Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase
Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase
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DOI：
10.1200/jco.1996.14.12.3085
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发表时间：
1996-12-01
影响因子：
45.3
通讯作者：
Rowinsky, EK
中科院分区：
文献类型：
--
作者：
Baker, SD;Khor, SP;Rowinsky, EK
目的：研究的绝对生物利用度和药物动力学的氟尿嘧啶（5-FU）的口服溶液中治疗的患者与776 C85，口服灭活剂二氢嘧啶脱氢酶（DPD），并评估的可行性，口服5-FU和776 C85上的一个多日剂量schedule.Patients和方法：12例难治性实体瘤被招募到这个三个阶段的研究。在第1和第2阶段，患者被随机分配至第2天口服或静脉（IV）途径给予5-FU 10 mg/m2，第1和第2天口服776 C85 3.7 mg/m2/d。在第3阶段，患者接受递增剂量的5-FU（10至25 mg/m2/d）口服给药5天（第2至6天），776 C85 3.7 mg/m2/d口服给药（第1至7天），每4周一次。在第1、2周期和第3周期第5次口服5-FU后进行药代动力学研究。结果：12例患者完成了生物利用度和药代动力学研究。口服5-FU 10 mg/m2后，生物利用度为122% ± 40%（平均值+/- SD），终末半衰期（1（1/2 β））为4.5 +/- 1.6小时，表观分布容积（V-β）为21.4 +/- 5.9 L/ m（2），全身清除率（Cl-sys）为57.6 +/- 16.4 mL/min/m（2）。观察到口服5-FU全身清除率与计算的肌酐清除率之间存在相关性（r = .74; P = .009）。每日多次给药似乎不影响口服5-FU的药代动力学。中性粒细胞减少是口服5-FU和776 C85的主要毒性反应，因此不能将口服5-FU的剂量增加到25 mg/m2/d，每4周一次，连续5天。结论：口服DPD灭活剂776 C85可使5-FU口服给药成为可能，并可能改变传统的5-FU给药方式。(C)1996年，美国临床肿瘤学会。
Purpose: To study the absolute bioavailability and pharmacokinetics of an oral solution of fluorouracil (5-FU) in patients treated with 776C85, an oral inactivator of dihydropyrimidine dehydrogenase (DPD), and to evaluate the feasibility of administering oral 5-FU and 776C85 on a multiple-daily dosing schedule.Patients and Methods: Twelve patients with refractory solid tumors were enrolled onto this three-period study. In periods 1 end 2, patients were randomly assigned to treatment with 5-FU 10 mg/m(2) on day 2 given by either the oral or intravenous (IV) route with oral 776C85 3.7 mg/m(2)/d on days 1 and 2. In period 3, patients received escalating doses of 5-FU (10 to 25 mg/m(2)/d) orally for 5 days (days 2 to 6) with 776C85 3.7 mg/m(2)/d orally (days 1 to 7) every 4 weeks. Pharmacokinetic studies were performed in periods 1 and 2, and after the fifth oral dose of 5-FU in period 3.Results: Twelve patients completed the bioavailability and pharmacokinetic studies. Following oral 5-FU 10 mg/m(2), the bioavailability was 122% +/- 40% (mean +/- SD), the terminal half-life (1(1/2 beta)) was 4.5 +/- 1.6 hours, the apparent volume of distribution (V-beta) was 21.4 +/- 5.9 L/ m(2), and the systemic clearance (Cl-sys) was 57.6 +/- 16.4 mL/min/m(2). A correlation was observed between oral 5-FU systemic clearance and calculated creatinine clearance (r = .74; P = .009). Multiple-daily dosing did not appear to affect the pharmacokinetics of oral 5-FU. Neutropenia was the principal toxicity of oral 5-FU and 776C85, precluding escalation of oral 5-FU to doses greater than 25 mg/m(2)/d for 5 days every 4 weeks with 776C85.Conclusion: The oral DPD inactivator 776C85 enables oral administration of 5-FU and may alter conventional 5-FU administration practices. (C) 1996 by American Society of Clinical Oncology.