The most suitable administration of antidepressive drug to avoid risk of side effects in patient

• Project/Area Number: 24590211
• 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: MURAYAMA Norie 昭和薬科大学, 薬学部, 講師 (90219949)
• Co-Investigator(Kenkyū-buntansha): YAMAZAKI Hiroshi 昭和薬科大学, 薬学部, 教授 (30191274) ; SHIMIZU Makiko 昭和薬科大学, 薬学部, 講師 (90307075)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: P450 / 向精神薬 / 相互作用 / 酵素誘導 / 遺伝子多型 / CYP3A5 / 薬物代謝酵素 / CYP2D6 / HepaRG / 抗精神薬 / P4503A4*22 / アレル頻度 / 抗うつ薬 / アルツハイマー治療薬 / HPLC / P4502D6

Outline of Final Research Achievements

The plasma concentrations of mirtzapine in patients are influenced by many factors, such as polymorphic cytochrome P450 enzymes contributing to its transformation to the metabolites.The aim of this study was to investigate the determinant factors for individual variations of metabolic clearance of mirtazapine using in vitro and in vivo methods. The plasma concentration/dose ratios of mirtazapine from 14 patients were significantly higher in the CYP2D6 IM/PM group than in the EM group and were also higher in the CYP3A5 poor-expressors group than in the expressors group (p<0.05). In vitro, mirtazapine 8-hydroxylation activities in individual liver microsomes were significantly lower in CYP2D6 intermediate metabolizers (IM) and poor metabolizers (PM) than in extensive metabolizers (EM) (p<0.05).These results suggested that mirtazapine metabolic clearance could be variously influenced by the CYP2D6 and CYP3A5 genotypes and coadministered drugs in clinical patients.

Research Products

• [Journal Article] Effects of cytochrome P450 2D6 and 3A5 genotypes and possible coadministered medicines on the metabolic clearance of antidepressant mirtazapine in Japanese patients. (2015)
  • Author(s): Okubo M, Murayama N, Miura J, Chiba Y, Yamazaki H.
  • Journal Title: Biochem Pharmacol. Volume: 93 Issue: 1 Pages: 104-109
  • DOI: 10.1016/j.bcp.2014.11.011
  • Peer Reviewed / Open Access
• [Journal Article] Human HepaRG Cells can be Cultured in Hanging-Drop Plates for Cytochrome P450 Induction and Function Assays. (2015)
  • Author(s): Murayama N, Usui T, Slawny N, Chesne; C, Yamazaki H.
  • Journal Title: Drug Metab Lett Volume: 42 Issue: 9 Pages: 111-112
  • DOI: 10.1124/dmd.114.059220
  • Peer Reviewed / Open Access
• [Journal Article] Regioselective hydroxylation of steroid hormones by human cytochromes P450. (2015)
  • Author(s): Niwa T, Murayama N, Imagawa Y, Yamazaki H.
  • Journal Title: Drug Metab Rev. Volume: 13 Pages: 1-22
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of 23 lots of commercially available cryopreserved hepatocytes for induction assays of human cytochromes p450 (2014)
  • Author(s): Yajima K, Uno Y, Murayama N, Uehara S, Shimizu M, Nakamura C, Iwasaki K, Utoh M, Yamazaki H
  • Journal Title: Drug Metab Dispos. Volume: 42 Issue: 5 Pages: 867-871
  • DOI: 10.1124/dmd.113.056804
  • Peer Reviewed
• [Journal Article] Thalidomide increases human hepatic cytochrome P450 3A enzymes by direct activation of pregnane X receptor (2014)
  • Author(s): Murayama, N., van Beuningen, R., Suemizu, H., Guguen-Guillouzo, C., Shibata, N., Yajima, K., Utoh, M., Shimizu, M., Chesne, C., Nakamura, M., Guengerich, F. P., Houtman, R., and Yamazaki, H
  • Journal Title: Chem.Res.Toxicol Volume: 27 Issue: 2 Pages: 304-307
  • DOI: 10.1021/tx4004374
  • Peer Reviewed
• [Journal Article] Metabolic activation of polycyclic aromatic hydrocarbons and aryl and heterocyclic amines by human cytochromes P450 2A13 and 2A6 (2013)
  • Author(s): Shimada T, Murayama N, Yamazaki H, Tanaka K, Takenaka S, Komori M, Kim D, Guengerich FP
  • Journal Title: Chem Res Toxicol. Volume: 26 Issue: 4 Pages: 529-537
  • DOI: 10.1021/tx3004906
  • Peer Reviewed
• [Journal Article] CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) is associated with reduced CYP3A4 protein level and function in human liver microsomes (2013)
  • Author(s): Okubo M, Murayama N, Shimizu M, Shimada T, Guengerich FP, Yamazaki H
  • Journal Title: J Toxicol Sci. Volume: 38 Pages: 349-354
  • NAID: 10031158900
  • Peer Reviewed
• [Journal Article] Monkey liver cytochrome P450 2C9 is involved in caffeine 7-N-demethylation to form theophylline (2013)
  • Author(s): Utoh M, Murayama N, Uno Y, Onose Y, Hosaka S, Fujino H, Shimizu M, Iwasaki K, Yamazaki H
  • Journal Title: Xenobiotica Volume: 43 Issue: 12 Pages: 1037-1042
  • DOI: 10.3109/00498254.2013.793874
  • Peer Reviewed
• [Journal Article] Characterization of microsomal glutathione S-transferases MGST1, MGST2, and MGST3 in cynomolgus macaque (2013)
  • Author(s): Uno Y, Murayama N, Kunori M, Yamazaki H.
  • Journal Title: Drug Metab Dispos. Volume: 41 Issue: 9 Pages: 1621-1625
  • DOI: 10.1124/dmd.113.052977
  • Peer Reviewed
• [Journal Article] Systematic identification and characterization of glutathione S-transferases in cynomolgus macaque (2013)
  • Author(s): Uno Y, Murayama N, Kunori M, Yamazaki H
  • Journal Title: Biochem Pharmacol. Volume: 86 Issue: 5 Pages: 679-690
  • DOI: 10.1016/j.bcp.2013.06.022
  • Peer Reviewed
• [Journal Article] In vivo drug interactions of the teratogen thalidomide with midazolam: Heterotropic cooperativity of human cytochrome P450 in humanized TK-NOG mice (2013)
  • Author(s): Yamazaki, H., Suemizu, H., Murayama, N., Utoh, M., Shibata, N., Nakamura, M., and Guengerich, F. P.
  • Journal Title: Chem.Res.Toxicol. Volume: 26 Issue: 3 Pages: 486-489
  • DOI: 10.1021/tx400008g
  • Peer Reviewed
• [Journal Article] <i>CYP2C76</i> Non-synonymous Variants in Cynomolgus and Rhesus Macaques (2012)
  • Author(s): Uehara S, Murayama N, Yamazaki H, Uno Y
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 27 Issue: 3 Pages: 344-348
  • DOI: 10.2133/dmpk.DMPK-11-NT-118
  • NAID: 130004463249
  • ISSN: 1347-4367, 1880-0920
  • Peer Reviewed
• [Journal Article] A rapid multiplex PCR assay that can reliably discriminate the cytochrome P450 2D6 whole-gene deletion allele from 2D6*10 alleles. (2012)
  • Author(s): Okubo, M., Murayama, N., Miura, J., Shimizu, M., and Yamazakik, H
  • Journal Title: Clinica Chimica Acta Volume: 413 Issue: 19-20 Pages: 1675-1677
  • DOI: 10.1016/j.cca.2012.05.013
  • Peer Reviewed
• [Journal Article] Monkey liver cytochrome P450 2C19 is involved in R- and S-warfarin 7-hydroxylation (2012)
  • Author(s): Hosoi, Y., Uno, Y., Murayama, N., Fujino, H., Shukuya, M., Iwasaki, K., Shimizu, M., Utoh, M., and Yamazaki, H.
  • Journal Title: Biochem. Pharmacol. Volume: 84 Issue: 12 Pages: 1691-1695
  • DOI: 10.1016/j.bcp.2012.09.026
  • Peer Reviewed
• [Journal Article] Simultaneous pharmacokinetics assessment of caffeine, warfarin, omeprazole, metoprolol, and midazolam intravenously or orally administered to Microminipigs. (2012)
  • Author(s): Mogi M, Toda A, Iwasaki K, Kusumoto S, Takehara H, Shimizu M, Murayama N, Izumi H, Utoh M, Yamazaki H.
  • Journal Title: J Toxicol Sci. Volume: 37 Pages: 1157-116
  • NAID: 10031126020
  • Peer Reviewed
• [Journal Article] Binding of Diverse Environmental Chemicals with Human Cytochromes P450 2A13, 2A6, and 1B1 and Enzyme Inhibition (2012)
  • Author(s): Shimada T, Kim D, Murayama N, Tanaka K, Takenaka S, Nagy LD, Folkman LM, Foroozesh MK, Komori M, Yamazaki H, Guengerich FP
  • Journal Title: Chem Res Toxicol. Volume: 26 Issue: 4 Pages: 517-523
  • DOI: 10.1021/tx300492j
  • Peer Reviewed
• [Presentation] 抗精神病薬リスペリドン投与日本人患者における血漿中薬物濃度の個人差 (2015)
  • Author(s): ○大久保真穂1、村山典恵1、森田翔子1、森亜沙美1、倉林優貴1、秋元洋一2、後藤晶子2、山崎浩史
  • Organizer: 日本薬学会第135 回年会
  • Place of Presentation: 神戸学院大学,兵庫医療大学(神戸市）
  • Year and Date: 2015-03-25 – 2015-03-29
• [Presentation] 抗精神病薬オランザピン投与日本人患者における血漿中薬物濃度の個人差 (2015)
  • Author(s): 大久保真穂、成田桃子、村山典恵、森田翔子、中村浩也、清水万紀子、秋元洋一、後藤晶子、○山崎浩史
  • Organizer: 日本薬学会第135 回年会
  • Place of Presentation: 神戸学院大学,兵庫医療大学(神戸市）
  • Year and Date: 2015-03-25 – 2015-03-29
• [Presentation] サリドマイドによるヒトP450酵素自己誘導機構の要因 (2015)
  • Author(s): ○村山典恵、矢島加奈子、柴田哲男、鵜藤雅裕、山崎浩史
  • Organizer: 日本薬学会第135 回年会
  • Place of Presentation: 神戸学院大学、兵庫医療大学(神戸市）
  • Year and Date: 2015-03-25 – 2015-03-29
• [Presentation] Roles of Auto-Induction of Human P450 3A Enzymes Involved in The Teratogenicity of Thalidomide (2014)
  • Author(s): ○Norie Murayama, Hiroshi Suemizu , Christophe Chesné, Norio Shibata,F. Peter Guengerich, Hiroshi Yamazaki
  • Organizer: 19th North American ISSX Meeting / 29th JSSX Meeting
  • Place of Presentation: Hilton San Francisco, San Francisco, California, USA
  • Year and Date: 2014-10-19 – 2014-10-23
• [Presentation] Effects of CYP2D6 and CYP3A5 genotypes and co-administrated drugs on the metabolic clearance of antidepressant mirtazapine (2014)
  • Author(s): ○Maho Okubo, Norie Murayama, Jun Miura, Yasuji Chiba and Hiroshi Yamazaki
  • Organizer: 19th North American ISSX Meeting / 29th JSSX Meeting
  • Place of Presentation: Hilton San Francisco, San Francisco, California, USA
  • Year and Date: 2014-10-19 – 2014-10-23
• [Presentation] サリドマイドは核内レセプターを介してヒト肝薬物代謝酵素を誘導する (2014)
  • Author(s): 村山典恵、矢島加奈子、Christophe Chesné、Rene Houtman、山崎浩史
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本大学 黒髪キャンパス、他 （熊本市）
• [Presentation] 抗うつ薬ミルタザピンの代謝消失に影響を与える因子 (2014)
  • Author(s): 大久保真穂、村山典恵、三浦淳、千葉泰二、山崎浩史
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本大学 黒髪キャンパス、他 （熊本市）
• [Presentation] Function of Thalidomide for Potential Inducer of Drug Metabolizing Enzymes in Human Livers (2013)
  • Author(s): Norie Murayama, Hiroshi Suemizu, Kanako Yajima, Masahiro Utoh, Christiane Guguen-Guillouzo, Christophe Chesné, René Houtman, Rinie van Beuningen, Norio Shibata, Masato Nakamura, and Hiroshi Yamazaki
  • Organizer: 10th International ISSX Meeting
  • Place of Presentation: Westin Harbour Castle Hotel (Tronto, Canada)
• [Presentation] Function of Thalidomide for Potential Inducer of Drug Metabolizing Enzymes in Human Livers (2013)
  • Author(s): Norie Murayama, Hiroshi Suemizu, Kanako Yajima, Masahiro Utoh, Masato Nakamura, and Hiroshi Yamazaki
  • Organizer: 28th JSSX Annual Metting
  • Place of Presentation: タワーホール船堀 （江戸川区）
• [Presentation] ヒト及びサル肝P450に認められるワルファリン代謝の立体選択性 (2013)
  • Author(s): 村山典恵、宇野泰広、細井祥生、岩崎一秀、清水万紀子、鵜藤雅裕、山崎浩史
  • Organizer: 日本学学会第133年会
  • Place of Presentation: パシフィコ横浜(神奈川)
• [Presentation] P4503A4タンパク発現量および薬物代謝酵素活性におよぼすCYP3A4:22遺伝子多型の影響 (2013)
  • Author(s): 大久保真穂、村山典恵、清水万紀子、山崎浩史
  • Organizer: 日本学学会第133年会
  • Place of Presentation: パシフィコ横浜(神奈川)
• [Presentation] Induction of cytochrome P450 3A enzymes by thalidomide in human hepatic cells (2012)
  • Author(s): Norie Murayama, Kanako Yajima Masahiro Utho, and Hiroshi Yamazaki
  • Organizer: JSSX
  • Place of Presentation: タワーホール船堀(千葉)
• [Remarks] 昭和薬科大学薬物動態学研究室
  • URL: http://www.shoyaku.ac.jp/labosite/doutai/index.html
• [Remarks] 薬物動態学研究室
  • URL: http://www.shoyaku.ac.jp/labosite/doutai/index.html
• [Remarks] 昭和薬科大学薬物動態学研究室
  • URL: http://www.shoyaku.ac.jp/labosite/doutai/2011/04/post.html