Predicting 5-Fluorouracil Toxicity: DPD Genotype and 5,6-Dihydrouracil: Uracil Ratio

• DOI: 10.2217/pgs.14.126
• Publication Date: 2014-11-20T13:22:24Z
• Authors: Johanna Sistonen; Barbara Büchel; Tanja K Froehlich; Dominic Kummer; Stefano Fontana; Markus Joerger; André BP van Kuil...; Carlo R Largiadèr
• Keywords: Uracil

Aim: Decreased DPD activity is a major cause of 5-fluorouracil (5-FU) toxicity, but known reduced-function variants in the gene (DPYD) explain only part DPD-related 5-FU toxicities. Here, we evaluated baseline (pretherapeutic) plasma 5,6-dihydrouracil:uracil (UH2:U) ratio as marker context DPYD genotypes. Materials & methods: were genotyped and U, UH2 concentrations determined by liquid chromatography-tandem mass spectrometry 320 healthy blood donors 28 cancer patients receiving 5-FU-based chemotherapy. Results: Baseline UH2:U ratios strongly correlated with generally low highly variable U concentrations. Reduced-function weakly associated lower ratios. However, interindividual variability was reduced stronger correlation between exposure observed during administration. Conclusion: These results suggest that most individuals reflects nonsaturated state not predictive decreased activity. It may, however, be at increased substrate concentrations, Original submitted 9 May 2014; Revision 20 August 2014