Fluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine, are among the most frequently prescribed anticancer drugs. They are inactivated by the enzyme dihydropyrimidine dehydrogenase (DPD... Show moreFluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine, are among the most frequently prescribed anticancer drugs. They are inactivated by the enzyme dihydropyrimidine dehydrogenase (DPD). Up to 5% of the population is DPD deficient and these patients have a significantly increased risk of severe and potentially lethal toxicity when treated with regular doses of 5-FU or capecitabine. DPD is encoded by the gene DPYD and variants in DPYD can lead to a decreased DPD activity. Although prospective DPYD genotyping is a valuable tool to identify patients with DPD deficiency, and thus those at risk for severe and potential life-threatening toxicity, prospective genotyping has not yet been implemented in daily clinical care.With this thesis we improved knowledge on different aspects of DPYD genotyping and DPD phenotyping, in order to better predict DPD deficient patients and personalize their therapy. In addition, we improved clinical implementation of DPYD genotyping, and reduced the risk of severe fluoropyrimidine-induced toxicity in DPYD variant allele carriers. Show less
Fluoropyrimidines are being used in the treatment of different types of cancer. The most common fluoropyrimidine is 5-flourouracil (5-FU), which is administered intravenously as a bolus or as... Show moreFluoropyrimidines are being used in the treatment of different types of cancer. The most common fluoropyrimidine is 5-flourouracil (5-FU), which is administered intravenously as a bolus or as prolonged infusion. Many tissues throughout the body express thymidine phosphorylase. Dihydropyrimidine Dehydrogenase (DPD) is involved in the degradation of endogenous pyrimidine nucleosides, but also in the degradation of fluoropyrimidines. More than 80% of the amount of 5-FU administered is catabolized primarily in the liver where DPD is abundantly expressed. DPD is encoded by the DPYD gene for which 567 coding variants are known to date, some of them being pathogenic by reducing enzyme capacity. Interindividual variability in the activity of DPD influences 5-FU pharmacokinetics and a reduced DPD activity can lead to severe toxicity and even death following administration of 5-FU or capecitabine. Knowledge regarding the clinical impact of reduced DPD activity on the pharmacokinetics and pharmacodynamics of fluoropyrimidines may be useful to dose individualize therapy. In this thesis, an in depth overview is given of methods and their potential to optimize fluoropyrimidine dosing based on individual DPD enzyme activity. Furthermore an oral uracil loading dose as probe for DPD deficiency in cancer patients treated with fluoropyrimdines for this purpose is studied. Show less
