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Physiologically based pharmacokinetic modelling of the three‐step metabolism of pyrimidine using 13 C‐uracil as an in vivo probe
Author(s) -
Ito Suminobu,
Kawamura Takeshi,
Inada Makoto,
Inoue Yoshiharu,
Hirao Yukihiro,
Koga Toshihisa,
Kunizaki Junichi,
Shimizu Takefumi,
Sato Hitoshi
Publication year - 2005
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2005.02472.x
Subject(s) - uracil , dihydropyrimidine dehydrogenase , chemistry , pharmacokinetics , pyrimidine , in vivo , urine , stereochemistry , pharmacology , fluorouracil , biochemistry , medicine , dna , cancer , biology , microbiology and biotechnology , thymidylate synthase
Aims Approximately 80% of uracil is excreted as β‐alanine, ammonia and CO 2 via three sequential reactions. The activity of the first enzyme in this scheme, dihydropyrimidine dehydrogenase (DPD), is reported to be the key determinant of the cytotoxicity and side‐effects of 5‐fluorouracil. The aim of the present study was to re‐evaluate the pharmacokinetics of uracil and its metabolites using a sensitive assay and based on a newly developed, physiologically based pharmacokinetic (PBPK) model. Methods [2– 13 C]Uracil was orally administrated to 12 healthy males at escalating doses of 50, 100 and 200 mg, and the concentrations of [2– 13 C]uracil, [2– 13 C]5,6‐dihydrouracil and β‐ureidopropionic acid (ureido‐ 13 C) in plasma and urine and 13 CO 2 in breath were measured by liquid chromatography–tandem mass spectrometry and gas chromatograph–isotope ratio mass spectrometry, respectively. Results The pharmacokinetics of [2– 13 C]uracil were nonlinear. The elimination half‐life of [2– 13 C]5,6‐dihydrouracil was 0.9–1.4 h, whereas that of [2– 13 C]uracil was 0.2–0.3 h. The AUC of [2– 13 C]5,6‐dihydrouracil was 1.9–3.1 times greater than that of [2– 13 C]uracil, whereas that of ureido‐ 13 C was 0.13–0.23 times smaller. The pharamacokinetics of 13 CO 2 in expired air were linear and the recovery of 13 CO 2 was approximately 80% of the dose. The renal clearance of [2– 13 C]uracil was negligible. Conclusion A PBPK model to describe 13 CO 2 exhalation after orally administered [2– 13 C]uracil was successfully developed. Using [2– 13 C]uracil as a probe, this model could be useful in identifying DPD‐deficient patients at risk of 5‐fuorouracil toxicity.

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