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

Authors' Affiliations: Divisions of ¹ Clinical Pharmacology and Toxicology and ² Biostatistics, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama and ³ Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan

Requests for reprints: Robert B. Diasio, Division of Clinical Pharmacology and Toxicology, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 6th Avenue South, Wallace Tumor Institute, Room 620, Birmingham, AL 35294-3300. Fax: 205-975-5650; E-mail: robert.diasio{at}ccc.uab.edu.

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 (r_p = 0.78), plasma [2-¹³C]uracil area under the curve (r_p = –0.73), [2-¹³C]dihydrouracil appearance rate (r_p = 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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