Plasma pharmacokinetics of uracil after an oral uracil challenge dose for dihydropyrimidine dehydrogenase (DPD) phenotyping

2120 Background: The initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU) is DPD, catalyzing the reduction of 5-FU into 5,6-dihydrofluorouracil. In patients with DPD enzyme deficiency, 5-FU chemotherapy is associated with severe, life-threatening toxicity. The current pharmacokinetic study was performed within the scope of the development of an oral, Uracil Challenge Test for DPD phenotyping in patients scheduled to receive 5-FU. Methods: The pharmacokinetics of uracil and its metabolite 5,6-dihydrouracil (DHU) were studied after oral administration of an uracil challenge dose in 12 human volunteers. The volunteers ingested 500 mg/m2 uracil as an oral solution on an empty stomach. Blood sampling was carried out on t = 15, 30, 45, 60, 80, 100, 120, 150, 180, 210 and 240 min after oral intake. Uracil and DHU were quantified in plasma by high performance liquid chromatography. DPD activity in peripheral blood mononuclear (PBM) cells was measured for reference DPD values. Results: All v...