Ho D H, Pazdur R, Covington W, Brown N, Huo Y Y, Lassere Y, Kuritani J
Department of Clinical Investigation, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Clin Cancer Res. 1998 Sep;4(9):2085-8.
Plasma 5-fluorouracil (5-FU) levels were compared in the same patients after approximately equimolar doses (1.9 mmol/ m2/day) of 5-day continuous i.v. infusion of 5-FU (CIFU) and oral administration of a formulation of two combined pharmacological agents, uracil (U) plus N1-(2'-tetrahydrofuryl)-5-fluorouracil (ftorafur or FT), a prodrug of 5-FU. Ten patients received CIFU for 5 days, then, after a week wash-out period, began the 28-day oral UFT regimen, which was given in three daily divided doses. Following 1 h of CIFU, the plasma 5-FU levels reached a steady state of 0.6+/-0.2 microM (mean+/-SD; day 1), which was maintained for the entire 5-day infusion period (0.6+/-0.1 microM). In contrast, the maximum 5-FU concentrations (Cpmax) generated from oral UFT at 1 h after dose administration on days 1 and 5 were 2.1+/-1.5 microM and 2.3+/-1.9 microM, respectively, which were higher than the steady-state levels during CIFU. These high 5-FU levels disappeared with an apparent elimination half-life (tl/2,beta) of 5.2+/-2.4 h (day 1) and 7.2+/-3.9 h (day 5). On day 1 of both regimens, CIFU patients had significantly larger 5-FU area under the concentration versus time curve (AUC0-8h) values (4.4+/-1.3 microM.h) than the AUC value when they received the UFT regimen (2.6+/-1.7 microM.h; P = 0.02). However, by day 5, there were no significant differences between AUC0-8 h values in patients receiving CIFU and UFT, respectively (4.8+/-1.5 microM.h versus 3.8+/-2.2 microM.h; P = 0.30)]. On day 5, the average concentration of the metabolite 5-FU at steady-state (Css,aver) within dose interval of 8 h (0.48+/-0.28 microM) for the oral UFT treatment is comparable with the Cpss values of 5-FU from CIFU-treated patients. The post-UFT generated 5-FU pharmacokinetic parameters (higher Cp(mx, comparable Css,aver, equal AUC values, and longer apparent t1/2,beta of 5-FU) may make oral UFT a preferred method of delivering this fluoropyrimidine over CIFU. In addition, oral UFT would eliminate the incidence of venous thrombosis and catheter-related infections sometimes seen in patients treated with CIFU. Furthermore, the convenience and decreased cost of oral administration may be preferable for many patients, particularly those receiving 5-FU for palliation.
对同一组患者在给予近似等摩尔剂量（1.9 mmol/m²/天）的5-氟尿嘧啶（5-FU）后，比较了5天持续静脉输注5-FU（CIFU）与口服两种联合药物制剂（尿嘧啶（U）加5-FU的前体药物N1-(2'-四氢呋喃基)-5-氟尿嘧啶（替加氟或FT））时的血浆5-FU水平。10名患者接受5天的CIFU治疗，然后在一周的洗脱期后，开始为期28天的口服优福定（UFT）方案，每日分三次给药。CIFU治疗1小时后，血浆5-FU水平达到0.6±0.2微摩尔/升的稳态水平（平均值±标准差；第1天），并在整个5天输注期内维持（0.6±0.1微摩尔/升）。相比之下，在第1天和第5天给药后1小时口服UFT产生的最大5-FU浓度（Cpmax）分别为2.1±1.5微摩尔/升和2.3±1.9微摩尔/升，高于CIFU期间的稳态水平。这些高浓度水平在表观消除半衰期（tl/2,β）为5.2±2.4小时（第1天）和7.2±3.9小时（第5天）时消失。在两种治疗方案的第1天，接受CIFU治疗的患者5-FU浓度-时间曲线下面积（AUC0-8h）值（4.4±1.3微摩尔·小时）显著大于接受UFT方案时的AUC值（2.6±1.7微摩尔·小时；P = 0.02）。然而，到第5天，接受CIFU和UFT治疗的患者AUC0-8 h值之间无显著差异（4.8±1.5微摩尔·小时对3.8±2.2微摩尔·小时；P = 0.30）。在第5天，口服UFT治疗在8小时剂量间隔内的代谢产物5-FU稳态平均浓度（Css,aver）（0.48±0.28微摩尔/升）与CIFU治疗患者的5-FU稳态血药浓度（Cpss）值相当。UFT产生的5-FU药代动力学参数（更高的Cpmax、相当的Css,aver、相等的AUC值以及更长的5-FU表观t1/2,β）可能使口服UFT成为比CIFU更优的氟嘧啶给药方法。此外，口服UFT可消除CIFU治疗患者中有时出现的静脉血栓形成和导管相关感染的发生率。此外，口服给药的便利性和成本降低可能对许多患者更有利，尤其是那些接受5-FU姑息治疗的患者。
