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

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.

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

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

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

Uracil is an endogenous pyrimidine base and an essential part of the structure
of RNA. The LD50 value of uracil is very high and ranges from 6-8 g/kg in rats,
mice and rabbits. Chronic oral administration of 1680 mg/kg uracil in dogs
during 1 year appeared completely safe. In a Dutch study in 12 healthy
volunteers, no adverse reaction was observed after oral ingestion of 500 mg/m2
and 1000 mg/m2uracil. Oral administration of 6 mg/kg 13C labeled uracil
(equivalent to about 230 mg/m2) in 255 American volunteers also did not reveal
adverse reactions.

Uracil is commercially marketed in combination with tegafur in the
pharmaceutical product
UFT® (Merck). This product is registered for the treatment of colorectal
cancer. The daily dose of uracil in this commercial formulation is 672 mg/m2.