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

• Published in: European journal of pharmaceutical sciences Vol. 81; pp. 36 - 41
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2016
• Subjects: Adult; Antimetabolites, Antineoplastic - adverse effects; Dihydrothymine; Fluorouracil - adverse effects; Fluorouracil toxicity; HPLC-MS/MS; Humans; Male; Middle Aged; Models, Biological; Pharmacokinetics; Pyrimidine load; Saliva - metabolism; Thymine; Thymine - blood; Thymine - pharmacokinetics; Thymine - urine; Urea - analogs & derivatives; Urea - blood; Urea - urine; Pyrimidine load; Dihydrothymine; HPLC-MS/MS; Pharmacokinetics; Thymine; Fluorouracil toxicity
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2015.10.001

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 250mg thymine in capsule form. Blood, urine and saliva samples were collected pre-dose and up to 5h 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 (30–45min) in plasma to a maximum concentration of 170±185μg/L (mean±SD). Clearance was high (mean 57.9L/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. [Display omitted]