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

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• 作者：John A. Duley^a ; ^{jduley@pharmacy.uq.edu.au" class="auth_mail" title="E-mail the corresponding author} ; Ming Ni^b ; ^{m.ni@uq.edu.au" class="auth_mail" title="E-mail the corresponding author} ; Catherine Shannon^c ; ^{Catherine.Shannon@mater.org.au" class="auth_mail" title="E-mail the corresponding author} ; Ross L. Norris^d ; ¹ ; ^{Ross.Norris@svha.org.au" class="auth_mail" title="E-mail the corresponding author} ; Lesley Sheffield^e ; ^{les.sheffield@genesfx.com" class="auth_mail" title="E-mail the corresponding author} ; Marion Harris^f ; ^{Marion.Harris@southernhealth.org.au" class="auth_mail" title="E-mail the corresponding author} ; Andre B.P. van Kuilenburg^g ; ^{a.b.vankuilenburg@amc.uva.nl" class="auth_mail" title="E-mail the corresponding author} ; Scott Mead^h ; ² ; ^{scott.mead@sesiahs.health.nsw.gov.au" class="auth_mail" title="E-mail the corresponding author} ; Andrew Cameronⁱ ; ³ ; ^{andrewcmrn2011@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Nuala Helsby^j ; ^{n.helsby@auckland.ac.nz" class="auth_mail" title="E-mail the corresponding author} ; Rani George^d ; ^{ranijee21@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Bruce G. Charles^b ; ^{b.charles1@uq.edu.au" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Thymine ; Dihydrothymine ; Pharmacokinetics ; Fluorouracil toxicity ; Pyrimidine load ; HPLC-MS/MS
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2016
• 出版时间：1 January 2016
• 年：2016
• 卷：81
• 期：Complete
• 页码：36-41
• 全文大小：482 K

文摘

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.