Relationship between 5-fluorouracil disposition, toxicity and dihydropyrimidine dehydrogenase activity in cancer patients

• Published in: Annals of oncology Vol. 12; no. 9; pp. 1301 - 1306
• Main Authors: DI PAOLO, A, DANESI, R, DEL TACCA, M, FALCONE, A, CIONINI, L, VANNOZZI, F, MASI, G, ALLEGRINI, G, MINI, E, BOCCI, G, CONTE, P. F
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.09.2001
• Subjects: Adult; Aged; Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - metabolism; Antimetabolites, Antineoplastic - pharmacokinetics; Antineoplastic agents; Biological and medical sciences; Chemotherapy; Chemotherapy, Adjuvant; Chromatography, High Pressure Liquid; Colorectal Neoplasms - drug therapy; Dihydrouracil Dehydrogenase (NADP); Female; Fluorouracil - adverse effects; Fluorouracil - metabolism; Fluorouracil - pharmacokinetics; Humans; Leucovorin - administration & dosage; Leukocytes, Mononuclear - enzymology; Male; Medical sciences; Middle Aged; Oxidoreductases - metabolism; Pharmacology. Drug treatments; Antineoplastic agent; Rectal disease; Intravenous administration; Metabolite; Toxicity; Calcium folinate; Enzymatic activity; Intestinal disease; Colon; Fluorouracil; Human; Drug combination; Enzyme; Treatment efficiency; Fluoropyrimidine derivatives; ); Bioavailability; Dihydropyrimidine dehydrogenase (NADP; Malignant tumor; Metabolism; Colonic disease; Chemotherapy; Treatment; Rectum; Digestive diseases; Pyrimidine derivatives; Oxidoreductases; Pharmacokinetics
• DOI: 10.1023/A:1012294617392
• ISSN: 0923-7534

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. 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. 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. 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.