The Uracil Breath Test in the Assessment of Dihydropyrimidine Dehydrogenase Activity: Pharmacokinetic Relationship between Expired 13CO2 and Plasma [2-13C]Dihydrouracil

Purpose: Dihydropyrimidine dehydrogenase (DPD) deficiency is critical in the predisposition to 5-fluorouracil dose-related toxicity. We recently characterized the phenotypic [2- 13 C]uracil breath test (UraBT) with 96% specificity and 100% sensitivity for identification of DPD deficiency. In the present study, we characterize the relationships among UraBT-associated breath 13 CO 2 metabolite formation, plasma [2- 13 C]dihydrouracil formation, [2- 13 C]uracil clearance, and DPD activity. Experimental Design: An aqueous solution of [2- 13 C]uracil (6 mg/kg) was orally administered to 23 healthy volunteers and 8 cancer patients. Subsequently, breath 13 CO 2 concentrations and plasma [2- 13 C]dihydrouracil and [2- 13 C]uracil concentrations were determined over 180 minutes using IR spectroscopy and liquid chromatography-tandem mass spectrometry, respectively. Pharmacokinetic variables were determined using noncompartmental methods. Peripheral blood mononuclear cell (PBMC) DPD activity was measured using the DPD radioassay. Results: The UraBT identified 19 subjects with normal activity, 11 subjects with partial DPD deficiency, and 1 subject with profound DPD deficiency with PBMC DPD activity within the corresponding previously established ranges. UraBT breath 13 CO 2 DOB 50 significantly correlated with PBMC DPD activity ( r p = 0.78), plasma [2- 13 C]uracil area under the curve ( r p = −0.73), [2- 13 C]dihydrouracil appearance rate ( r p = 0.76), and proportion of [2- 13 C]uracil metabolized to [2- 13 C]dihydrouracil ( r p = 0.77; all P s Conclusions: UraBT breath 13 CO 2 pharmacokinetics parallel plasma [2- 13 C]uracil and [2- 13 C]dihydrouracil pharmacokinetics and are an accurate measure of interindividual variation in DPD activity. These pharmacokinetic data further support the future use of the UraBT as a screening test to identify DPD deficiency before 5-fluorouracil-based therapy.