Comparative pharmacokinetic study of continuous venous infusion fluorouracil and oral fluorouracil with eniluracil in patients with advanced solid tumors
Comparative pharmacokinetic study of continuous venous infusion fluorouracil and oral fluorouracil with eniluracil in patients with advanced solid tumors
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DOI：
10.1200/jco.20.6.1683
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发表时间：
2002-03-15
影响因子：
45.3
通讯作者：
Erlichman, C
中科院分区：
文献类型：
--
作者：
Adjei, AA;Reid, JM;Erlichman, C
目的：比较连续静脉输注 (CVI) 氟尿嘧啶 (5-FU) 与口服恩尿嘧啶/5-FU 的药代动力学，并描述长期口服恩尿嘧啶/5-FU 的毒性和临床活性。患者和方法：一项随机、开放标签、交叉研究比较了 CVI 5-FU 与口服 5-FU/恩尿嘧啶组合。 17 名患者（A 组）被随机分配在第一个研究期间接受恩尿嘧啶/5-FU 组合片剂（10:1 mg/m(2) BID，持续 7 天），随后在第 2 阶段接受 5-FU（300 mg/m(2) CVI，持续 7 天），期间之间有 14 天的清除期。 16 名患者（B 组）按相反顺序接受治疗。在第 3 阶段，所有患者均每日两次接受恩尿嘧啶/5-FU 片剂治疗，持续 28 天。在第 1 和第 2 阶段分析 CVI 和口服给药期间 5-FU 的血浆水平。通过测量血浆尿嘧啶、尿液 α-氟-β-丙氨酸和外周血单核细胞 (PBMC) DPD 活性来确定二氢嘧啶脱氢糖 (DPD) 活性。结果：两组均未出现 3 级或 4 级毒性。在三名患者中观察到部分缓解。另外三名患者病情稳定2：3个月。恩尿嘧啶和 5-FU 药代动力学与之前研究中观察到的相似，并且不受给药顺序的影响。 CVI 5-FU 的平均 +/- SD 稳态血浆浓度 (C-p) 和曲线下面积 (AUC) (144-168h)（分别为 104 +/- 45 ng/mL 和 2,350 +/- 826 ng.h/mL）是口服 5-FU 的三倍（38.1 +/- 7.7 ng/mL 和 722 +/- 182）分别为 ng.h/mL [P < .00001]）。 CVI 期间的各个 5-FU 浓度变化很大，而恩尿嘧啶/5-FU 后的浓度重复性非常好。每个研究周期前 PBMC 中的 DPD 活性均正常。结论：CVI 5-FU 和口服恩尿嘧啶/5-FU 均耐受性良好，在这些经过大量预处理的患者中具有中等活性。然而，口服恩尿嘧啶/5-FU 达到的 5-FU 稳态 C-p 和 AUC 显着低于 CVI 5-FU。
Purpose: To compare the pharmacokinetics of continuous venous infusion (CVI) fluorouracil (5-FU) with that of oral eniluracil/5-FU and to describe toxicities and clinical activity of prolonged oral administration of eniluracil/5-FU.Patients and Methods: A randomized, open-label, cross-over study compared CVI 5-FU to an oral 5-FU/eniluracil combination. Seventeen patients (arm A) were randomly assigned to receive eniluracil/5-FU combination tablets (10:1 mg/m(2) BID for 7 days) during the first study period, followed by 5-FU (300 mg/m(2) CVI for 7 days) during period 2, with a 14-day washout between periods. Sixteen patients (arm B) received treatment in the opposite sequence. In period 3, all patients received eniluracil/5-FU tablets BID for 28 days. Plasma levels of 5-FU during CVI and oral administration were analyzed in periods 1 and 2. Dihydropyrimidine dehydrogenose (DPD) activity was determined by measuring plasma uracil, urinary alpha-fluoro-beta-alanine, and peripheral-blood mononuclear cell (PBMC) DPD activity.Results: There were no grade 3 or 4 toxicities in either arm. Partial responses were observed in three patients. Another three patients had stable disease for 2: 3 months. Eniluracil and 5-FU pharmacokinetics were similar to those observed in previous studies and were unaffected by administration sequence. The mean +/- SD steady-state plasma concentration (C-p) and area under the curve (AUC)(144-168h) for CVI 5-FU (104 +/- 45 ng/mL and 2,350 +/- 826 ng.h/mL, respectively) were three-fold greater than those for oral 5-FU (38.1 +/- 7.7 ng/mL and 722 +/- 182 ng.h/mL, respectively [P < .00001]). Individual 5-FU concentrations during CVI were highly variable, whereas those after eniluracil/5-FU were very reproducible. DPD activity in PBMCs before each study period was normal.Conclusion: Both CVI 5-FU and oral eniluracil/5-FU were well tolerated, with moderate activity in these heavily pretreated patients. However, 5-FU steady-state C-p and AUCs achieved with oral eniluracil/5-FU were significantly less than with CVI 5-FU.