Cancer Chemotherapy and Pharmacology

, Volume 79, Issue 3, pp 629–633

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

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

DOI: 10.1007/s00280-017-3249-1

Cite this article as:
Nishikawa, Y., Funakoshi, T., Horimatsu, T. et al. Cancer Chemother Pharmacol (2017) 79: 629. doi:10.1007/s00280-017-3249-1

Abstract

Purpose

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).

Methods

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.

Results

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.

Conclusion

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.

Keywords

5-Fluorouracil Hyperammonemia End-stage renal disease Pharmacokinetics 

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)

Funding information

Funder NameGrant NumberFunding Note
Kyoto University
  • Kyoto University Research Development Program

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Yoshitaka Nishikawa
    • 1
    • 2
  • 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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