Blood-brain barrier transport of opioid agonists mediated by organic cation-sensitive transporter

• Project/Area Number: 19790136
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Medical pharmacy
• Research Institution: Teikyo University
• Principal Investigator: OKURA Takashi Teikyo University, 薬学部, 講師 (80326123)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥3,780,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥480,000); Fiscal Year 2008: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2007: ¥1,700,000 (Direct Cost: ¥1,700,000)
• Keywords: 薬物動態学 / PMAT / 血液脳関門 / モノアミン / オキシコン / トランスポーター / 鎮痛補助薬 / アミトリプチリン / 相互作用 / オキシコドン / 脳関門

Research Abstract

研究成果の概要:麻薬性鎮痛薬であるオキシコドンは、特殊なトランスポーター(運び屋タンパク質)によって脳内へ運ばれ、鎮痛作用を発揮することが示された。このトランスポーター分子を探索したところ、血液と脳の間の関門に、新たなトランスポーターを発見した。このトランスポーターは薬物のみでなく、セロトニンなどの神経伝達物質を脳から血液に汲み出すことにより、脳内の神経伝達物質の濃度を調節すると考えられた。研究成果の概要:麻薬性鎮痛薬であるオキシコドンは、特殊なトランスポーター(運び屋タンパク質)によって脳内へ運ばれ、鎮痛作用を発揮することが示された。このトランスポーター分子を探索したところ、血液と脳の間の関門に、新たなトランスポーターを発見した。このトランスポーターは薬物のみでなく、セロトニンなどの神経伝達物質を脳から血液に汲み出すことにより、脳内の神経伝達物質の濃度を調節すると考えられた。

Research Products

• [Journal Article] Effects of quinidine on antinociception and pharmacokinetics of morphine in rats (2009)
  • Author(s): Takashi Okura, Yuki Morita, Yoshihiko Ito, Yoshiyuki Kagawa, Shizuo Yamada
  • Journal Title: J. Pharm. Pharmacol 61 Pages: 593-597
  • Peer Reviewed
• [Journal Article] Effects of quinidine on antinociception and pharmacokinetics of morphine in rats (2009)
  • Author(s): Takashi Okura, et.al.
  • Journal Title: J. Pharm. Pharmacol (印刷中)
  • Peer Reviewed
• [Journal Article] Enhancement by grapefruit juice of morphine antinociception (2008)
  • Author(s): Takashi Okura, Tadahiro Ozawa, Yoshihiko Ito, Midori Kimura, Yoshiyuki Kagawa, Shizuo Yamada
  • Journal Title: Biol. Pharm. Bull 31 Pages: 2338-2341
  • Peer Reviewed
• [Journal Article] Involvement of the pyrilamine transporter, a putative organic cation transporter, in blood-brain barrier transport of oxycodone (2008)
  • Author(s): Takashi Okura, Asami Hattori, Yusuke Takano, Takenori Sato, Margareta Hammarlund- Udenaes, Tetsuya Terasaki, Yoshiharu Deguchi
  • Journal Title: Drug Metab. Dispos 36 Pages: 2005-2013
  • Peer Reviewed
• [Journal Article] Involvement of the pyrilamine transporter, a putative organic cation transporter, in blood-brain barrier transport of oxvcodone (2008)
  • Author(s): Takashi Okura, et.al.
  • Journal Title: Drug Metab. Dispos 36 Pages: 2005-2013
  • Peer Reviewed
• [Journal Article] Enhancement by grapefruit juice of morphine antinociception (2008)
  • Author(s): Takashi Okura, et.al.
  • Journal Title: Biol. Pharm. Bull 31 Pages: 2338-2341
  • Peer Reviewed
• [Journal Article] Prediction of α1-adrenoceptor occupancy in the human prostate from plasma concentrations of silodosin, tamsulosin and terazosin to treat urinary obstruction in benign prostatic hyperplasia (2007)
  • Author(s): Ohkura, Yoshiyuki Kagawa, Kazuki Kawabe
  • Journal Title: Biol. Pharm. Bull 30 Pages: 1237-1241
  • Peer Reviewed
• [Journal Article] Prediction of α_1-adrenoceptor occupancy in the human prostate from plasma concentrations of silodosin, tamsulosin and terazosin to treat urinary obstruction in benign prostatic hyperplasia. (2007)
  • Author(s): Shizuo, Yamada・Takashi, Okura, et. al.
  • Journal Title: Biol. Pharm. Bull. 30 Pages: 1237-1241
  • Peer Reviewed
• [Presentation] The pyrilamine transporter functions as the multispecific organic cation transporter at the blood-brain barrier (2008)
  • Author(s): Takashi Okura, Keita Shimomura, Sayaka Kato, Margareta Hummarlund-Udenaes, Tetsuya Terasaki, Yoshiharu Deguchi
  • Organizer: 第23回日本薬物動態学会年会
  • Place of Presentation: 熊本
  • Year and Date: 2008-10-31
• [Presentation] Expression and functional characterization of plasma membrane monoamine transporter (PMAT) in the rat blood-brain barrier (2008)
  • Author(s): Takenori Sato, Sayaka Kato, Takashi Okura, Sumio Ohtsuki, Tetsuya Terasaki, Yoshiharu Deguchi
  • Organizer: 第23回日本薬物動態学会年会
  • Place of Presentation: 熊本
  • Year and Date: 2008-10-31
• [Presentation] Plasma membrane monoamine transporter (PMAT) mediates the efflux t ransport of organic cations in the brain barrier system (2008)
  • Author(s): Takenori Sato, Takashi Okura, et.al.
  • Organizer: 第23回日本薬物動態学会年会
  • Place of Presentation: 熊本
  • Year and Date: 2008-10-31
• [Presentation] Blood-brain barrier transport and pharmacological effect of opioids (2008)
  • Author(s): Takashi Okura, Asami Hattori, Yusuke Takano, Takenori Sato, Margareta Hammarlund-Udenaes, Tetsuya Terasaki, Yoshiharu Deguchi
  • Organizer: 11th International Symposium on Signal Transduction in the Blood-Brain Barrier
  • Place of Presentation: Amsterdam
  • Year and Date: 2008-09-20
• [Presentation] Expression and functional characterization of plasma membrane monoamine transporter (PMAT) in therat blood-brain barrier (2008)
  • Author(s): Yoshiharu Deguchi, Takashi Okura, Yusuke Takano, Takenori Sato, Atsushi Yamashita, Sumio Ohtsuki, Tetsuya Terasaki
  • Organizer: 11th International Symposium on Signal Transduction in the Blood-Brain Barrier
  • Place of Presentation: Amsterdam
  • Year and Date: 2008-09-20
• [Presentation] Blood-brain barrier transport and pharmacological effect of opioids (2008)
  • Author(s): Takashi Okura, et.al.
  • Organizer: 11^<th> International Symposium on Signal Transduction in the Blood-Brain Barrier
  • Place of Presentation: オランダ・アムステルダム
  • Year and Date: 2008-09-20
• [Presentation] Expression and functional characterization of plasma membrane monoamine transporter (PMAT) in the rat blood-brain barrier (2008)
  • Author(s): Yoshiharu Deguchi, Takashi Okura, et.al.
  • Organizer: 11^<th> International Symposium on Signal Transduction in the Blood-Brain Barrier
  • Place of Presentation: オランダ・アムステルダム
  • Year and Date: 2008-09-20
• [Presentation] カチオントランスポーターPMATの脳関門における発現と輸送機能解析 (2008)
  • Author(s): 佐藤武則、黄倉 崇、高野祐輔、山下 純、寺崎哲也、出口芳春
  • Organizer: 日本薬剤学会第23年会
  • Place of Presentation: 札幌
  • Year and Date: 2008-05-20
• [Presentation] Blood-brain barrier transport of cationic drugs (2007)
  • Author(s): Takashi Okura
  • Organizer: APSTJ Global Education Seminar
  • Place of Presentation: Tokyo
  • Year and Date: 2007-09-14
• [Presentation] Blood-brain barrier transport of cationic drugs (2007)
  • Author(s): Takashi, Okura
  • Organizer: APSTJ Global Education Seminar 2007
  • Place of Presentation: 東京
  • Year and Date: 2007-09-14
• [Presentation] 麻薬性鎮痛薬オキシコドンと鎮痛補助薬の相互作用解析 (2007)
  • Author(s): 黄倉 崇、中澤佑介、服部麻美、寺崎哲也、出口芳春
  • Organizer: 日本薬剤学会第22年会
  • Place of Presentation: 大宮
  • Year and Date: 2007-05-23
• [Presentation] Expression and transport function of rat plasma membrane transporter (rPMAT) in the brain barrier system (2007)
  • Author(s): 黄倉 崇、高野祐輔、佐藤武則、山下 純、大槻純男、寺崎哲也、出口芳春
  • Organizer: 第29回生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 仙台
• [Presentation] Drug-drug interactions between oxycodone and adjuvant analgesics at the blood-brain barrier (2007)
  • Author(s): Takashi Okura, Yusuke Nakazawa, Asami Hattori, Tetsuya Terasaki, Yoshiharu Deguchi
  • Organizer: 8th International ISSX Meeting
  • Place of Presentation: Sendai
• [Presentation] Blood-brain barrier transport of oxycodone, an opioid receptor agonist (2007)
  • Author(s): Asami Hattori, Takashi Okura, Yusuke Nakazawa, Margareta Hammarlund-Udenaes, Tetsuya Terasaki, Yoshiharu Deguchi
  • Organizer: The 5th International Symposium on Membrane Receptors, Signal Transduction and Drug Action
  • Place of Presentation: Shizuoka
• [Presentation] Blood-brain barrier transport of oxycodone, and opiooid receptor agonist (2007)
  • Author(s): Y, Deguchi, ・T, Okura, et. al.
  • Organizer: The 5th International Symposium on Membrane Receptors, Signal Transduction and Drug Action
  • Place of Presentation: 静岡
• [Presentation] Drug-drug interactions between oxycodone and adjuvant analgesics at the blood-brain barrier (2007)
  • Author(s): Takashi, Okura, et. al.
  • Organizer: 8th International ISSX Meeting
  • Place of Presentation: 仙台
• [Presentation] 脳冠門におけるrat plasma membrane transporter (rPMAT)の発現と輸送機能 (2007)
  • Author(s): 黄倉 崇, 他
  • Organizer: 第29回生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 仙台