Towards a test to predict 5-fluorouracil toxicity: pharmacokinetic data for thymine and two sequential metabolites following oral thymine administration to healthy adult males

Duley, John A., Ni, Ming, Shannon, Catherine, Norris, Ross L., Sheffield, Lesley, Harris, Marion, van Kuilenburg, Andre B. P., Mead, Scott, Cameron, Andrew, Helsby, Nuala, George, Rani and Charles, Bruce G. (2016) Towards a test to predict 5-fluorouracil toxicity: pharmacokinetic data for thymine and two sequential metabolites following oral thymine administration to healthy adult males. European Journal of Pharmaceutical Sciences, 81 36-41. doi:10.1016/j.ejps.2015.10.001

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Author Duley, John A.
Ni, Ming
Shannon, Catherine
Norris, Ross L.
Sheffield, Lesley
Harris, Marion
van Kuilenburg, Andre B. P.
Mead, Scott
Cameron, Andrew
Helsby, Nuala
George, Rani
Charles, Bruce G.
Title Towards a test to predict 5-fluorouracil toxicity: pharmacokinetic data for thymine and two sequential metabolites following oral thymine administration to healthy adult males
Journal name European Journal of Pharmaceutical Sciences   Check publisher's open access policy
ISSN 1879-0720
0928-0987
Publication date 2016-01-01
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.ejps.2015.10.001
Open Access Status File (Author Post-print)
Volume 81
Start page 36
End page 41
Total pages 6
Place of publication Amsterdam, Netherlands
Publisher Elsevier
Collection year 2016
Language eng
Formatted abstract
The fluoropyrimidine drugs 5-fluorouracil and its oral prodrug capecitabine remain first line therapy for solid tumours of the neck, breast and colon. However, significant and unpredictable toxicity affects about 10–25% of patients depending upon the mode of 5-fluorouracil delivery. The pharmacokinetics of thymine (5-methyluracil) may provide an approach for screening for 5-fluorouracil toxicity, based on the rationale that thymine is a close structural analogue of 5-fluorouracil and is catabolized by the same enzymatic pathway.

Oral thymine loading tests were performed on 12 healthy volunteers. Each subject was given a single oral dose of 250 mg thymine in capsule form. Blood, urine and saliva samples were collected pre-dose and up to 5 h post-dose. Concentrations of thymine, and its catabolites dihydrothymine and ß-ureidoisobutyrate were analysed by HPLC-tandem mass spectrometry in plasma, urine and saliva. The pharmacokinetic data of healthy volunteers were analysed assuming a non-compartmental model. Thymine peaked quickly (30–45 min) in plasma to a maximum concentration of 170 ± 185 μg/L (mean ± SD). Clearance was high (mean 57.9 L/h/kg) exceeding normal human liver blood flow, suggesting low systemic bioavailability; urinary recovery of the thymine dose was low (< 1%). Apparent formation rate-limited kinetics were observed for dihydrothymine, and the plasma concentration of dihydrothymine was consistently 10-fold higher than that of thymine. Plasma ß-ureidoisobutyrate concentrations, on the other hand, were similar to that of thymine. Genotyping confirmed that pathological mutations of the DPYD gene were absent. The urinary excretion ratio of thymine/dihydrothymine was informative of the maximum concentration. Saliva thymine was highly variable. These data are potentially useful as a basis for developing of a screening procedure to prospectively identify patients who are at risk of toxicity from fluoropyrimidine drugs.
Keyword Thymine
Dihydrothymine
Pharmacokinetics
Fluorouracil toxicity
Pyrimidine load
HPLC-MS/MS
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
Official 2016 Collection
School of Pharmacy Publications
 
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