title: Pharmacokinetics of orally administered uracil in healthy volunteers and in DPD-deficient patients, a possible tool for screening of DPD deficiency.
abstract: OBJECTIVE
  Dihydropyrimidine dehydrogenase (DPD) deficiency can lead to severe toxicity in patients treated with standard doses of 5-fluorouracil (5-FU). Oral uracil administration and subsequent measurement of uracil and dihydrouracil (DHU) plasma concentrations might detect patients with DPD deficiency. This study compares the pharmacokinetics of uracil and DHU after oral uracil administration in subjects with normal and deficient DPD status.
  
  
  METHODS
  Five hundred milligrams of uracil per metre square was administered orally to 11 subjects with normal DPD status and to 10 subjects with reduced DPD activity. Repeated administration (n = 3) of this dose was performed in 4 subjects, and 1,000 mg uracil/m(2) was administered to 4 subjects to assess intra-individual variation and linearity of pharmacokinetics.
  
  
  RESULTS
  In subjects with normal DPD status, 500 mg/m(2) uracil resulted in uracil C (max) levels of 14.4 ± 4.7 mg/L at T (max) = 30.0 ± 11.6 min, and in DPD-deficient subjects, 20.0 ± 4.5 mg/L at 31.5 ± 1.1 min. The uracil AUC(0>180) was 31.2 ± 5.1 mg L/h in DPD-deficient subjects, which was significantly higher (P < 0.05) than in the subjects with normal DPD status (13.8 ± 3.9 mg L/h). Repeated uracil dosing showed reproducible uracil PK in subjects with normal DPD status, and dose elevation of uracil suggested linear pharmacokinetics.
  
  
  CONCLUSIONS
  The pharmacokinetics of uracil differs significantly between subjects with a normal DPD activity and those with a deficient DPD status. The AUC and C (max) of uracil can be useful as a diagnostic tool to differentiate patients with regard to DPD status.
authors: Department of Pharmacy, Scheper Hospital Emmen and Röpcke Zweers Hospital Hardenberg, Boermarkeweg 60, 7824 AA Emmen, The Netherlands. m.vanstaveren@sze.nl
authors: Maurice C
authors: MC
authors: van Staveren
authors: Barbara
authors: B
authors: Theeuwes-Oonk
authors: Henk Jan
authors: HJ
authors: Guchelaar
authors: André B P
authors: AB
authors: van Kuilenburg
authors: Jan Gerard
authors: JG
authors: Maring
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