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
School of Pharmacy and Mater Research Institute, The University of Queensland, PACE building, Cornwall St, Woolloongabba, QLD 4102, Australia.
School of Pharmacy, The University of Queensland, PACE building, Cornwall St, Woolloongabba, QLD 4102, Australia.
Eur J Pharm Sci. 2016 Jan 1;81:36-41. doi: 10.1016/j.ejps.2015.10.001. Epub 2015 Oct 3.
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.
氟嘧啶类药物5-氟尿嘧啶及其口服前体药物卡培他滨仍是颈部、乳腺和结肠实体瘤的一线治疗药物。然而，根据5-氟尿嘧啶的给药方式不同，约10%-25%的患者会受到显著且不可预测的毒性影响。胸腺嘧啶（5-甲基尿嘧啶）的药代动力学可能为筛查5-氟尿嘧啶毒性提供一种方法，其依据是胸腺嘧啶是5-氟尿嘧啶的紧密结构类似物，且通过相同的酶促途径进行分解代谢。对12名健康志愿者进行了口服胸腺嘧啶负荷试验。每位受试者口服一粒含250mg胸腺嘧啶的胶囊。在给药前及给药后长达5小时采集血液、尿液和唾液样本。采用高效液相色谱-串联质谱法分析血浆、尿液和唾液中胸腺嘧啶及其分解代谢产物二氢胸腺嘧啶和β-脲基异丁酸的浓度。采用非房室模型分析健康志愿者的药代动力学数据。胸腺嘧啶在血浆中迅速达到峰值（30-45分钟），最大浓度为170±185μg/L（平均值±标准差）。清除率较高（平均57.9L/h/kg），超过正常人体肝脏血流量，表明全身生物利用度较低；胸腺嘧啶剂量的尿液回收率较低（<1%）。观察到二氢胸腺嘧啶存在明显的形成速率限制动力学，且二氢胸腺嘧啶的血浆浓度始终比胸腺嘧啶高10倍。另一方面，血浆β-脲基异丁酸浓度与胸腺嘧啶相似。基因分型证实不存在DPYD基因的病理性突变。胸腺嘧啶/二氢胸腺嘧啶的尿液排泄率与最大浓度相关。唾液中胸腺嘧啶的含量变化很大。这些数据可能有助于开发一种筛查程序，以前瞻性地识别有氟嘧啶类药物毒性风险的患者。
