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.
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 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.
authors.affiliation: School of Pharmacy and Mater Research Institute, The University of Queensland, PACE building, Cornwall St, Woolloongabba, QLD 4102, Australia. Electronic address: jduley@pharmacy.uq.edu.au.
authors.forename: John A
authors.initials: JA
authors.lastname: Duley
authors.affiliation: School of Pharmacy, The University of Queensland, PACE building, Cornwall St, Woolloongabba, QLD 4102, Australia. Electronic address: m.ni@uq.edu.au.
authors.forename: Ming
authors.initials: M
authors.lastname: Ni
authors.affiliation: Department of Medical Oncology and Mater Research Institute, The University of Queensland, Mater Adult Hospital, Raymond Tce, South Brisbane, QLD 4101, Australia. Electronic address: Catherine.Shannon@mater.org.au.
authors.forename: Catherine
authors.initials: C
authors.lastname: Shannon
authors.affiliation: Mater Health Services and Griffith University, Mater Adult Hospital, Raymond Tce, South Brisbane, QLD 4101, Australia. Electronic address: Ross.Norris@svha.org.au.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Norris
authors.affiliation: GenesFX Health, Flemington Rd, North Melbourne, VIC 3051, Australia. Electronic address: les.sheffield@genesfx.com.
authors.forename: Lesley
authors.initials: L
authors.lastname: Sheffield
authors.affiliation: Monash Health, East Bentleigh, VIC 3165, Australia. Electronic address: Marion.Harris@southernhealth.org.au.
authors.forename: Marion
authors.initials: M
authors.lastname: Harris
authors.affiliation: Academic Medical Center, Laboratory for Genetic Metabolic Diseases, Meibergdreef, Amsterdam, 1105 AZ, The Netherlands. Electronic address: a.b.vankuilenburg@amc.uva.nl.
authors.forename: Andre B P
authors.initials: AB
authors.lastname: van Kuilenburg
authors.affiliation: Department of Pathology, Otago School of Medicine, Canterbury Health Laboratories, Christchurch Hospital, Riccarton Ave., Christchurch 8104, New Zealand. Electronic address: scott.mead@sesiahs.health.nsw.gov.au.
authors.forename: Scott
authors.initials: S
authors.lastname: Mead
authors.affiliation: Department of Medical Oncology, Mater Adult Hospital, Raymond Tce, South Brisbane, QLD 4101, Australia. Electronic address: andrewcmrn2011@gmail.com.
authors.forename: Andrew
authors.initials: A
authors.lastname: Cameron
authors.affiliation: Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Auckland, New Zealand. Electronic address: n.helsby@auckland.ac.nz.
authors.forename: Nuala
authors.initials: N
authors.lastname: Helsby
authors.affiliation: Mater Health Services and Griffith University, Mater Adult Hospital, Raymond Tce, South Brisbane, QLD 4101, Australia. Electronic address: ranijee21@gmail.com.
authors.forename: Rani
authors.initials: R
authors.lastname: George
authors.affiliation: School of Pharmacy, The University of Queensland, PACE building, Cornwall St, Woolloongabba, QLD 4102, Australia. Electronic address: b.charles1@uq.edu.au.
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Charles
mesh_terms: D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D005472:Fluorouracil / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012463:Saliva / Q000378:metabolism; D013941:Thymine / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D014508:Urea / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine
chemical_list: D000964:Antimetabolites, Antineoplastic; C066926:beta-ureidoisobutyric acid; D014508:Urea; D013941:Thymine; D005472:Fluorouracil
keywords: Dihydrothymine; Fluorouracil toxicity; HPLC-MS/MS; Pharmacokinetics; Pyrimidine load; Thymine