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-C-13] uracil breath test (UraBT) with 96% specificity and 100% sensitivity for identification of DPD deficiency. In the present study, we characterize the relationships among Ura BT-associated breath (CO2)-C-13 metabolite formation, plasma [2-C-13]dihydrouracil formation, [2-C-13] uracil clearance, and DPD activity. Experimental Design: An aqueous solution of [2-C-13] uracil (6 mg/kg) was orally administered to 23 healthy volunteers and 8 cancer patients. Subsequently, breath (CO2)-C-13 concentrations and plasma [2-C-13] dihydrouracil and [2-C-13] 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 (CO2)-C-13 DOB50 significantly correlated with PBMC DPD activity (r(p) = 0.78), plasma [2-C-13] uracil area under the curve (rp = -0.73), [2-C-13]dihydrouracil appearance rate (r(p) = 0.76), and proportion of [2-C-13] uracil metabolized to [2-C-13]dihydrouracil (r(p) = 0.77; all Ps < 0.05). Conclusions: UraBT breath (CO2)-C-13 pharmacokinetics parallel plasma [2-C-13] uracil and [2-C-13]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.