IngentaConnect Relationship between 5-fluorouracil disposition, toxicity and dih...

Authors: Paolo A.D.¹; Danesi R.¹; Falcone A.²; Cionini L.³; Vannozzi F.¹; Masi G.²; Allegrini G.²; Mini E.⁴; Bocci G.¹; Conte P.F.⁵; Tacca M.D.¹

Source: Annals of Oncology, Volume 12, Number 9, September 2001 , pp. 1301-1306(6)

Publisher: Springer

Abstract:

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.

Patients and 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/m^2 plus L-folinic acid 100 mg/m^2 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 1) was 197.22 ± 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/m^2), and the area under the curve (AUC) was higher (range 14.70–26.20 h×µg/ml) than those observed in 84 patients with mild toxicities (CL, 56.30 ± 3.60 l/h/m^2; AUC, 7.91 ± 0.44 h×µg/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.

Conclusion: 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.

Keywords: DPD; 5-fluorouracil; metabolism; pharmacokinetics; toxicity

Language: English

Document Type: Regular paper

Affiliations: 1: Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Italy 2: Division of Medical Oncology, General Hospital, Livorno, Italy 3: Division of Radiotherapy, Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Italy 4: Department of Pharmacology, University of Florence, Italy 5: Division of Medical Oncology, University Hospital, Pisa, Italy

The full text electronic article is available for purchase. You will be able to download the full text electronic article after payment.

$47.00 plus tax Refund Policy

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