Portal levels and hepatic clearance of 5-fluorouracil after intraperitoneal administration in humans

Intrahepatic tumor is a major problem in clinical oncology. While direct intravascular infusions provide high local drug concentrations and variable rates of tumor response, they are limited by technical considerations and complications. In this study, we have tested whether high portal venous and hepatic arterial concentrations of 5-fluorouracil (5-FUra) can be achieved by administering drug via peritoneal dialysis. Four patients with metastatic colon carcinoma had a Tenckhoff catheter surgically implanted. During dialysis therapy with 4 mM 5-FUra, simultaneous samples of peritoneal fluid and of portal venous, hepatic venous, and peripheral venous, and arterial blood were obtained, and 5-FUra concentrations were determined. Mean peak portal vein drug concentrations were 60 microM and exceeded the measured concentrations in the other vessels. Total drug exposures as measured by concentration x time (mM x min) during Exchange 1 were: portal, 3.8 +/- 0.65; hepatic vein, 0.97 +/- 0.44; peripheral vein, 0.90 +/- 0.32; and arterial, 1.1 +/- 0.26. During Exchange 7, total drug exposures were: portal, 6.3 +/- 1.4; hepatic vein, 2.5 +/- 1.3; peripheral vein, 2.3 +/- 1.1; and arterial, 2.7 +/- .85. The fraction of i.p. drug that exited the peritoneal cavity through the portal venous system ranged from 0.29 to 1.0. This variation resulted in part from uncertainty in estimating portal blood flow and gastrointestinal drug elimination. Calculated hepatic extraction was 67% (range, 0.23 to 0.89). Extrahepatic metabolism was demonstrated. Measured 5-FUra concentrations compared favorably to values predicted by a pharmacokinetic model for 5-FUra. Dialysis therapy (i.p.) with 5-FUra provides a means of achieving high drug concentrations for treating both i.p. and intrahepatic tumor. Further clinical testing of this route of administration is warranted.