Relationship between 5-fluorouracil disposition, toxicity and dihydropyrimidine dehydrogenase activity in cancer patients.
BACKGROUND
Previous work demonstrated that 5-fluorouracil (5-FU) metabolism is a critical factor for treatment tolerability. In order to study the predictivity of pharmacokinetics with respect to the occurrence of 5-FU toxicity, this study investigates the relationship between the pharmacokinetics of 5-FU and its metabolite 5-fluoro-5,6-dihydrouracil (5-FDHU), dihydropyrimidine dehydrogenase (DPD) activity in peripheral blood mononuclear cells (PBMNC) and treatment tolerability.


METHODS
Pharmacokinetics and metabolism of 5-FU and activity of DPD in PBMNC were examined in 110 colorectal cancer patients given adjuvant 5-FU 370 mg/m2 plus L-folinic acid 100 mg/m2 for five days every four weeks. Drug levels were examined by HPLC. while toxicities were graded according to WHO criteria.


RESULTS
DPD activity in patients with mild toxicities (WHO grade < or = 1) was 197.22 < or = 11.34 pmol of 5-FDHU/min/ mg of protein, while in five patients with grade 3-4 gastrointestinal toxicity, DPD ranged from low to normal values (range 31.12-182.37 pmol/min/mg of protein). In these patients. 5-FU clearance (CL) was lower (range 14.12-25.17 l/h/m2), and the area under the curve (AUC) was higher (range 14.70-26.20 h x microg/ml) than those observed in 84 patients with mild toxicities (CL, 56.30 +/- 3.60 l/h/M2; AUC, 7.91 +/- 0.44 h x microg/ml). The severity of adverse events was associated with increased 5-FU/5-FDHU AUC ratio and reduced 5-FU CL, while 5-FU and 5-FDHU pharmacokinetics were not related to DPD activity.


CONCLUSIONS
This study shows that DPD activity in PBMNC is unrelated to 5-FU/5-FDHU disposition and patients with severe toxicity display marked pharmacokinetic alterations while a reduction of DPD activity may not occur.
Di Paolo
A
A
Division of Pharmacology and Chemotherapy, University of Pisa, Italy.
Danesi
R
R
Falcone
A
A
Cionini
L
L
Vannozzi
F
F
Masi
G
G
Allegrini
G
G
Mini
E
E
Bocci
G
G
Conte
P F
PF
Del Tacca
M
M
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics*; D017024:Chemotherapy, Adjuvant; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D042943:Dihydrouracil Dehydrogenase (NADP); D005260:Female; D005472:Fluorouracil / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D002955:Leucovorin; D005472:Fluorouracil