Young A M, Daryanani S, Kerr D J
CRC Institute of Cancer Studies, University of Birmingham, Edgbaston, England.
Clin Pharmacokinet. 1999 Jun;36(6):391-8. doi: 10.2165/00003088-199936060-00001.
Fluorouracil is used clinically against a variety of solid tumors. It is a prodrug that undergoes a series of intracellular conversions to active cytotoxic species. There is wide interindividual variability in fluorouracil metabolism; furthermore, it has nonlinear kinetics that make it relatively more difficult to predict plasma concentrations after brief infusions compared with prolonged infusions. There is an increasing body of evidence that relates plasma fluorouracil concentrations to toxicity and effectiveness, and consequently there may be a definable mathematical relationship that describes a 'therapeutic window'. Dose nomograms and pharmacokinetic models based on limited sampling strategies have been developed, as have empirical dose escalation schedules based on multivariate analysis of the determinants of toxicity, The utility of these approaches should be tested in properly powered, prospective, randomised trials.
氟尿嘧啶在临床上用于治疗多种实体瘤。它是一种前体药物，会经历一系列细胞内转化形成具有细胞毒性的活性物质。氟尿嘧啶的代谢存在广泛的个体差异；此外，它具有非线性动力学，这使得与长时间输注相比，在短时间输注后预测血浆浓度相对更困难。越来越多的证据表明血浆氟尿嘧啶浓度与毒性和疗效相关，因此可能存在一种可定义的数学关系来描述“治疗窗”。基于有限采样策略的剂量列线图和药代动力学模型已被开发出来，基于毒性决定因素多变量分析的经验性剂量递增方案也已出现。这些方法的实用性应在有充分效力的前瞻性随机试验中进行检验。
