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.
OBJECTIVE
To describe the altered pharmacokinetics of 5-fluorouracil (5-FU) and its major catabolite 5-fluoro-5,6-dihydrouracil (5-FDHU) in a 52-year-old woman affected by a severe 5-FU toxicity.


METHODS
Toxicities were rated according to World Health Organization. 5-FU and 5-FDHU plasma concentrations and dihydropyrimidine dehydrogenase (DPD) activity of peripheral blood mononuclear cells (PBMC) were measured by HPLC analysis.


RESULTS
After a single cycle of 5-FU therapy the patient developed grade 4 diarrhea and stomatitis, grade 3 vomiting, neutropenia, and dermatitis. Compared to a control population, 5-FU AUC, elimination half-life, and C(max) were markedly increased (24.75 vs. 9.25 +/- 0.63 h microg/ml, >5 vs. 0.36 +/- 0.05 h, and 58.54 vs. 37.2 +/- 4.03 microg/ml, respectively) whereas systemic clearance was decreased (12 vs. 51.29 +/- 2.97 l/h/m2); also 5-FDHU AUC (3.3 vs. 12.35 +/- 0.7 h microg/ml) and C(max) (3.4 vs. 4.56 +/- 0.15 microg/ml), which was reached with delay, were reduced. Surprisingly, the PBMC DPD activity (110.8 pmol/min/mg protein) and urinary uracil (68.32 micromol/g urinary creatinine) were within normal range.


CONCLUSIONS
Our results show the altered 5-FU and 5-FDHU pharmacokinetics in a severe 5-FU toxicity case due to an impairment of the hepatic DPD activity and suggest the necessity of a pharmacological evaluation of 5-FU treated patients.
Bocci
G
G
Molecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada. gbocci@srcl.sunnybrook.utoronoto.ca
Danesi
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R
Allegrini
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G
Innocenti
F
F
Di Paolo
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A
Falcone
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A
Conte
P F
PF
Del Tacca
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M
D000505:Alopecia / Q000139:chemically induced; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D003967:Diarrhea / Q000139:chemically induced; D003875:Drug Eruptions / Q000209:etiology; D005260:Female; D005334:Fever / Q000139:chemically induced; D005472:Fluorouracil / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D013280:Stomatitis / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced
D000964:Antimetabolites, Antineoplastic; C019389:5-fluorodihydrouracil; D005472:Fluorouracil