nach oben

Erschienen in:

15.02.2017 | Short Communication

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

verfasst von: Yoshitaka Nishikawa, Taro Funakoshi, Takahiro Horimatsu, Shin’ichi Miyamoto, Takeshi Matsubara, Motoko Yanagita, Shunsaku Nakagawa, Atsushi Yonezawa, Kazuo Matsubara, Manabu Muto

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 3/2017

Einloggen, um Zugang zu erhalten

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.

Nur mit Berechtigung zugänglich

Pinedo HM, Peters GF (1988) Fluorouracil: biochemistry and pharmacology. J Clin Oncol 6:1653–1664CrossRefPubMed

Koenig H, Patel A (1970) Biochemical basis for fluorouracil neurotoxicity. The role of Krebs cycle inhibition by fluoroacetate. Arch Neurol 23:155–160. doi:10.1001/archneur.1970.00480260061008 CrossRefPubMed

Yeh KH, Cheng AL (1997) High-dose 5-fluorouracil infusional therapy is associated with hyperammonaemia, lactic acidosis and encephalopathy. Br J Cancer 75:464–465CrossRefPubMedPubMedCentral

Nakamura M, Kobashikawa K, Tamura J et al (2009) A case of 5-fluorouracil-induced hyperammmonia after chemotherapy for metastatic colon cancer. Nihon Shokakibyo Gakkai Zasshi 106:1744–1750. doi:10.11405/nisshoshi.106.1744 PubMed

Misumi N, Goto T, Miyoshi T et al (2013) Risk factors for hyperammonemia during mFOLFOX6 treatment. Gan To Kagaku Ryoho 40:483–487PubMed

Iida T, Wagatsuma K, Tani M et al (2015) Four cases of 5-fluorouracil-related hyperammonemia in patients with large intestinal cancer and multiple liver metastases, including a case of hyperammonemia treated using hemodialysis. Nihon Shokakibyo Gakkai Zasshi 112:287–296. doi:10.11405/nisshoshi.112.287 PubMed

Horimatsu T, Miyamoto S, Morita S et al (2011) Pharmacokinetics of oxaliplatin in a hemodialytic patient treated with modified FOLFOX-6 plus bevacizumab therapy. Cancer Chemother Pharmacol 68:263–266. doi:10.1007/s00280-011-1633-9 CrossRefPubMed

Gamelin E, Delva R, Jacob J et al (2008) Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: Results of a multicenter randomized trial of patients with metastatic colorectal cancer. J Clin Oncol 26:2099–2105. doi:10.1200/JCO.2007.13.3934 CrossRefPubMed

Kikuta S, Asakage T, Nakao K et al (2008) The aggravating factors of hyperammonemia related to 5-fluorouracil infusion–a report of two cases. Auris Nasus Larynx 35:295–299. doi:10.1016/j.anl.2007.04.012 CrossRefPubMed

10.

Heggie GD, Sommadossi JP, Cross DS et al (1987) Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res 47:2203–2206PubMed

11.

Thiberville L, Compagnon P, Moore N et al (1994) Plasma 5-fluorouracil and alpha-fluoro-beta-alanin accumulation in lung cancer patients treated with continuous infusion of cisplatin and 5-fluorouracil. Cancer Chemother Pharmacol 35:64–70CrossRefPubMed

12.

Casale F, Canaparo R, Serpe L et al (2004) Plasma concentrations of 5-fluorouracil and its metabolites in colon cancer patients. Pharmacol Res 50:173–179. doi:10.1016/j.phrs.2004.01.006 CrossRefPubMed

13.

Lichtman SM, Wildiers H, Launay-Vacher V et al (2007) International Society of Geriatric Oncology (SIOG) recommendations for the adjustment of dosing in elderly cancer patients with renal insufficiency. Eur J Cancer 43:14–34. doi:10.1016/j.ejca.2006.11.004 CrossRefPubMed

14.

Janus N, Thariat J, Boulanger H et al (2010) Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients. Ann Oncol 21:1395–1403. doi:10.1093/annonc/mdp598 CrossRefPubMed

15.

Bocci G, Danesi R, Allegrini G et al (2002) Severe 5-fluorouracil toxicity associated with a marked alteration of pharmacokinetics of 5-fluorouracil and its catabolite 5-fluoro-5,6-dihydrouracil: a case report. Eur J Clin Pharmacol 58:593–595. doi:10.1007/s00228-002-0534-6 CrossRefPubMed

16.

van Kuilenburg AB, Haasjes J, Richel DJ et al (2000) Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res 6:4705–4712PubMed

Titel: Accumulation of alpha-fluoro-beta-alanine and fluoro mono acetate in a patient with 5-fluorouracil-associated hyperammonemia
verfasst von: Yoshitaka Nishikawa
Taro Funakoshi
Takahiro Horimatsu
Shin’ichi Miyamoto
Takeshi Matsubara
Motoko Yanagita
Shunsaku Nakagawa
Atsushi Yonezawa
Kazuo Matsubara
Manabu Muto
Publikationsdatum: 15.02.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 3/2017
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-017-3249-1

Springer Medizin

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