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

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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.

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Acknowledgements

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

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Authors and Affiliations

  1. Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Yoshitaka Nishikawa, Taro Funakoshi, Takahiro Horimatsu & Manabu Muto

  2. Department of Health Informatics, School of Public Health, Kyoto University Yoshida-Konoe, Sakyo-ku, Kyoto, 606-8501, Japan

    Yoshitaka Nishikawa

  3. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Shin’ichi Miyamoto

  4. Department of Nephrology, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Takeshi Matsubara & Motoko Yanagita

  5. Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Shunsaku Nakagawa, Atsushi Yonezawa & Kazuo Matsubara

Authors
  1. Yoshitaka Nishikawa
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  2. Taro Funakoshi
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  3. Takahiro Horimatsu
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  4. Shin’ichi Miyamoto
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  5. Takeshi Matsubara
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  6. Motoko Yanagita
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  7. Shunsaku Nakagawa
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  8. Atsushi Yonezawa
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  9. Kazuo Matsubara
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  10. Manabu Muto
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Corresponding author

Correspondence to Yoshitaka Nishikawa.

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Funding

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.

Electronic supplementary material

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280_2017_3249_MOESM1_ESM.tif

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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Nishikawa, Y., Funakoshi, T., Horimatsu, T. et al. Accumulation of alpha-fluoro-beta-alanine and fluoro mono acetate in a patient with 5-fluorouracil-associated hyperammonemia. Cancer Chemother Pharmacol 79, 629–633 (2017). https://doi.org/10.1007/s00280-017-3249-1

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  • DOI: https://doi.org/10.1007/s00280-017-3249-1

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