Speyer J L, Collins J M, Dedrick R L, Brennan M F, Buckpitt A R, Londer H, DeVita V T, Myers C E
Cancer Res. 1980 Mar;40(3):567-72.
A Phase I study was conducted of 5-fluorouracil administered i.p. in a 2-liter volume of 1.5% Inpersol. The drug was administered via Tenckhoff peritoneal dialysis catheters to ten patients with tumors confined to the i.p. space. Dialysis concentrations ranged from 5 micro M to mM. Complications of the dialysis procedure alone included mild abdominal discomfort and 2 cases of gram-negative bacterial peritonitis, both easily controlled with antibiotics. 5-Fluorouracil caused the same pattern of toxicity as when administered by other routes. There was no local or central nervous system toxicity. Dose-limiting toxicity included pancytopenia and mucositis at a dialysis concentration of 4.5 to 5 mM administered for eight consecutive 4-hr exchanges. There were two documented responses in eight evaluable patients. 5-Fluorouracil concentrations were measured by high-pressure liquid chromatography. Peritoneal fluid concentrations decline in a first-order fashion with a half-life of 1.6 hr. The mean permeability area product was 14 ml/min. A mean of 82% of drug was absorbed in 4 hr. Plasma levels rise over the first 30 to 45 min and decline in a nonlinear fashion. Plasma levels are substantially lower than are peritoneal fluid levels. Mean 4-hr peritoneal fluid concentration was 298 times the simultaneously measured plasma levels. Total body clearance ranged from 0.9 to 15 liters/min and declined with increasing dialysate concentration. We conclude the i.p. route is a relatively safe way to deliver high concentrations and large amounts of drug to the i.p. cavity with a significant pharmacological advantage over conventional routes of administration.
进行了一项I期研究，将5-氟尿嘧啶以2升1.5%的Inpersol腹腔内给药。通过Tenckhoff腹膜透析导管向10名肿瘤局限于腹腔的患者给药。透析液浓度范围为5微摩尔至毫摩尔。仅透析过程的并发症包括轻度腹部不适和2例革兰氏阴性细菌性腹膜炎，两者均易于用抗生素控制。5-氟尿嘧啶产生的毒性模式与通过其他途径给药时相同。没有局部或中枢神经系统毒性。剂量限制性毒性包括在连续8次4小时交换、透析液浓度为4.5至5毫摩尔时出现的全血细胞减少和粘膜炎。8名可评估患者中有2例有记录的反应。通过高压液相色谱法测量5-氟尿嘧啶浓度。腹膜液浓度以一级方式下降，半衰期为1.6小时。平均通透面积乘积为14毫升/分钟。平均82%的药物在4小时内被吸收。血浆水平在最初30至45分钟内升高，然后以非线性方式下降。血浆水平明显低于腹膜液水平。4小时腹膜液平均浓度是同时测量的血浆水平的298倍。全身清除率范围为0.9至15升/分钟，并随着透析液浓度的增加而下降。我们得出结论，腹腔内给药途径是向腹腔输送高浓度和大量药物的相对安全的方式，与传统给药途径相比具有显著的药理学优势。
