title: Predicting 5-fluorouracil toxicity: DPD genotype and 5,6-dihydrouracil:uracil ratio.
abstract: OBJECTIVE
  Decreased DPD activity is a major cause of 5-fluorouracil (5-FU) toxicity, but known reduced-function variants in the DPD gene (DPYD) explain only a part of DPD-related 5-FU toxicities. Here, we evaluated the baseline (pretherapeutic) plasma 5,6-dihydrouracil:uracil (UH2:U) ratio as a marker of DPD activity in the context of DPYD genotypes.
  
  
  METHODS
  DPYD variants were genotyped and plasma U, UH2 and 5-FU concentrations were determined by liquid chromatography-tandem mass spectrometry in 320 healthy blood donors and 28 cancer patients receiving 5-FU-based chemotherapy.
  
  
  RESULTS
  Baseline UH2:U ratios were strongly correlated with generally low and highly variable U concentrations. Reduced-function DPYD variants were only weakly associated with lower baseline UH2:U ratios. However, the interindividual variability in the UH2:U ratio was reduced and a stronger correlation between ratios and 5-FU exposure was observed in cancer patients during 5-FU administration.
  
  
  CONCLUSIONS
  These results suggest that the baseline UH2:U plasma ratio in most individuals reflects the nonsaturated state of DPD and is not predictive of decreased DPD activity. It may, however, be highly predictive at increased substrate concentrations, as observed during 5-FU administration.
authors.affiliation: Institute of Clinical Chemistry, Inselspital, Bern University Hospital, & University of Bern, INO-F, CH-3010 Bern, Switzerland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Sistonen
authors.forename: Barbara
authors.initials: B
authors.lastname: Büchel
authors.forename: Tanja K
authors.initials: TK
authors.lastname: Froehlich
authors.forename: Dominic
authors.initials: D
authors.lastname: Kummer
authors.forename: Stefano
authors.initials: S
authors.lastname: Fontana
authors.forename: Markus
authors.initials: M
authors.lastname: Joerger
authors.forename: André B P
authors.initials: AB
authors.lastname: van Kuilenburg
authors.forename: Carlo R
authors.initials: CR
authors.lastname: Largiadèr
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000633:toxicity*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D014498:Uracil / Q000031:analogs & derivatives* / Q000097:blood*
chemical_list: D000964:Antimetabolites, Antineoplastic; C007419:dihydrouracil; D014498:Uracil; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil
keywords: 5-fluorouracil; DPYD; chemotherapy; dihydropyrimidine dehydrogenase; dihydrouracil; genotype; pharmacogenomics; pharmacokinetics; uracil