title: Endogenous plasma and salivary uracil to dihydrouracil ratios and DPYD genotyping as predictors of severe fluoropyrimidine toxicity in patients with gastrointestinal malignancies.
abstract: OBJECTIVE
  The aim of this study was to evaluate the use of plasma and saliva uracil (U) to dihydrouracil (UH2) metabolic ratio and DPYD genotyping, as a means to identify patients with dihydropyrimidine dehydrogenase (DPD) deficiency and fluoropyrimidine toxicity.
  
  
  METHODS
  Paired plasma and saliva samples were obtained from 60 patients with gastrointestinal cancer, before fluoropyrimidine treatment. U and UH2concentrations were measured by LC-MS/MS. DPYD was genotyped for alleles *7, *2A, *13 and Y186C. Data on toxicity included grade 1 to 4 neutropenia, mucositis, diarrhea, nausea/vomiting and cutaneous rash.
  
  
  RESULTS
  35% of the patients had severe toxicity. There was no variant allele carrier for DPYD. The [UH2]/[U] metabolic ratios were 0.09-26.73 in plasma and 0.08-24.0 in saliva, with higher correlation with toxicity grade in saliva compared to plasma (rs=-0.515 vs rs=-0.282). Median metabolic ratios were lower in patients with severe toxicity as compared to those with absence of toxicity (0.59 vs 2.83 saliva; 1.62 vs 6.75 plasma, P<0.01). A cut-off of 1.16 for salivary ratio was set (AUC 0.842), with 86% sensitivity and 77% specificity for the identification of patients with severe toxicity. Similarly, a plasma cut-off of 4.0 (AUC 0.746), revealed a 71% sensitivity and 76% specificity.
  
  
  CONCLUSIONS
  DPYD genotyping for alleles 7, *2A, *13 and Y186C was not helpful in the identification of patients with severe DPD deficiency in this series of patients. The [UH2]/[U] metabolic ratios, however, proved to be a promising functional test to identify the majority of cases of severe DPD activity, with saliva performing better than plasma.
authors.affiliation: Pós-Graduação em Ciências Médicas, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Serviço de Oncologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Andrés Fernando Andrade
authors.initials: AF
authors.lastname: Galarza
authors.affiliation: Instituto de Ciências da Saúde, Universidade Feevale, Novo Hamburgo, RS, Brazil.
authors.forename: Rafael
authors.initials: R
authors.lastname: Linden
authors.affiliation: Instituto de Ciências da Saúde, Universidade Feevale, Novo Hamburgo, RS, Brazil. Electronic address: marinaantunes@feevale.br.
authors.forename: Marina Venzon
authors.initials: MV
authors.lastname: Antunes
authors.affiliation: Instituto de Ciências da Saúde, Universidade Feevale, Novo Hamburgo, RS, Brazil.
authors.forename: Roberta Zilles
authors.initials: RZ
authors.lastname: Hahn
authors.affiliation: Instituto de Ciências da Saúde, Universidade Feevale, Novo Hamburgo, RS, Brazil.
authors.forename: Suziane
authors.initials: S
authors.lastname: Raymundo
authors.affiliation: Instituto de Ciências da Saúde, Universidade Feevale, Novo Hamburgo, RS, Brazil.
authors.forename: Anne Caroline Cezimbra
authors.initials: AC
authors.lastname: da Silva
authors.affiliation: Instituto de Ciências da Saúde, Universidade Feevale, Novo Hamburgo, RS, Brazil.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Staggemeier
authors.affiliation: Instituto de Ciências da Saúde, Universidade Feevale, Novo Hamburgo, RS, Brazil.
authors.forename: Fernando Rosado
authors.initials: FR
authors.lastname: Spilki
authors.affiliation: Pós-Graduação em Ciências Médicas, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Serviço de Oncologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Schwartsmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002853:Chromatography, Liquid; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000652:urine; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000009:adverse effects* / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry; D014498:Uracil / Q000031:analogs & derivatives* / Q000097:blood* / Q000652:urine*
chemical_list: D011743:Pyrimidines; C007419:dihydrouracil; D014498:Uracil; D042943:Dihydrouracil Dehydrogenase (NADP)
keywords: DPYD; Dihydropyrimidine dehydrogenase; Dihydrouracil; Fluoropyrimidine; Toxicity; Uracil