Physiologically based pharmacokinetic modelling of the three-step metabolism of pyrimidine using C-uracil as an in vivo probe.
OBJECTIVE
Approximately 80% of uracil is excreted as beta-alanine, ammonia and CO2 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 beta-ureidopropionic acid (ureido-(13)C) in plasma and urine and (13)CO2 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 pharmacokinetics of (13)CO2 in expired air were linear and the recovery of (13)CO2 was approximately 80% of the dose. The renal clearance of [2-(13)C]uracil was negligible.


CONCLUSIONS
A PBPK model to describe (13)CO2 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-fluorouracil toxicity.
Ito
Suminobu
S
Department of Clinical Pharmacology, Juntendo University School of Medicine, Tokyo, Japan.
Kawamura
Takeshi
T
Inada
Makoto
M
Inoue
Yoshiharu
Y
Hirao
Yukihiro
Y
Koga
Toshihisa
T
Kunizaki
Jun-ichi
J
Shimizu
Takefumi
T
Sato
Hitoshi
H
D000328:Adult; D001944:Breath Tests / Q000379:methods; D002245:Carbon Dioxide / Q000502:physiology; D002247:Carbon Isotopes; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000097:blood / Q000652:urine; D004305:Dose-Response Relationship, Drug; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D014498:Uracil / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D002247:Carbon Isotopes; D002245:Carbon Dioxide; D014498:Uracil; D042943:Dihydrouracil Dehydrogenase (NADP)