Toxicology, The Department of Biochemistry, Canterbury Health Laboratories, Christchurch, New Zealand.
Ther Drug Monit. 2020 Oct;42(5):660-664. doi: 10.1097/FTD.0000000000000788.
5-Fluorouracil (5-FU) response prediction and therapeutic drug monitoring (TDM) are required to minimize toxicity while preserving efficacy. Conventional 5-FU dose normalization uses body surface area. It is characterized by up to 100-fold interindividual variability of pharmacokinetic (PK) parameters, and typically >50% of patients have plasma 5-FU concentrations outside the optimal range. This underscores the need for a different dose rationalization paradigm, hence there is a case for 5-FU TDM. An association between 5-FU PK parameters and efficacy/toxicity has been established. It is believed that 5-FU response is enhanced and toxicity is reduced by PK management of its dosing. The area under the concentration-time curve is the most relevant PK parameter associated with 5-FU efficacy/toxicity, and optimal therapeutic windows have been proposed. Currently, there is no universally applied a priori test for predicting 5-FU response and identifying individuals with an elevated risk of toxicity. The following two-step strategy: prediction of response/toxicity and TDM for subsequent doses seems plausible. Approximately 80% of 5-FU is degraded in a three-step sequential metabolic pathway. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme. Its deficiency can cause toxicity with standard 5-FU doses. DPD also metabolizes uracil (U) into 5,6-dihydrouracil (UH2). The UH2/U ratio is an index of DPD activity and a credible biomarker of response and toxicity. This article outlines the UH2/U ratio as a parameter for 5-FU response/toxicity prediction and highlights key studies emphasizing the value of 5-FU TDM. Broad application of 5-FU response/toxicity prediction and blood level-guided therapy remains unmet, despite ever-increasing clinical interest. Considered collectively, existing evidence is compelling and fundamentally supports universal instigation of response/toxicity prediction and TDM.
5-氟尿嘧啶（5-FU）的疗效预测和治疗药物监测（TDM）是必需的，以在保留疗效的同时最小化毒性。传统的 5-FU 剂量标准化使用体表面积。它的特点是药代动力学（PK）参数的个体间变异性高达 100 倍，通常 >50%的患者的血浆 5-FU 浓度不在最佳范围内。这凸显了需要一种不同的剂量合理化范式，因此需要进行 5-FU TDM。已经建立了 5-FU PK 参数与疗效/毒性之间的关联。人们相信通过 PK 管理 5-FU 的给药剂量可以增强 5-FU 的疗效并降低毒性。浓度-时间曲线下面积是与 5-FU 疗效/毒性最相关的 PK 参数，并提出了最佳治疗窗。目前，还没有普遍应用的预测 5-FU 反应和识别毒性升高风险个体的先验测试。以下两步策略似乎合理：预测反应/毒性和为随后的剂量进行 TDM。大约 80%的 5-FU 在一个三步连续代谢途径中被降解。二氢嘧啶脱氢酶（DPD）是初始和限速酶。其缺乏可导致标准 5-FU 剂量的毒性。DPD 还将尿嘧啶（U）代谢为 5,6-二氢尿嘧啶（UH2）。UH2/U 比值是 DPD 活性的指标，也是反应和毒性的可靠生物标志物。本文概述了 UH2/U 比值作为 5-FU 反应/毒性预测的参数，并强调了强调 5-FU TDM 价值的关键研究。尽管临床兴趣不断增加，但广泛应用 5-FU 反应/毒性预测和基于血液水平的治疗仍未实现。综合考虑，现有证据令人信服，从根本上支持普遍开展反应/毒性预测和 TDM。
