 results)

All 2019 2018 2017 2016 Other

All Journal Article (9 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 9 results,  Acknowledgement Compliant: 1 results) Presentation (13 results) (of which Int'l Joint Research: 4 results) Book (4 results) Remarks (1 results)

  • [Journal Article] Study on the drug permeation mechanism from flurbiprofen-loaded glyceryl monooleyl ether-based lyotropic liquid crystalline nanoparticles across the skin: Synchrotron X-ray diffraction and confocal laser scanning microscopy study2019

    • Author(s)
      Uchino Tomonobu、Kato Sayaka、Hatta Ichiro、Miyazaki Yasunori、Suzuki Tomonori、Sasaki Kohta、Kagawa Yoshiyuki
    • Journal Title

      International Journal of Pharmaceutics

      Volume: 555 Pages: 259-269

    • DOI

      10.1016/j.ijpharm.2018.11.031

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Influence of Inflammation on the Pharmacokinetics of Perampanel.2018

    • Author(s)
      Yamamoto Y, Takahashi Y, Horino A, Usui N, Nishida T, Imai K, Kagawa Y, Inoue Y
    • Journal Title

      Therapeutic Drug Monitoring

      Volume: 40 Issue: 6 Pages: 725-729

    • DOI

      10.1097/ftd.0000000000000556

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Influence of renal function on pharmacokinetics of antiepileptic drugs metabolized by CYP3A4 in a patient with renal impairment2018

    • Author(s)
      Yamamoto Yoshiaki、Usui Naotaka、Nishida Takuji、Mori Miho、Takahashi Yukitoshi、Imai Katsumi、Kagawa Yoshiyuki、Inoue Yushi
    • Journal Title

      Therapeutic Drug Monitoring

      Volume: 40 Issue: 1 Pages: 144-147

    • DOI

      10.1097/ftd.0000000000000461

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Development of phospholipid nanoparticles encapsulating 3-O-cetyl ascorbic acid and tocopherol acetate (TA-Cassome) for improving their skin accumulation2018

    • Author(s)
      Fushimi Tomoka、Uchino Tomonobu、Miyazaki Yasunori、Hatta Ichiro、Asano Miyuki、Fujino Hiyori、Suzuki Rie、Fujimori Shun、Kamiya Daichi、Kagawa Yoshiyuki
    • Journal Title

      International Journal of Pharmaceutics

      Volume: 548 Issue: 1 Pages: 192-205

    • DOI

      10.1016/j.ijpharm.2018.06.030

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Prediction of neutrophil reduction using plasma paclitaxel concentration after administration in patients with uterine, ovarian, or cervical cancers in an outpatient clinic2018

    • Author(s)
      Ishikawa Motoaki、Kawai Michiyasu、Maeda Toshio、Kagawa Yoshiyuki
    • Journal Title

      Cancer Chemotherapy and Pharmacology

      Volume: 81 Issue: 2 Pages: 399-411

    • DOI

      10.1007/s00280-017-3506-3

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Influence of cytochrome P450 genotype on the plasma disposition of prochlorperazine metabolites and their relationships with clinical responses in cancer patients2017

    • Author(s)
      Tashiro Masaki、Naito Takafumi、Kagawa Yoshiyuki、Kawakami Junichi
    • Journal Title

      Annals of Clinical Biochemistry: International Journal of Laboratory Medicine

      Volume: 55 Issue: 3 Pages: 385-393

    • DOI

      10.1177/0004563217731432

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Therapeutic Drug Monitoring for Perampanel in Japanese Epilepsy Patients2017

    • Author(s)
      Yamamoto Yoshiaki、Usui Naotaka、Nishida Takuji、Takahashi Yukitoshi、Imai Katsumi、Kagawa Yoshiyuki、Inoue Yushi
    • Journal Title

      Therapeutic Drug Monitoring

      Volume: 39 Issue: 4 Pages: 446-449

    • DOI

      10.1097/ftd.0000000000000416

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Effect of CYP Inducers/Inhibitors on Topiramate Concentration: Clinical Value of Therapeutic Drug Monitoring.2017

    • Author(s)
      Yamamoto Y, Takahashi Y, Imai K, Kagawa Y, Inoue Y
    • Journal Title

      Ther Drug Monit

      Volume: 39 Issue: 1 Pages: 55-61

    • DOI

      10.1097/ftd.0000000000000367

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Influence of antiepileptic drugs on serum lipid levels in adult epilepsy patients.2016

    • Author(s)
      Yoshiaki Yamamoto, Kiyohito Terada, Yukitoshi Takahashia, Katsumi Imaia, Yoshiyuki Kagawa, Yushi Inoue
    • Journal Title

      Epilepsy Research

      Volume: 127 Pages: 101-106

    • DOI

      10.1016/j.eplepsyres.2016.08.027

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Presentation] Risk factors for hyponatremia in Japanese patients with epilepsy.2018

    • Author(s)
      Yoshiaki Yamamoto, Yukitoshi Takahashi, Katsumi Imai, Yoshiyuki Kagawa, Yushi Inoue
    • Organizer
      13th China-Japan International Symposium on Health Science
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 内因性CYP3A活性を指標とした抗てんかん薬の薬物間相互作用発現様式の解明2018

    • Author(s)
      禾本 大樹、山本 吉章、谷澤 康玄、賀川 義之
    • Organizer
      医療薬学フォーラム2018 第26回クリニカルファーマシーシンポジウム
    • Related Report
      2018 Annual Research Report
  • [Presentation] Drug interaction study among antiepileptic drugs using plasma 4β-hydroxycholesterol as an endogenous biomarker.2018

    • Author(s)
      3.Hiroki Nogimoto, Yoshiaki Yamamoto, Yasuharu Yazawa, Yoshiyuki Kagawa
    • Organizer
      第23回 静岡健康・長寿学術フォーラム
    • Related Report
      2018 Annual Research Report
  • [Presentation] Determination of N-acetylglucosamine concentration in plasma by liquid chromatography tandem mass spectrometry.2018

    • Author(s)
      Satoru Nagumo, Yasuharu Yazawa, Yoshiyuki Kagawa
    • Organizer
      第23回 静岡健康・長寿学術フォーラム
    • Related Report
      2018 Annual Research Report
  • [Presentation] 内因性CYP3A活性指標を用いた抗てんかん薬の薬物間相互作用発現機序の解明2018

    • Author(s)
      賀川義之
    • Organizer
      中部乳酸菌研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Donepezil薬物動態と遺伝子多型との関連性2017

    • Author(s)
      榊原綾海、前田利男、谷澤康玄、山本吉章、小尾智一、賀川義之
    • Organizer
      日本薬学会第137年会
    • Related Report
      2017 Research-status Report
  • [Presentation] Relationship between blood disposition of donepezil and development of BPSD (behavioral and psychological symptom of dementia) in patients with dementia.2017

    • Author(s)
      Yoshiyuki Kagawa, Ayami Sakakibara, Tomokazu Obi, Yoshiaki Yamamoto
    • Organizer
      12th China-Japan International Symposium on Health Sciences
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 認知症患者のQOL改善を目的としたMemantineのPK-PD解析2017

    • Author(s)
      鈴木利昌、山本吉章、小尾智一、石橋由美子、谷澤康玄、賀川義之
    • Organizer
      日本病院薬剤師会東海ブロック・日本薬学会東海支部合同学術大会
    • Related Report
      2017 Research-status Report
  • [Presentation] バルプロ酸の体内動態に及ぼす個体間差要因に関する研究2017

    • Author(s)
      飯塚美帆、石井康子、江川仁美、長江優吾、加藤純、酒井直樹、竹原誠也、池谷延房、中島重紀、賀川義之
    • Organizer
      日本病院薬剤師会東海ブロック・日本薬学会東海支部合同学術大会
    • Related Report
      2017 Research-status Report
  • [Presentation] donepezil薬物動態と遺伝子多型との関連性2017

    • Author(s)
      榊原綾海、山本吉章、小尾智一、前田利男、谷澤康玄、賀川義之
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台市
    • Related Report
      2016 Research-status Report
  • [Presentation] Use of antiepileptic drugs and risk of dyslipidemia: a large-scale cross-sectional study2016

    • Author(s)
      Yoshiaki Yamamoto, Yukitoshi Takahashi, Kiyohito Terada, Katsumi Imai, Yoshiyuki Kagawa, Yushi Inoue
    • Organizer
      11th Asia Oceania Epilepsy Congress
    • Place of Presentation
      Hong Kong, China
    • Year and Date
      2016-05-13
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Therapeutic monitoring for topiramate in patients with refractory epilepsy2016

    • Author(s)
      Yoshiaki Yamamoto, Yukitoshi Takahashi, Katsumi Imai, Yoshiyuki Kagawa, Yushi Inoue
    • Organizer
      第50回日本てんかん学会学術集会
    • Place of Presentation
      静岡
    • Related Report
      2016 Research-status Report
  • [Presentation] Inhibitory effect of stiripentol on pharmacokinetics of clobazam in patients with Dravet syndrome2016

    • Author(s)
      Yoshiaki Yamamoto, Yukitoshi Takahashi, Katsumi Imai, Yoshiyuki Kagawa, Yushi Inoue
    • Organizer
      American Epirepsy Scoiety Annual Meeting
    • Place of Presentation
      Houston, LA, USA
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Book] visual core pharma 薬物治療学2018

    • Author(s)
      吉尾隆, 鍋島俊隆, 賀川義之ほか
    • Total Pages
      891
    • Publisher
      南山堂
    • ISBN
      9784525720582
    • Related Report
      2018 Annual Research Report
  • [Book] visual core pharma 薬物治療学2018

    • Author(s)
      吉尾 隆、鍋島俊隆、渡辺泰裕、早勢伸正、賀川義之、大井一弥、丸山 徹、渡辺朋子、野田幸裕、本屋敏郎、松尾和廣、髙村徳人、唯野貢司、加藤裕芳
    • Total Pages
      891
    • Publisher
      南山堂
    • ISBN
      4525720573
    • Related Report
      2017 Research-status Report
  • [Book] 図解 薬害・副作用学2017

    • Author(s)
      川西正祐、小野秀樹、賀川義之
    • Total Pages
      543
    • Publisher
      南山堂
    • ISBN
      4525720727
    • Related Report
      2017 Research-status Report
  • [Book] 臨床薬理学 第4版2017

    • Author(s)
      一般社団法人 日本臨床薬理学会
    • Total Pages
      456
    • Publisher
      医学書院
    • ISBN
      4260028731
    • Related Report
      2017 Research-status Report
  • [Remarks] 静岡県立大学臨床薬剤学分野ホームページ

    • URL

      http://w3pharm.u-shizuoka-ken.ac.jp/rinyaku/

    • Related Report
      2017 Research-status Report

URL: 

Published: 2016-04-21   Modified: 2020-03-30  

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