Rapid identification of dihydropyrimidine dehydrogenase deficiency by using a novel 2-13C-uracil breath test.
OBJECTIVE
Dihydropyrimidine dehydrogenase (DPD)-deficient cancer patients have been shown to develop severe toxicity after administration of 5-fluorouracil. Routine determination of DPD activity is limited by time-consuming and labor-intensive methods. The purpose of this study was to develop a simple and rapid 2-(13)C-uracil breath test, which could be applied in most clinical settings to detect DPD-deficient cancer patients.


METHODS
Fifty-eight individuals (50 "normal," 7 partially, and 1 profoundly DPD-deficient) ingested an aqueous solution of 2-(13)C-uracil (6 mg/kg). (13)CO(2) levels were determined in exhaled breath at various time intervals up to 180 min using IR spectroscopy (UBiT-IR(300)). DPD enzyme activity and DPYD genotype were determined by radioassay and denaturing high-performance liquid chromatography, respectively.


RESULTS
The mean (+/-SE) C(max), T(max), delta over baseline values at 50 min (DOB(50)) and cumulative percentage of (13)C dose recovered (PDR) for normal, partially, and profoundly DPD-deficient individuals were 186.4 +/- 3.9, 117.1 +/- 9.8, and 3.6 DOB; 52 +/- 2, 100 +/- 18.4, and 120 min; 174.1 +/- 4.6, 89.6 +/- 11.6, and 0.9 DOB(50); and 53.8 +/- 1.0, 36.9 +/- 2.4, and <1 PDR, respectively. The differences between the normal and DPD-deficient individuals were highly significant (all Ps <0.001).


CONCLUSIONS
We demonstrated statistically significant differences in the 2-(13)C-uracil breath test indices (C(max), T(max), DOB(50), and PDR) among healthy and DPD-deficient individuals. These data suggest that a single time-point determination (50 min) could rapidly identify DPD-deficient individuals with a less costly and time-consuming method that is applicable for most hospitals or physicians' offices.
Mattison
Lori K
LK
University of Alabama at Birmingham, Division of Clinical Pharmacology and Toxicology, 35294, USA.
Ezzeldin
Hany
H
Carpenter
Mark
M
Modak
Anil
A
Johnson
Martin R
MR
Diasio
Robert B
RB
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001944:Breath Tests; D002245:Carbon Dioxide / Q000737:chemistry; D002247:Carbon Isotopes; D002851:Chromatography, High Pressure Liquid; D003955:Diagnostic Tests, Routine / Q000379:methods*; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D005472:Fluorouracil / Q000633:toxicity; D005838:Genotype; D006801:Humans; D010641:Phenotype; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013997:Time Factors; D014498:Uracil
D000964:Antimetabolites, Antineoplastic; D002247:Carbon Isotopes; D002245:Carbon Dioxide; D014498:Uracil; D005472:Fluorouracil