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Rapid Identification of Dihydropyrimidine Dehydrogenase Deficiency by Using a Novel 2-¹³C-Uracil Breath Test

¹ University of Alabama at Birmingham, Division of Clinical Pharmacology and Toxicology and ² Biostatistics Unit/Medical Statistics Section, Comprehensive Cancer Center, Birmingham, Alabama, and ³ Cambridge Isotope Laboratories, Inc., Andover, Massachusetts

Purpose: 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 2-¹³C-uracil breath test, which could be applied in most clinical settings to detect DPD-deficient cancer patients.

Experimental Design: Fifty-eight individuals (50 "normal," 7 partially, and 1 profoundly DPD-deficient) ingested an aqueous solution of 2-¹³C-uracil (6 mg/kg). ¹³CO₂ levels were determined in exhaled breath at various time intervals up to 180 min using IR spectroscopy (UBiT-IR₃₀₀). 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, over baseline values at 50 min (DOB₅₀) and cumulative percentage of ¹³C 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 DOB₅₀; 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 2-¹³C-uracil breath test indices (C_max, T_max, DOB₅₀, 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.

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