Comparison of pharmacokinetics of 5-fluorouracil and 5-fluorouracil with concurrent thymidine infusions in a Phase I trial.
Comparison of pharmacokinetics of 5-fluorouracil and 5-fluorouracil with concurrent thymidine infusions in a Phase I trial.
复制标题
I 期试验中 5-氟尿嘧啶和 5-氟尿嘧啶同时输注胸苷的药代动力学比较。
作者：
J. Kirkwood;W. Ensminger;A. Rosowsky;N. Papathanasopoulos;E. Frei
5-氟尿嘧啶 (5-FUra) 在人体中的血清半衰期最好描述为双指数衰减函数，在单独使用该药物的初始疗程中，t1/2 α = 7.8 +/- 2.6 (S.E.) 分钟，t1/2 β = 36.8 +/- 13.5 分钟。 5-FUra 在每日治疗过程中（持续 5 天）的药代动力学显示，衰减曲线的两个组成部分的 t1/2 均延长，此前未曾报道过。尽管连续静脉注射胸苷 (dThd) 具有疗效。输注8克/平方米/天可预防高剂量甲氨蝶呤毒性，在此剂量下连续输注dThd不能预防5-FUra的毒性或5-fura对DNA和RNA合成的反向抑制。相反，连续输注 dThd 似乎会增加 5-FUra 的毒性，在连续 dThd 输注期间，显示 5-FUra t1/2 延长，在 5-FUra 与 dThd 的 5 天疗程中，5-FUra t1/2 保持稳定。这种延长的 t1/2 被认为至少部分地解释了 5-FUra 与 dThd 的毒性增加。在相似的每日推注治疗疗程（持续 5 天）中，在 5-FUra 剂量范围为单独 5-FUra 惯常耐受剂量的二分之一至三分之二时，观察到剂量限制性粘膜炎、骨髓抑制和胃肠道毒性。
The serum half-life of 5-fluorouracil (5-FUra) in humans is best described as a biexponential decay function, with t1/2 alpha = 7.8 +/- 2.6 (S.E.) min and t1/2 beta = 36.8 +/- 13.5 min during initial courses of this drug alone. Pharmacokinetics of 5-FUra during courses of daily therapy (for 5 days) revealed prolongation of t1/2 in both components of the decay curve, which has not been previously reported. Despite the efficacy of thymidine (dThd) given as a continous i.v. infusion of 8 g/sq m/day in prevention of high-dose methotrexate toxicity, continuous infusion of dThd at this dose does not prevent the toxicity of 5-FUra orreverse inhibition of DNA and RNA synthesis by 5-fura. On the contrary, continuous infusion of dThd appears to increase the toxicity of 5-FUra during continuous dThd infusion revealed prolongation of the 5-FUra t1/2 which remained stable through the course of 5 days of 5-FUra with dThd. This protracted t1/2 is believed to account at least in part for the increased toxicity of 5-FUra with dThd. Dose-limiting mucositis, myelosuppression, and gastrointestinal toxicity were observed at 5-FUra doses ranging from one-half to two-thirds the customarily tolerated dose of 5-FUra alone in similar courses of daily bolus therapy (for 5 days).