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

Autor: Scott Mead, Lesley Sheffield, André B.P. van Kuilenburg, Andrew Cameron, Ross Norris, Marion Harris, Bruce G. Charles, Rani George, Ming Ni, Catherine Shannon, John A. Duley, Nuala A. Helsby
Přispěvatelé: Amsterdam Gastroenterology Endocrinology Metabolism, Cancer Center Amsterdam, Laboratory Genetic Metabolic Diseases
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Zdroj: European journal of pharmaceutical sciences, 81, 36-41. Elsevier
ISSN: 0928-0987
DOI: 10.1016/j.ejps.2015.10.001
Popis: 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 s-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 s-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.
Databáze: OpenAIRE
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