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

Abstract

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 volunteers (6 male and 6 female, age 27–53) had DPD activities within normal range and normal liver- and renal function parameters. After oral ingestion, uracil was rapidly absorbed from the intestinal tract in all subjects. The mean Cmax was (mean ± SD) 14.8 ± 4.2 mg/L (range 11.4–22.2) and was reached at t = 0.47 ± 0.11 hr (range 0.35–0.70 hr) after ingestion. The mean distribution volume was 30.2 ± 10.8 L (range 14.4–46.2 L). The area under the curve (AUC), calculated with the trapezoid rule, was 15.9 ± 5.1 mg.hr/L (range 10.9–26.1 mg.h/L) and the mean uracil clearance rate was 61.0 ± 16.5 L/hr (range 39.0–84.8 L/hr). Conclusions: After oral ingestion, uracil is rapidly absorbed from the gastrointestinal tract and subsequently rapidly metabolized into DHU in humans with normal DPD activity. The oral Uracil Challenge Test is currently investigated in previously characterized, partially DPD deficient patients to determine its use in pre-chemotherapy DPD-phenotyping. No significant financial relationships to disclose.