TY - JOUR
T1 - The uracil breath test in the assessment of dihydropyrimidine dehydrogenase activity
T2 - Pharmacokinetic relationship between expired13CO 2 and plasma [2-13C] dihydrouracil
AU - Mattison, Lori K.
AU - Fourie, Jeanne
AU - Hirao, Yukihiro
AU - Koga, Toshihisa
AU - Desmond, Renee A.
AU - King, Jennifer R.
AU - Shimizu, Takefumi
AU - Diasio, Robert B.
PY - 2006/1/15
Y1 - 2006/1/15
N2 - Purpose: Dihydropyrimidine dehydrogenase (DPD) deficiency is critical in the predisposition to 5-fluorouracil dose-related toxicity. We recently characterized the phenotypic [2-13C]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 13CO2 metabolite formation, plasma [2- 13C]dihydrouracil formation, [2-13C]uracil clearance, and DPD activity. Experimental Design: An aqueous solution of [2-13C] uracil (6 mg/kg) was orally administered to 23 healthy volunteers and 8 cancer patients. Subsequently, breath 13CO2 concentrations and plasma [2-13C]dihydrouracil and [2-13C]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 13CO2 DOB50 significantly correlated with PBMC DPD activity (rp = 0.78), plasma [2-13C] uracil area under the curve (rp = -0.73), [2-13C]dihydrouracil appearance rate (rp = 0.76), and proportion of [2- 13C]uracil metabolized to [2-13C] dihydrouracil (r p = 0.77; all Ps < 0.05). Conclusions: UraBT breath 13CO2 pharmacokinetics parallel plasma [2- 13C]uracil and [2-13C] 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.
AB - Purpose: Dihydropyrimidine dehydrogenase (DPD) deficiency is critical in the predisposition to 5-fluorouracil dose-related toxicity. We recently characterized the phenotypic [2-13C]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 13CO2 metabolite formation, plasma [2- 13C]dihydrouracil formation, [2-13C]uracil clearance, and DPD activity. Experimental Design: An aqueous solution of [2-13C] uracil (6 mg/kg) was orally administered to 23 healthy volunteers and 8 cancer patients. Subsequently, breath 13CO2 concentrations and plasma [2-13C]dihydrouracil and [2-13C]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 13CO2 DOB50 significantly correlated with PBMC DPD activity (rp = 0.78), plasma [2-13C] uracil area under the curve (rp = -0.73), [2-13C]dihydrouracil appearance rate (rp = 0.76), and proportion of [2- 13C]uracil metabolized to [2-13C] dihydrouracil (r p = 0.77; all Ps < 0.05). Conclusions: UraBT breath 13CO2 pharmacokinetics parallel plasma [2- 13C]uracil and [2-13C] 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.
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U2 - 10.1158/1078-0432.CCR-05-2020
DO - 10.1158/1078-0432.CCR-05-2020
M3 - Article
C2 - 16428499
AN - SCOPUS:31544475978
SN - 1078-0432
VL - 12
SP - 549
EP - 555
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 2
ER -