Laboratoire de Pharmacocinétique et Toxicologie, CHU Timone, APHM, Marseille, France.
SMARTc unit, Centre de Recherche en Cancérologie de Marseille, Marseille, France.
Br J Clin Pharmacol. 2022 Nov;88(11):4928-4932. doi: 10.1111/bcp.15482. Epub 2022 Aug 21.
Measuring uracil (U) levels in plasma is a convenient surrogate to establish dihydropyrimidine dehydrogenase (DPD) status in patients scheduled with 5-fluorouracil (5-FU) or capecitabine. To what extent renal impairment could impact on U levels and thus be a confounding factor is a rising concern. Here, we report the case of a cancer patient with severe renal impairment scheduled for 5-FU-based regimen. Determination of his DPD status was complicated because of his condition and the influence of intermittent haemodialysis when monitoring U levels. The patient was initially identified as markedly DPD-deficient upon U measurement (i.e., U = 40 ng/mL), but further monitoring between and immediately after dialysis showed mild deficiency only (i.e., U = 34 and U = 19 ng/mL, respectively). Despite this discrepancy, a starting dose of 5-FU was cut by 50% upon treatment initiation. Tolerance was good and 5-FU dosing was next shifted to 25% reduction, then further shifted to normal dosing at the 5th course, with still no sign for drug-related toxicities. Further DPYD genotyping showed none of the four allelic variants usually associated with loss of DPD activity. Of note, the excellent tolerance upon standard dosing strongly suggests that this patient was actually not DPD-deficient, despite U values always above normal concentrations. This case report highlights how critical is the information regarding the renal function of patients with cancer when phenotyping DPD using U plasma as a surrogate, and that U accumulation in patients with such condition is likely to yield false-positive results.
测量血浆中的尿嘧啶（U）水平是一种方便的替代方法，可以确定接受 5-氟尿嘧啶（5-FU）或卡培他滨治疗的患者的二氢嘧啶脱氢酶（DPD）状态。肾功能损害在多大程度上会影响 U 水平并成为混杂因素是一个日益引起关注的问题。在这里，我们报告了一名患有严重肾功能损害的癌症患者的病例，该患者计划接受 5-FU 为基础的治疗方案。由于他的病情和监测 U 水平时间歇性血液透析的影响，确定他的 DPD 状态变得很复杂。该患者最初通过 U 测量被确定为明显的 DPD 缺乏症（即 U=40ng/mL），但在透析前后的进一步监测显示仅轻度缺乏症（即 U=34 和 U=19ng/mL）。尽管存在这种差异，但在开始治疗时将 5-FU 的起始剂量减少了 50%。耐受性良好，5-FU 剂量随后减少 25%，然后在第 5 个疗程进一步减少到正常剂量，仍然没有药物相关毒性的迹象。进一步的 DPYD 基因分型显示，通常与 DPD 活性丧失相关的四种等位基因变体均不存在。值得注意的是，在标准剂量下的良好耐受性强烈表明，尽管 U 值始终高于正常浓度，但该患者实际上不是 DPD 缺乏症。本病例报告强调了当使用 U 血浆作为替代物对 DPD 进行表型分析时，了解癌症患者肾功能信息的重要性，并且在这种情况下，U 的积累很可能产生假阳性结果。
