Studies on the urinary assay of CYP-mediated endogenous corticosteroid metabolites with a LC-MS method

• Project/Area Number: 18590542
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Meiji Pharmaceutical University
• Principal Investigator: ECHIZEN Hirotoshi Meiji Pharmaceutical University, 薬学部, 教授 (00191924)
• Co-Investigator(Kenkyū-buntansha): OHNISHI Akihiro 東京慈恵会医科大学, 医学部, 助教授 (00194225)
• Project Period (FY): 2006 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥4,360,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥660,000); Fiscal Year 2009: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2008: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
• Keywords: 薬物代謝 / 個人差 / ステロイドホルモン / LC-MS / ステロイド

Research Abstract

Interindividual variability of the drug metabolizing enzyme activity is associated with those of drug responses and adverse drug reactions. Recent advances in molecular biology have made it possible to account for a part of interindividual variability of important drug metabolizing enzymes, particularly cytochrome P-450s (CYPs) in the light of pharmacogenomics. Nevertheless, it has also become evident that a large interindividual variability still exists in subjects or patients having none of the previously known loss-of-function SNPs in the respective CYP isoforms. Thus, there is a surge of interest to reappraise for assessing CYP isoform activity as phenotype individually. We have previously reported that in vivo CYP3A4 activity may be assessed by urinary excretion of 6β-hydroxycortisol, a CYP3A4 metabolite of adrenal cortisol, or its metabolic ratio of cortisol. In order to extend this idea to other steroid hormones which are thought to be metabolized by different CYP isoforms, we aimed to establish a comprehensive assay method using HPLC-UV and LC-MS. We have established a simultaneous assay method for urinary 2- and 4-hydroxyestradiol and 17-hydroxyprogesterone, of which metabolism are associated with CYP1A2 and CYP2C19, respectively, with an HPLC-UV method as a preliminary study. We found that there is a large interindividual variability in the urinary excretion of those sex steroid metabolites, indicating that there is a good chance to measure interindividual variability of the these CYP activities. Then, we advanced our study to establish a LC-MS method. We consider that this method would be useful for a population study where a large number of clinical samples are to be assayed.

Research Products

• [Journal Article] Urinary Lipocalin-Type Prostaglandin D Synthase : A Potential Marker for Early Gentamicin-Induced Renal Damage? (2009)
  • Author(s): Nakayama H, Echizen H, et al.
  • Journal Title: Ther Drug Monit 32 Pages: 126-130
  • Peer Reviewed
• [Journal Article] A Novel Microsatellite Polymorphism of Sodium Channel β1-Subunit Gene(SCN1B)May Underlie Abnormal Cardiac Excitation Manifested by Coved-type ST-elevation Compatible With Brugada Syndrome in Japanese (2009)
  • Author(s): Ogawa R, Kishi R, Takagi A, Sakaue I, Takahashi H, Matsumoto N, Echizen H
  • Journal Title: Int J Clin Pharmacol Ther 48 Pages: 109-119
  • Peer Reviewed
• [Journal Article] Urinary Lipocalin Type Prosta- glandin D Synthase : A Potential Marker for Early Gentamicin-Induced Renal Damage? (2009)
  • Author(s): Nakayama H, Echizen H, Gomi T, Shibuya Y, Nakamura Y, Nakano K, Arashi H, Ohnishi S, Tanaka M, Orii T
  • Journal Title: Ther Drug Monit 32 Pages: 126-130
  • Peer Reviewed
• [Journal Article] Urinary Lipocalin-Type Prostaglandin D Synthase : A Potential Marker for Early Gentamicin-Induced Renal Damage? (2009)
  • Author(s): Nakayama H, Echizen H, Gomi T, Shibuya Y, Nakamura Y, Nakano K, Arashi H, Ohnishi S, Tanaka M, Orii T
  • Journal Title: Ther Drug Monit 32 Pages: 126-130
  • Peer Reviewed
• [Journal Article] Reduced vancomycin clearance despite unchanged creatinine clearance in patients treated with vancomycin for longer than 4 weeks (2008)
  • Author(s): Nakayama H, Echizen H, Tanaka M, Sato M, Orii T
  • Journal Title: Ther Drug Monit 30 Pages: 103-107
  • Peer Reviewed
• [Journal Article] Bioequivalence studies between 0.5, 1, and 5 mg warfarin potassium tablets of new formula and those of standard formula (2008)
  • Author(s): Dochiguchi Y, Shiba S, Masuda Y, Kurihara Y, Hasegawa S, Echizen H
  • Journal Title: Jpn Pharmacol Ther 36 Pages: 401-409
  • Peer Reviewed
• [Journal Article] Proteomic & Transcriptomic Analyses of Retinal Pigment Epithelial Cells Exposed t-o REF-1/TFPI-2, a Growth Promoting Factor (2007)
  • Author(s): Shibuya M, Okamoto H, Nozawa T, Utsumi J, Reddy VN, Echizen H, Tanaka Y, Iwata T.
  • Journal Title: Invest Ophthalmol Vis Sci 48 Pages: 516-521
  • Peer Reviewed
• [Journal Article] A meta-analysis on the risk of developing malignancy associated with use of immunosuppressive agents in patients with inflammatory bowel disease (2007)
  • Author(s): Masunaga Y, Ohno K, Ogawa R, Hashiguchi M, Echizen H, Ogata H
  • Journal Title: Ann Pharmacother 41 Pages: 21-28
  • Peer Reviewed
• [Journal Article] Effect of low-dose macrolide antibiotics on theophylline disposition in pediatric patients (2007)
  • Author(s): Abe Y, Nanri Y, Oto H, Kitabayashi T, Watanabe S, Odajima Y, Itabashi K, Takahashi H, Echizen H
  • Journal Title: 日本小児呼吸器疾患学会誌 18 Pages: 7-13
  • NAID: 10019544744
  • Peer Reviewed
• [Journal Article] Proteomic & Transcriptomic Analyses of Retinal Pigment Epithelial Cells Exposed t-o REF-1/TFPI-2,a Growth Promoting Factor (2007)
  • Author(s): Shibuya M, Okamoto H, Nozawa T, Utsumi J, Reddy VN, Echizen H, Tanaka Y, Iwata T.
  • Journal Title: Invest Ophthalmol Vis Sci 48 Pages: 516-521
  • Peer Reviewed
• [Journal Article] A meta-analysis on the risk of developing malignancy associated with use of immunosunnressive agents in natients with inflammatory bowel disease (2007)
  • Author(s): Masunaga Y, Ohno K, Ogawa R, Hashiguchi M, Echizen H, Ogata H
  • Journal Title: Ann Pharmacother 41 Pages: 21-28
  • Peer Reviewed
• [Journal Article] Effect of low-dose macrolide antibiotics on the ophylline disposition in pediatric patlents (2007)
  • Author(s): Abe Y, Nanri Y, Oto H, Kitabayashi T, Watanabe S, Odajima Y, Itabashi K, Takahashi H, Echizen H
  • Journal Title: 日本小児呼吸器疾患学会誌 18 Pages: 7-13
  • Peer Reviewed
• [Journal Article] Proteomic ＆ Transcriptomic Analyses of Retinal Pigment Epithelial Cells Exposed to REF-1/TFPI-2, a Growth Promoting Factor (2007)
  • Author(s): Shibuya M, Okamoto H, Nozawa T, Utsumi J, Reddy VN, Echizen H, Tanaka Y, Iwata T.
  • Journal Title: Invest Ophthalmol Vis Sci 48 Pages: 516-521
• [Journal Article] Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra-and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African Americans. (2006)
  • Author(s): Takahashi, H, Wilkinson, GR, Nutescu, EA, Morita, T, Ritchie, M, Scordo, MG, Pengo, V, Barban, M, Padrini, R, Ieiri I, Otsubo, K, Kashima T, Kimura S, Kijima S, Echizen H
  • Journal Title: Pharmacogenetics & Genomics 16 Pages: 101-110
• [Journal Article] Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African Americans (2006)
  • Author(s): Takahashi, H, Wilkinson, GR, Nutescu, EA, Morita, T, Ritchie, M, Scordo, MG, Pengo, V, Barban, M, Padrini, R, Ieiri I, Otsubo, K, Kashima T, Kimura S, Kijima S, Echizen H
  • Journal Title: Pharmacogenetics &amp ; Genomics 16 Pages: 101-110
  • Peer Reviewed
• [Journal Article] Population Pharmacokinetic and Pharmacodynamic Analysis of a Class IC Antiarrhythmic, Pilsicainide, in Patients with Cardiac Arrhythmias (2006)
  • Author(s): Ogawa, R, Kishi, R, Mihara, K, Takahashi, H, Takagi, A, Matsumoto, N, Masuhara, K, Nakazawa, K, Miyake, F, Kobayashi, S, Echizen, H.
  • Journal Title: J Clin Pharmaol 46 Pages: 59-68
  • Peer Reviewed
• [Journal Article] Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African Americans (2006)
  • Author(s): Takahashi, H, Wilkinson, GR, Nutescu, EA, Morita, T, Ritchie, M, Scordo, MG, Pengo, V, Barban, M, Padrini, R, Ieiri I, Otsubo, K, Kashima T, Kimura S, Kijima S, Echizen H
  • Journal Title: Pharmacogenetics ＆ Genomics 16 Pages: 101-110
• [Journal Article] Population Pharmacokinetic and Pharmacodynamic Analysis of a Class IC Antiarrhythmic, Pilsicainide, in Patients with Cardiac Arrhythmias. (2006)
  • Author(s): Ogawa, R, Kishi, R, Mihara, K, Takahashi, H, Takaga, A, Matsumoto, N, Masuhara, K, Nakazawa, K, Miyake, F, Kobayashi, S, Echizen,H.
  • Journal Title: J Clin Pharmaol 46 Pages: 59-68
• [Journal Article] 個別化されたワルファリン療法への道 (2006)
  • Author(s): 越前宏俊
  • Journal Title: 日本血栓止血学会誌 17 Pages: 430-433
• [Journal Article] CYPの遺伝多型と抗不整脈薬 (2006)
  • Author(s): 越前宏俊
  • Journal Title: Jpn J Electrocardiol 26 Pages: 195-200
  • NAID: 10019171937
• [Presentation] 白癬患者に対するイトラコナゾールパルス療法施行時のCYP3A活性の経時的変化 (2009)
  • Author(s): 柴田壮一、高橋晴美、小野紀子、和田直子、久保博昭、篠崎公一、齋藤京、稲本伸子、越前宏俊、厚田幸一郎
  • Organizer: 日本臨床薬理学会第30回年会
  • Place of Presentation: 横浜
• [Presentation] 内因性N^-メチルニコチンアミドおよびL^-カルニチンによる腎尿細管トランスポーター活性評価の試み (2008)
  • Author(s): 小川竜一、越前宏俊
  • Organizer: 医療薬学フォーラム2008
  • Place of Presentation: 東京
  • Year and Date: 2008-07-10
• [Presentation] 内因性N^1-メチルニコチンアミドの腎クリアランスによる腎有機カチオントランスポーター活性の評価 (2007)
  • Author(s): 小川竜一、越前宏俊
  • Organizer: 第28回日本臨床薬理学会年会
  • Place of Presentation: 宇都宮
  • Year and Date: 2007-11-12
• [Presentation] Population differences in the contribution of genetic polymolphism of phamlacoki netics/phaarmacodynamics toward drug response (2007)
  • Author(s): Echizen H
  • Organizer: 4th World Conference on Drug Absorption, Transport and Delivery
  • Place of Presentation: Kanazawa
  • Year and Date: 2007-06-21
• [Book] 医療薬物代謝学 (2010)
  • Author(s): 越前宏俊
  • Publisher: 医学評論社
• [Book] 医療薬物代謝学 (2009)
  • Author(s): 越前宏俊(分担執筆)
  • Total Pages: 187
  • Publisher: 医学評論社
• [Book] 最新創薬学2007臨床薬物動態の実戦-トランスレーショナルPKIPD研究:ワルファリン (2007)
  • Author(s): 高橋 晴美、越前 宏俊
  • Total Pages: 15
  • Publisher: メディカルドゥ
• [Remarks]
  • URL: http://www.my-pharm.ac.jp/~pharmaco/index.html