PHASE-I AND PHARMACOLOGICAL STUDIES OF 5-FLUOROURACIL ADMINISTERED INTRAPERITONEALLY

Abstract

A phase I study was conducted of 5-fluorouracil administered i.p. in a 2-l volume of 1.5% inpersol. The drug was administered via Tenckhoff peritoneal dialysis catheters to 10 patients with tumors confined to the i.p. space. Dialysis concentrations ranged from 5 .mu.M to 8 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 CNS toxicity. Dose-limiting toxicity included pancytopenia and mucositis at a dialysis concentration of 4.5-5 mM administered for 8 consecutive 4-h exchanges. There were 2 documented responses in 8 evaluable patients. 5-Fluorouracil concentrations were measured by high-pressure liquid chromatography. Peritoneal fluid concentrations declined in a 1st-order fashion with a half-life of 1.6 h. The mean permeability area product was 14 ml/min. A mean of 82% of drug was absorbed in 4 h. Plasma levels rose over the first 30-45 min and declined in a nonlinear fashion. Plasma levels were substantially lower than were peritoneal fluid levels. Mean 4-h peritoneal fluid concentration was 298 times the simultaneously measured plasma levels. Total body clearance ranged from 0.9-15 l/min and declined with increasing dialysate concentration. The i.p route apparently 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. [The use of 5-fluorouracil as an antineoplastic drug was discussed].