Sistonen, Johanna; Büchel, Barbara; Fröhlich, Tanja; Kummer, Dominic; Fontana, Stefano; Joerger, Markus; van Kuilenburg, André B P; Largiadèr, Carlo Rodolfo (2014). Predicting 5-fluorouracil toxicity: DPD genotype and 5,6-dihydrouracil:uracil ratio. Pharmacogenomics, 15(13), pp. 1653-1666. Future Medicine 10.2217/pgs.14.126
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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.
MATERIALS & 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.
CONCLUSION
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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry |
UniBE Contributor: |
Sistonen, Johanna, Büchel, Barbara, Fröhlich, Tanja, Kummer, Dominic (B), Largiadèr, Carlo Rodolfo |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1462-2416 |
Publisher: |
Future Medicine |
Language: |
English |
Submitter: |
Barbara Keller |
Date Deposited: |
05 May 2015 14:41 |
Last Modified: |
29 Mar 2023 23:34 |
Publisher DOI: |
10.2217/pgs.14.126 |
PubMed ID: |
25410891 |
Uncontrolled Keywords: |
5-fluorouracil; DPYD; chemotherapy; dihydropyrimidine dehydrogenase; dihydrouracil; genotype; pharmacogenomics; pharmacokinetics; uracil |
URI: |
https://boris.unibe.ch/id/eprint/68040 |
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