title: Evaluation of an oral uracil loading test to identify DPD-deficient patients using a limited sampling strategy.
abstract: OBJECTIVE
  Dihydropyrimidine dehydrogenase (DPD) deficiency can lead to severe toxicity following 5-fluorouracil (5FU) or capecitabine (CAP) treatment. Uracil (U) can be used as a probe to determine systemic DPD activity. The present study was performed to assess the sensitivity and specificity of a U loading dose for detecting DPD deficiency.
  
  
  METHODS
  Cancer patients with Common Toxicity Score (CTC) grade III or IV toxicity after the first or second cycle of 5-FU or CAP treatment were asked to participate. Based on DPD activity in PBMCs, patients were divided into two groups: DPD activity in peripheral blood mononuclear cells (PBMCs) <5 nmol mg(-1) *h(-1) (deficient group) and ≥ 5 nmol mg(-1) *h(-1) . U 500 mg m(-2) was administered orally and plasma concentrations of U and dihydrouracil (DHU) were determined. In the deficient group, polymerase chain reaction amplification of all 23 coding exons and flanking intronic regions of DPYD was performed. A U pharmacokinetic model was developed and used to determine the maximum enzymatic conversion capacity (Vmax ) of the DPD enzyme for each patient. The sensitivity and specificity of Vmax, U concentration and the U/DHU concentration ratio were determined.
  
  
  RESULTS
  A total of 47 patients were included (19 DPD deficient, 28 DPD normal). Of the pharmacokinetic parameters investigated, a sensitivity and specificity of 80% and 98%, respectively, was obtained for the U/DHU ratio at t = 120 min.
  
  
  CONCLUSIONS
  The high sensitivity of the U/DHU ratio at t = 120 min for detecting DPD deficiency, as defined by DPD activity in PBMCs, showed that the oral U loading dose can effectively identify patients with reduced DPD activity.
authors.affiliation: Department of Clinical Pharmacy, Treant Healthgroup, Scheper Hospital, Emmen, The Netherlands.
authors.forename: Maurice C
authors.initials: MC
authors.lastname: van Staveren
authors.affiliation: Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Andre B P
authors.initials: AB
authors.lastname: van Kuilenburg
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.affiliation: Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Judith
authors.initials: J
authors.lastname: Meijer
authors.affiliation: Department of Medical Oncology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Cornelis J A
authors.initials: CJ
authors.lastname: Punt
authors.affiliation: Department of Oncology, Martini Hospital, Groningen, The Netherlands.
authors.forename: Robert S
authors.initials: RS
authors.lastname: de Jong
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center, University Hospital of Leiden, Leiden, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.affiliation: Department of Pharmacy, Isala Diaconessen Hospital, Meppel and Bethesda Hospital,Hoogeveen, The Netherlands.
authors.forename: Jan Gerard
authors.initials: JG
authors.lastname: Maring
mesh_terms: D000284:Administration, Oral; D016022:Case-Control Studies; D054067:Dihydropyrimidine Dehydrogenase Deficiency / Q000097:blood / Q000175:diagnosis*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism*; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D014498:Uracil / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: C007419:dihydrouracil; D014498:Uracil; D042943:Dihydrouracil Dehydrogenase (NADP)
keywords: 5-fluorouracil; dihydropyrimidine dehydrogenase; pharmacogenetics; pharmacokinetics; uracil