The uracil breath test in the assessment of dihydropyrimidine dehydrogenase activity

Pharmacokinetic relationship between expired13CO 2 and plasma [2-13C] dihydrouracil

Lori K. Mattison, Jeanne Fourie, Yukihiro Hirao, Toshihisa Koga, Renee A. Desmond, Jennifer R. King, Takefumi Shimizu, Robert B Diasio

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)549-555
Number of pages7
JournalClinical Cancer Research
Volume12
Issue number2
DOIs
StatePublished - Jan 15 2006
Externally publishedYes

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Dihydrouracil Dehydrogenase (NADP)
Breath Tests
Uracil
Pharmacokinetics
Dihydropyrimidine Dehydrogenase Deficiency
Blood Cells
Fluorouracil
dihydrouracil
Tandem Mass Spectrometry
Liquid Chromatography
Area Under Curve

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The uracil breath test in the assessment of dihydropyrimidine dehydrogenase activity : Pharmacokinetic relationship between expired13CO 2 and plasma [2-13C] dihydrouracil. / Mattison, Lori K.; Fourie, Jeanne; Hirao, Yukihiro; Koga, Toshihisa; Desmond, Renee A.; King, Jennifer R.; Shimizu, Takefumi; Diasio, Robert B.

In: Clinical Cancer Research, Vol. 12, No. 2, 15.01.2006, p. 549-555.

Research output: Contribution to journalArticle

Mattison, Lori K. ; Fourie, Jeanne ; Hirao, Yukihiro ; Koga, Toshihisa ; Desmond, Renee A. ; King, Jennifer R. ; Shimizu, Takefumi ; Diasio, Robert B. / The uracil breath test in the assessment of dihydropyrimidine dehydrogenase activity : Pharmacokinetic relationship between expired13CO 2 and plasma [2-13C] dihydrouracil. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 2. pp. 549-555.
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abstract = "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.",
author = "Mattison, {Lori K.} and Jeanne Fourie and Yukihiro Hirao and Toshihisa Koga and Desmond, {Renee A.} and King, {Jennifer R.} and Takefumi Shimizu and Diasio, {Robert B}",
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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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