title: Accumulation of alpha-fluoro-beta-alanine and fluoro mono acetate in a patient with 5-fluorouracil-associated hyperammonemia.
abstract: 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.
authors.affiliation: Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. ynishikawa-tky@umin.ac.jp.|Department of Health Informatics, School of Public Health, Kyoto University Yoshida-Konoe, Sakyo-ku, Kyoto, 606-8501, Japan. ynishikawa-tky@umin.ac.jp.
authors.forename: Yoshitaka
authors.identifier: 0000-0003-3313-1990
authors.initials: Y
authors.lastname: Nishikawa
authors.affiliation: Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Funakoshi
authors.affiliation: Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Horimatsu
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Miyamoto
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsubara
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Yanagita
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Shunsaku
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yonezawa
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Matsubara
authors.affiliation: Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Muto
mesh_terms: D000368:Aged; D000641:Ammonia / Q000097:blood; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000601:surgery; D003131:Combined Modality Therapy; D003928:Diabetic Nephropathies / Q000150:complications / Q000628:therapy; D005463:Fluoroacetates / Q000097:blood*; D005472:Fluorouracil / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D022124:Hyperammonemia / Q000139:chemically induced* / Q000378:metabolism* / Q000628:therapy; D008297:Male; D006435:Renal Dialysis; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: D000964:Antimetabolites, Antineoplastic; D005463:Fluoroacetates; D015091:beta-Alanine; C032348:alpha-fluoro-beta-alanine; D000641:Ammonia; C014815:fluoroacetic acid; D005472:Fluorouracil
keywords: 5-Fluorouracil; End-stage renal disease; Hyperammonemia; Pharmacokinetics