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

a test to predict 5-fluorouracil toxicity: Pharmacokinetic data for thymine and two sequential metabolites following oral thymine administration to healthy adult males, (2015), doi: 10.1016/j.ejps.2015.10.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A C C E P T E DM A N U S C R I P T A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT2 AbstractThe 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 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.

A case–control study to assess the ability of the thymine challenge test to predict patients with severe to life threatening fluoropyrimidine‐induced gastrointestinal toxicity

“…The values for the 0–4 h‐urinary THY/DHT ratios in the current study were comparable to the range reported previously in healthy volunteers and also in the previous case series . We observed a non‐normal distribution of urinary THY/DHT ratios, with a remarkably high number of patients in the cohort (48%) with elevated ratios (THY/DHT > 4).…”

“…Our earlier work assessing the THY challenge test focussed on the plasma pharmacokinetics of THY and its catabolites in healthy participants and in a group of 6 patients who had previously experienced G3–4 fluoropyrimidine toxicity . Intensive serial blood sampling was required to detect individuals with aberrant THY pharmacokinetic disposition (either the ETA phenotype or decreased metabolic clearance).…”

“…Recently we have developed a challenge test using thymine (THY) . Challenge tests may be particularly useful as the pyrimidine dose temporarily saturates the DPD enzyme resulting in zero order kinetics in a similar way to 5‐FU dosing.…”

Repeated cycles of 5-fluorouracil chemotherapy impaired anti-tumor functions of cytotoxic T cells in a CT26 tumor-bearing mouse model

“…5-FU is an analog of uracil that operates as an anti-metabolite by inhibiting thymidylate synthase [ 29 ] and is a widely used chemotherapeutic agent for colorectal cancer. However adverse effects including life-threatening mucositis or bone marrow suppression occur in approximately 11 % of patients on infusion therapy and 25 % with bolus therapy [ 30 ]. In our CT26 tumor-bearing murine model, we imitated the clinical chemotherapy schedule for the cycles and examined the immune functions after one- and three-cycle treatment rather than only final evaluation of immune status after chemotherapy [ 6 , 8 , 22 ].…”

Feature of Heart Rate Variability and Metabolic Mechanism in Female College Students with Depression

“…In addition, this study found that the relative level of dihydrothymine in the pyrimidine metabolic pathway was significantly decreased in students with depression. Dihydrothymine is a marker of thymine synthesis and metabolism that is often used to evaluate the metabolic level of thymine [49]. As a basic base unit of DNA and RNA, thymine plays an important physiological role in skin cancer caused by ultraviolet injury and in other diseases [50].…”