Safe use of fluoropyrimidines in oncology: Development of a method for the determination of plasma uracil and dihydrouracil levels by UHPLC-MS-MS and screening for Dihydropyrimidine Dehydrogenase deficiency

Abstract

5-Fluorouracil (5-FU) is a widely used drug in oncology. It can cause toxicity, especially in the case of Dihydropyrimidine Dehydrogenase (DPD) deficiency. An enzyme responsible for the inactivation of more than 80% of the 5-FU dose and for the transformation of uracil (U) into dihydrouracile (UH2). A sensitive method is needed to screen for DPD deficiency by determination of U level, as recommended by the European Medicine Agency (EMA). Separation was performed by an UHPLC on a C18 column and a tandem mass spectrometer performed the detection of U and UH2. The method’s performance was validated according to ICH M10 recommendations. The validated method was used to screen for DPD deficiency in fifty-seven hospitalized patients. None of the patients showed DPD deficiency based on the U-rate instead of the metabolic ratio UH2/U (7.08%) which might be a more sensitive tool for this screening