Effect of renal dysfunction on the pharmacokinetics and pharmacodynamics of fluorouracil and its derivatives

• Project/Area Number: 17K08446
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Kyoto University
• Principal Investigator: Matsubara Kazuo 京都大学, 医学研究科, 教授 (20127533)
• Co-Investigator(Kenkyū-buntansha): 大村 友博 京都大学, 医学研究科, 助教 (00439035) ; 中川 俊作 京都大学, 医学研究科, 助教 (50721916) ; 今井 哲司 京都大学, 医学研究科, 講師 (80468579)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: スペシャルポピュレーション / 薬物動態 / 腎機能低下 / フッ化ピリミジン系抗がん薬 / 質量分析

Outline of Final Research Achievements

This study aimed to assess the changes in pharmacokinetics and pharmacodynamics of fluorouracil and its derivatives. We developed an analytical method to quantify the concentrations of fluorouracil and its metabolites in plasma and urine. Then, we examined the effect of renal dysfunction on the fluorouracil using rat models of renal disease. The result showed that the clearance of fluorouracil and its derivatives significantly decreased in rats of chronic kidney disease.

Academic Significance and Societal Importance of the Research Achievements

透析患者の増加に伴い、透析時にがんや慢性疾患を発症し薬物治療が選択される機会が増加している。一般に、腎機能低下時には薬物の体内動態が大きく変動し、有害反応のリスクが上昇するとされるが、詳細な検討は行われないまま不明であることが多い。そのため、重篤な有害反応を生じうる薬物に関して、腎機能 低下時における体内動態や有害反応のリスクを評価する研究を実施し、科学的根拠に基づいた薬物治療へとつなげることが重要な課題と考えられる。本研究では、腎機能低下時においてフッ化ピリミジン系抗がん剤の体内動態が変動すること示した。この結果、腎機能低下時における抗がん薬治療にあたって有用な情報を提供するものと考える。

Research Products

• [Journal Article] Cisplatin, rather than oxaliplatin, increases paracellular permeability of LLC-PK1 cells via activating protein kinase C. (2020)
  • Author(s): Zhang Y, Yonezawa A, Nakagawa S, Imai S, Denda M, Omura T, Nakagawa T, Matsubara K.
  • Journal Title: Drug Metab Pharmacokinet Volume: 35 Issue: 1 Pages: 111-116
  • DOI: 10.1016/j.dmpk.2019.09.001
  • NAID: 120006796498
  • Peer Reviewed
• [Journal Article] Schwann cell-derived CXCL1 contributes to human immunodeficiency virus type 1 gp120-induced neuropathic pain by modulating macrophage infiltration in mice (2020)
  • Author(s): Ntogwa Mpumelelo、Imai Satoshi、Hiraiwa Ren、Koyanagi Madoka、Matsumoto Mayuna、Ogihara Takashi、Nakagawa Shunsaku、Omura Tomohiro、Yonezawa Atsushi、Nakagawa Takayuki、Matsubara Kazuo
  • Journal Title: Brain, Behavior, and Immunity Volume: in press Pages: 31233-4
  • DOI: 10.1016/j.bbi.2020.03.027
  • Peer Reviewed
• [Journal Article] Influence of Pharmaceutical Formulation on the Mucosal Concentration of 5-Aminosalicylic Acid and <i>N</i>-Acetylmesalamine in Japanese Patients with Ulcerative Colitis (2019)
  • Author(s): Yamamoto Y, Masuda S, Nakase H, Matsuura M, Maruyama S, Hisamatsu T, Suzuki Y, Matsubara K.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 42 Issue: 1 Pages: 81-86
  • DOI: 10.1248/bpb.b18-00561
  • NAID: 130007542208
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2019-01-01
  • Peer Reviewed / Open Access
• [Journal Article] Effects of fasting on warfarin sensitivity index in patients undergoing cardiovascular surgery. (2019)
  • Author(s): Katada Y, Nakagawa S, Nishimura A, Sato Y, Taue H, Matsumura K, Yamazaki K, Minakata K, Yano I, Omura T, Imai S, Yonezawa A, Sato Y, Nakagawa T, Minatoya K, Matsubara K.
  • Journal Title: Eur J Clin Pharmacol Volume: 75 Issue: 4 Pages: 561-568
  • DOI: 10.1007/s00228-018-2592-4
  • Peer Reviewed
• [Journal Article] Concentration and Glycoform of Rituximab in Plasma of Patients with B Cell Non-Hodgkin’s Lymphoma (2019)
  • Author(s): Yonezawa Atushi、Otani Yuki、Kitano Toshiyuki、Mori Mayuko、Masui Sho、Isomoto Yui、Tsuda Masahiro、Imai Satoshi、Ikemi Yasuaki、Denda Masaya、Sato Yuki、Nakagawa Shunsaku、Omura Tomohiro、Nakagawa Takayuki、Yano Ikuko、Hayakari Makoto、Takaori-Kondo Akifumi、Matsubara Kazuo
  • Journal Title: Pharmaceutical Research Volume: 36 Issue: 6 Pages: 82-82
  • DOI: 10.1007/s11095-019-2624-5
  • NAID: 120006624113
  • Peer Reviewed
• [Journal Article] A Minimal PBPK Model for Tacrolimus in Living-Donor Liver Transplantation : Perspectives related to Liver Regeneration and CYP3A5 genotype. (2019)
  • Author(s): Itohara K, Yano I, Tsuzuki T, Uesugi M, Nakagawa S, Yonezawa A, Okajima H, Kaido T, Uemoto S, Matsubara K.
  • Journal Title: CPT : Pharmacometrics & Systems Pharmacology Volume: 8 Issue: 8 Pages: 587-595
  • DOI: 10.1002/psp4.12420
  • Description: In press
  • Peer Reviewed / Open Access
• [Journal Article] Improvement of peripheral vascular impairment by a phosphodiesterase type 5 inhibitor tadalafil prevents oxaliplatin-induced peripheral neuropathy in mice (2019)
  • Author(s): Ogihara Takashi、Nakagawa Takayuki、Hayashi Maho、Koyanagi Madoka、Yonezawa Atsushi、Omura Tomohiro、Nakagawa Shunsaku、Kitada Noriaki、Imai Satoshi、Matsubara Kazuo
  • Journal Title: Journal of Pharmacological Sciences Volume: 141 Issue: 4 Pages: 131-138
  • DOI: 10.1016/j.jphs.2019.10.005
  • NAID: 120006844940
  • Peer Reviewed
• [Journal Article] Analysis of Glycoforms and Amino Acids in Infliximab and a Biosimilar Product Using New Method with LC/TOF-MS (2018)
  • Author(s): Tsuda M, Otani Y, Yonezawa A, Masui S, Ikemi Y, Denda M, Sato Y, Nakagawa S, Omura T, Imai S, Nakagawa T, Hayakari M, Matsubara K.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 41 Issue: 11 Pages: 1716-1721
  • DOI: 10.1248/bpb.b18-00491
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2018-11-01
  • Peer Reviewed
• [Journal Article] Oxicam-derived non-steroidal anti-inflammatory drugs suppress 1-methyl-4-phenyl pyridinium-induced cell death via repression of endoplasmic reticulum stress response and mitochondrial dysfunction in SH-SY5Y cells. (2018)
  • Author(s): Omura T, Sasaoka M, Hashimoto G, Imai S, Yamamoto J, Sato Y, Nakagawa S, Yonezawa A, Nakagawa T, Yano I, Tasaki Y, Matsubara K.
  • Journal Title: Biochem Biophys Res Commun Volume: 503 Issue: 4 Pages: 2963-2969
  • DOI: 10.1016/j.bbrc.2018.08.078
  • Peer Reviewed
• [Journal Article] Pharmacokinetics and Pharmacodynamics of Once-Daily Tacrolimus Compared With Twice-Daily Tacrolimus in the Early Stage After Living Donor Liver Transplantation. (2018)
  • Author(s): Iwasaki M, Yano I, Fukatsu S, Hashi S, Yamamoto Y, Sugimoto M, Fukudo M, Masuda S, Nakagawa S, Yonezawa A, Kaido T, Uemoto S, Matsubara K.
  • Journal Title: Ther Drug Monit Volume: 40 Issue: 6 Pages: 675-681
  • DOI: 10.1097/ftd.0000000000000551
  • NAID: 120006559313
  • Peer Reviewed
• [Journal Article] Effects of fasting on warfarin sensitivity index in patients undergoing cardiovascular surgery. (2018)
  • Author(s): Katada Y, Nakagawa S, Nishimura A, Sato YK, Taue H, Matsumura K, Yamazaki K, Minakata K, Yano I, Omura T, Imai S, Yonezawa A, Sato Y, Nakagawa T, Minatoya K, Matsubara K.
  • Journal Title: Eur J Clin Pharmacol Volume: 75 Pages: 561-568
  • Peer Reviewed
• [Journal Article] Effect of medication adherence on disease activity among Japanese patients with rheumatoid arthritis. (2018)
  • Author(s): Nakagawa S, Nakaishi M, Hashimoto M, Ito H, Yamamoto W, Nakashima R, Tanaka M, Fujii T, Omura T, Imai S, Nakagawa T, Yonezawa A, Imai H, Mimori T, Matsubara K.
  • Journal Title: PLoS One Volume: 13 Issue: 11 Pages: e0206943-e0206943
  • DOI: 10.1371/journal.pone.0206943
  • NAID: 120006539574
  • Peer Reviewed / Open Access
• [Journal Article] Chemotherapy in cancer patients undergoing haemodialysis: a nationwide study in Japan. (2018)
  • Author(s): Funakoshi T, Horimatsu T, Nakamura M, Shiroshita K, Suyama K, Mukoyama M, Mizukami T, Sakurada T, Baba E, Tsuruya K, Nozaki A, Yahata K, Ozaki Y, Ubara Y, Yasui H, Yoshimoto A, Fukuma S, Kondo N, Matsubara T, Matsubara K, Fukuhara S, Yanagita M, Muto M.
  • Journal Title: ESMO Open Volume: 23 Issue: 2 Pages: e000301-e000301
  • DOI: 10.1136/esmoopen-2017-000301
  • Peer Reviewed / Open Access
• [Journal Article] Pharmacokinetic and Pharmacodynamic Markers of Mycophenolic Acid Associated with Effective Prophylaxis for Acute Graft-Versus-Host Disease and Neutrophil Engraftment in Cord Blood Transplant Patients (2018)
  • Author(s): Yoshimura Kazuaki、Yano Ikuko、Yamamoto Takashi、Kondo Tadakazu、Kawanishi Misaki、Isomoto Yui、Yonezawa Atsushi、Takaori-Kondo Akifumi、Matsubara Kazuo
  • Journal Title: Biol. Blood Marrow Transplant. Volume: - Issue: 7 Pages: 1441-1448
  • DOI: 10.1016/j.bbmt.2018.01.040
  • NAID: 120006501237
  • Peer Reviewed
• [Journal Article] Accumulation of alpha-fluoro-beta-alanine and fluoro mono acetate in a patient with 5-fluorouracil-associated hyperammonemia. (2017)
  • Author(s): Nishikawa Y, Funakoshi T, Horimatsu T, Miyamoto S, Matsubara T, Yanagita M, Nakagawa S, Yonezawa A, Matsubara K, Muto M.
  • Journal Title: Cancer Chemother Pharmacol. Volume: 79 Issue: 3 Pages: 619-633
  • DOI: 10.1007/s00280-017-3249-1
  • Peer Reviewed
• [Journal Article] Population pharmacokinetics of topiramate in Japanese pediatric and adult patients with epilepsy using routinely monitored data. (2017)
  • Author(s): Takeuchi M, Yano I, Ito S, Sugimoto M, Yamamoto S, Yonezawa A, Ikeda A,Matsubara K
  • Journal Title: Therapeutic Drug Monitoring Volume: 39 Issue: 2 Pages: 124-131
  • DOI: 10.1097/ftd.0000000000000383
  • Peer Reviewed / Open Access