The Pharmacokinetics of an oral uracil dose in patients with colorectal carcinoma.

Background of the study:

Dihydropyrimidine Dehydrogenase (DPD) is the initial and rate-limiting enzyme in the metabolism of 5-fluorouracil (5-FU).

Patients with a partial or complete DPD deficiency are at risk to develop severe toxicity after 5-FU administration. Uracil is
degraded in dihydrouracil in a similar way as 5-FU. Hypothetically, DPD deficiency may cause higher uracil levels and a reduced
turnover of uracil into dihydrouracil. An oral uracil test dose might be useful to determine the systemic DPD activity by measuring
uracil and its metabolite dihydrouracil in plasma.



Objective of the study:

To compare the pharmacokinetic profile of uracil in cancer patients and healthy volunteers.



Study design:

Case control PK study with 24 patients diagnosed with colorectal cancer.



Study population:

Cancer patients with or without metastasis, age > 18 jaar, DPD activity in PBMC ? 6 nmol/mg/hour treated with 5-FU or
capecitabine.



Intervention:

An oral dose of 500 mg/m2 is adminstered to patients. Bloodsamples are obtained just before and on several timepoints after
dosage.



Primary study parameters/outcome of the study:

AUC of uracil. The second objective of the study is to determine if there is a interpatient correlation between uracil levels
determined in blood sampled with a newly developed bloodspot method and venapunction.

Dihydropyrimidine Dehydrogenase (DPD) is the initial and rate-limiting enzyme in the metabolism of 5-fluorouracil (5-FU). Patients with a partial or complete DPD deficiency are at risk to develop severe toxicity after 5-FU administration. Uracil is degraded in dihydrouracil in a similar way as 5-FU. Hypothetically, DPD deficiency may cause higher uracil levels and a reduced turnover of uracil into dihydrouracil. An oral uracil test dose might be useful to determine the systemic DPD activity by measuring uracil and its metabolite dihydrouracil in plasma.

t = 0, 15, 30, 45, 60, 80, 100, 120, 150, 180 en 240 minutes after intake of uracil.

An oral dose of 500 mg/m2 is adminstered to patients. Bloodsamples are obtained just before and on several timepoints after dosage.