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LBOVI‐B‐2
Author(s) -
Mattison L. K.,
Acosta E. P.,
Fourie J.,
Diasio R. B.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.298
Subject(s) - dihydropyrimidine dehydrogenase , metabolite , catabolism , breath test , pharmacokinetics , medicine , uracil , endocrinology , chemistry , metabolism , cancer , biochemistry , fluorouracil , thymidylate synthase , dna , helicobacter pylori
BACKGROUND Dihydropyrimidine dehydrogenase (DPD) deficiency leads to life‐threatening 5‐Fluorouracil toxicity. We developed a 2‐ 13 C‐uracil ( 13 C‐Ura) breath test (BT) to rapidly screen cancer patients. Deficient patients have low breath 13 CO 2 concentrations due to reduced catabolism of 13 C‐Ura to 13 C‐dihydrouracil ( 13 C‐DHU) and 13 CO 2.AIM Develop a pharmacokinetic (PK) model to simultaneously describe 13 C‐Ura and catabolite concentrations in plasma and breath from normal and DPD deficient subjects. METHODS Blood and breath samples were collected for 3h after oral 13 C‐Ura (6 mg/kg) administration to 19 normal and 10 DPD deficient subjects. Plasma 13 C‐Ura, 13 C‐DHU, and breath 13 CO 2 concentrations were quantified. ADAPT II simultaneously fitted parent, metabolite, and breath concentration‐time data. Akaike's Information Criterion was used to select the model. RESULTS A one compartment linear absorption/elimination parent/metabolite model with cumulative breath 13 CO 2 elimination described concentration‐time data of 13 C‐Ura, 13 C‐DHU, and 13 CO 2 . Significant differences in modeled PK parameters between normal and DPD deficient subjects were observed. CONCLUSION This is the first model to simultaneously describe orally administered 13 C‐Ura disposition in normal and DPD deficient subjects. Bayesian parameter estimation and simulation studies will be used to identify an optimal limited sampling strategy to detect DPD deficiency in patients who aren't candidates for BT screening. (See Table)PK Parameter Normal Subjects (Mean ± SD) DPD Deficient Subjects (Mean ± SD) Mann‐Whitney U Test p Value13 C‐Ura Half‐life (h) 0.18 ± 0.07 0.60 ± 0.67 ≤ 0.00113 C‐Ura Clearance (L/kg/h) 1.54 ± 0.63 0.77 ± 0.30 ≤ 0.00113 C‐DHU Formation Rate Constant (1/h) 3.23 ± 2.48 1.24 ± 0.64 ≤ 0.001Clinical Pharmacology & Therapeutics (2005) 79 , P83–P83; doi: 10.1016/j.clpt.2005.12.298