Mechanisms underlying clinical drug-drug interactions of antiepileptic drugs

• Project/Area Number: 16K08407
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: University 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: ¥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)
• Keywords: 4β-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。

Research Products

• [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 study (2019)
  • 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
  • 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
  • Peer Reviewed
• [Journal Article] Influence of renal function on pharmacokinetics of antiepileptic drugs metabolized by CYP3A4 in a patient with renal impairment (2018)
  • 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
  • Peer Reviewed
• [Journal Article] Development of phospholipid nanoparticles encapsulating 3-O-cetyl ascorbic acid and tocopherol acetate (TA-Cassome) for improving their skin accumulation (2018)
  • 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
  • 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 clinic (2018)
  • 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
  • Peer Reviewed
• [Journal Article] Influence of cytochrome P450 genotype on the plasma disposition of prochlorperazine metabolites and their relationships with clinical responses in cancer patients (2017)
  • 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
  • Peer Reviewed
• [Journal Article] Therapeutic Drug Monitoring for Perampanel in Japanese Epilepsy Patients (2017)
  • 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
  • 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
  • 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
  • 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
  • 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
• [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
• [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
• [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
• [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
• [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
  • 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
• [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
• [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
• [Presentation] Use of antiepileptic drugs and risk of dyslipidemia: a large-scale cross-sectional study (2016)
  • 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
  • Int'l Joint Research
• [Presentation] Therapeutic monitoring for topiramate in patients with refractory epilepsy (2016)
  • 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
• [Presentation] Inhibitory effect of stiripentol on pharmacokinetics of clobazam in patients with Dravet syndrome (2016)
  • Author(s): Yoshiaki Yamamoto, Yukitoshi Takahashi, Katsumi Imai, Yoshiyuki Kagawa, Yushi Inoue
  • Organizer: American Epirepsy Scoiety Annual Meeting
  • Place of Presentation: Houston, LA, USA
  • 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
• [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
• [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
• [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
• [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/