Predicting 5-fluorouracil toxicity: DPD genotype and 5,6-dihydrouracil:uracil ratio

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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AIM 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 and 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:

09 Nov 2015 11:40

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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