Cancer Chemotherapy and Pharmacology

, Volume 79, Issue 3, pp 629–633 | Cite as

Accumulation of alpha-fluoro-beta-alanine and fluoro mono acetate in a patient with 5-fluorouracil-associated hyperammonemia

  • Yoshitaka NishikawaEmail author
  • Taro Funakoshi
  • Takahiro Horimatsu
  • Shin’ichi Miyamoto
  • Takeshi Matsubara
  • Motoko Yanagita
  • Shunsaku Nakagawa
  • Atsushi Yonezawa
  • Kazuo Matsubara
  • Manabu Muto
Short Communication



High-dose 5-fluorouracil (5-FU) containing chemotherapy occasionally causes hyperammonemia and can be lethal. However, the mechanism of 5FU-associated hyperammonemia has not been known. The aim of this study was to reveal the pharmacokinetics of 5-FU-associated hyperammonemia in a recurrent colorectal cancer patient with end-stage renal disease (ESRD).


We experienced a case of hyperammonemia during mFOLFOX6 plus bevacizumab therapy for recurrent colorectal cancer. He was a dialyzed patient due to diabetic nephropathy and was registered to prospective blood sampling for pharmacokinetics analysis during chemotherapy. Blood concentrations of 5-FU and its catabolites were determined by inductively coupled plasma-mass spectrometry.


The patient developed hyperammonemia encephalopathy 41 h after the initiation of continuous 5-FU infusion (on the third day). Before onset of hyperammonemia encephalopathy, serum alpha-fluoro-beta-alanine (FBAL, 59.2 µg/ml) and fluoro mono acetate (FMA, 905.8 ng/ml) were gradually increased. After hemodialysis for hyperammonemia, FBAL and FMA were collaterally decreased and his symptom was improved. Other intermediate catabolites of 5-FU, dihydrofluorouracil, and alpha-fluoro-beta-ureidopropionic acid were not changed.


We found increases of serum FBAL and FMA under the condition of hyperammonemia in the patient with ESRD during mFOLFOX6 plus bevacizumab therapy. This research supported the hypothesis that impairment of tricarboxylic acid (TCA) cycle by FMA would cause 5-FU-associated hyperammonemia.


5-Fluorouracil Hyperammonemia End-stage renal disease Pharmacokinetics 



The authors express gratitude to all the staffs involved in this case.

Compliance with ethical standards


This research was partially supported by a grant from Kyoto University Research Development Program.

Conflict of interest

YN, TF, TH, SM, TM, SN, AY, and KM have no conflicts of interest to disclose. MY receives research grants from Astellas, Chugai, Daiichi Sankyo, Fujiyakuhin, Kyowa Hakko Kirin, Mitsubishi Tanabe Pharma Corporation, MSD, Nippon Boehringer Ingelheim, and Torii and is on advisory boards of Astellas. MM receives research funding from Chugai, Mitsui Knowledge Industry, Taiho, Nissha Printing, Olympus and Theravalues and is on advisory boards of Kewpie and Eisai.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

Informed consent

Informed consent was obtained from the patient included in the study.

Supplementary material

280_2017_3249_MOESM1_ESM.tif (5.9 mb)
Catabolism of 5-FU and hypothetic pathway of developing hyperammonemia during 5-FU-based chemotherapy. Abbreviations: FDHU dihydrofluorouracil, FUPA alpha-fluoro-beta-ureidopropionic acid, FBAL alpha-fluoro-beta-alanine, FMA fluoro mono acetate, DPD dihydropyrimidine dehydrogenase, and TCA cycle tricarboxylic acid cycle. (TIF 6077 KB)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Yoshitaka Nishikawa
    • 1
    • 2
    Email author
  • Taro Funakoshi
    • 1
  • Takahiro Horimatsu
    • 1
  • Shin’ichi Miyamoto
    • 3
  • Takeshi Matsubara
    • 4
  • Motoko Yanagita
    • 4
  • Shunsaku Nakagawa
    • 5
  • Atsushi Yonezawa
    • 5
  • Kazuo Matsubara
    • 5
  • Manabu Muto
    • 1
  1. 1.Department of Therapeutic Oncology, Graduate School of MedicineKyoto UniversityKyotoJapan
  2. 2.Department of Health Informatics, School of Public HealthKyoto University Yoshida-KonoeKyotoJapan
  3. 3.Department of Gastroenterology and Hepatology, Graduate School of MedicineKyoto UniversityKyotoJapan
  4. 4.Department of Nephrology, Graduate School of MedicineKyoto UniversityKyotoJapan
  5. 5.Department of Clinical Pharmacology and TherapeuticsKyoto University HospitalKyotoJapan

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