Evaluation of an oral uracil loading test to identify DPD-deficient patients using a limited sampling strategy.
نویسندگان
چکیده
AIM Dihydropyrimidine dehydrogenase (DPD) deficiency can lead to severe toxicity following 5-fluorouracil (5FU) or capecitabine (CAP) treatment. Uracil (U) can be used as a probe to determine systemic DPD activity. The present study was performed to assess the sensitivity and specificity of a U loading dose for detecting DPD deficiency. METHODS Cancer patients with Common Toxicity Score (CTC) grade III or IV toxicity after the first or second cycle of 5-FU or CAP treatment were asked to participate. Based on DPD activity in PBMCs, patients were divided into two groups: DPD activity in peripheral blood mononuclear cells (PBMCs) <5 nmol mg(-1) *h(-1) (deficient group) and ≥ 5 nmol mg(-1) *h(-1) . U 500 mg m(-2) was administered orally and plasma concentrations of U and dihydrouracil (DHU) were determined. In the deficient group, polymerase chain reaction amplification of all 23 coding exons and flanking intronic regions of DPYD was performed. A U pharmacokinetic model was developed and used to determine the maximum enzymatic conversion capacity (Vmax ) of the DPD enzyme for each patient. The sensitivity and specificity of Vmax, U concentration and the U/DHU concentration ratio were determined. RESULTS A total of 47 patients were included (19 DPD deficient, 28 DPD normal). Of the pharmacokinetic parameters investigated, a sensitivity and specificity of 80% and 98%, respectively, was obtained for the U/DHU ratio at t = 120 min. CONCLUSIONS The high sensitivity of the U/DHU ratio at t = 120 min for detecting DPD deficiency, as defined by DPD activity in PBMCs, showed that the oral U loading dose can effectively identify patients with reduced DPD activity.
منابع مشابه
Rapid identification of dihydropyrimidine dehydrogenase deficiency by using a novel 2-13C-uracil breath test.
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-(13)C-uracil breath test, which could be applied in most clinical settings to detect...
متن کاملRapid Identification of Dihydropyrimidine Dehydrogenase Deficiency by Using a Novel 2-C-Uracil Breath Test
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-C-uracil breath test, which could be applied in most clinical settings to detect DP...
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The Uracil Breath Test in theAssessment of Dihydropyrimidine Dehydrogenase Activity: Pharmacokinetic Relationship between Expired
Purpose:Dihydropyrimidine dehydrogenase (DPD) deficiency is critical in the predisposition to 5-fluorouracil dose-related toxicity. We recently characterized the phenotypic [2-C]uracil breath test (UraBT) with 96% specificity and100% sensitivity for identification of DPD deficiency. In the present study, we characterize the relationships among UraBT-associated breath CO2 metabolite formation, p...
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Dihydropyrimidine dehydrogenase (DPD), the first enzyme in the sequential metabolism of pyrimidine, regulates blood concentrations of 5-fluorouracil and is deeply involved in its toxicity. This study was designed to examine the effects of a DPD inhibitor on blood concentrations of [2-(13)C]uracil ([(13)C]uracil) and (13)CO(2) concentration (Delta(13)C) expired in breath after oral or intravenou...
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ورودعنوان ژورنال:
- British journal of clinical pharmacology
دوره 81 3 شماره
صفحات -
تاریخ انتشار 2016